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Simple Summary: Metformin is one of the most widely used drugs in the world, since its first use in the second part of the 1950s in France (Aron, 1957) and in the United Kingdom (Rona, 1958), and is on the World Health Organization's List of Essential Medicines. Traditionally, metformin is used in diabetes mellitus, mainly in overweight and obese subjects, but also in other conditions of impaired glucose metabolism, such as insulin resistance. In recent years, in vitro and in vivo data on this molecule as an antiproliferative modulator have suggested a series of clinical trials in several tumors that—at the moment—have not confirmed the expected positive results. The aim of this paper is to offer a double vision of this molecule, with a very light side about the metabolic aspects and a darker side concerning its antineoplastic activity, focusing on molecular and subcellular pathways involved in both fields and discussing the contrast between preliminary cellular data and real clinical outcomes in different neoplasms. The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open? [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the most common causes of death worldwide. Today, this disease does not have an effective treatment, leading to the exploration of novel pharmacological molecules. In this paper, we design and synthesize with a new synthetic route the lipophilic cation derived from gallic acid (TPP+C10) and gentisic acid (GA-TPP+C10), both able to reach mitochondria and uncouple the electron transport chain. Our results show that combining 5-fluorouracil with GA-TPP+C10 has a synergistic cytotoxic effect on CRC cells. Both compounds show antimigratory effects, decreasing signaling pathways and biomarkers. Our results show that mitochondrial agents could be an alternative to standard CRC drugs against this disease. Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores cryopreservation thyroid autotransplantation as an alternative to hormonal replacement therapy for patients who underwent thyroidectomy during childhood or adulthood. The research evaluates the impact of modern cryopreservation techniques on follicular cell integrity through a feasibility study and literature review. Results indicate preserved tissue architecture and cell viability. Animal and human studies demonstrate successful transplantation outcomes. However, long-term follow-up data are lacking. The findings suggest promising viability of cryopreserved thyroid tissue, yet further research is needed to assess hormone secretion and ensure sustained functionality. This alternative therapy could offer tailored hormone production, aligning with physiological needs. Background and aims: This paper aims to study an alternative solution to hormonal replacement therapy in specific groups of patients who underwent thyroidectomy during childhood or adulthood. After cryopreservation, thyroid autotransplantation could be an alternative solution which would allow us to use the ability of the thyroid tissue of producing hormones according to the physiological needs of the body. Materials and methods: A feasibility study about the effects of the most modern cryopreservation techniques on the structural and functional integrity of the follicular cells of the thyroid tissue has been carried out. Patients who could benefit from the treatment have been found for both autotransplant techniques. Additionally, a literature review has been conducted. Results: The histological analysis has shown that cryopreservation does not alter the original architecture, and the culture examination that cell viability is successfully preserved. Moreover, both thyroid autotransplantation studies on animals and those on humans that were found in the literature have shown good results regarding the viability and functionality of the transplant. Conclusions: The viability of cryopreserved thyroid tissue found in this study is encouraging. Further studies to evaluate the levels of FT3, FT4 and thyroglobulin in thyroid tissue after cryopreservation are needed to verify that the secretory properties of the thyrocytes have been maintained intact. Furthermore, autotransplanted cases found in the literature do not have a long-term follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: As a first-line chemotherapeutic for colorectal cancer (CRC), FOLFOX, XELOX, and similar regimens are recommended as adjuvant therapies following CRC surgery, according to the NCCN guidelines. In stage IV patients, targeted therapies like cetuximab and bevacizumab are used in combination. The decision to add either irinotecan-based regimens or oxaliplatin-based regimens, FOLFIRI is typically based on a physician's subjective judgment due to the lack of clear selection criteria. Therefore, having the ability to precisely predict the therapeutic response to these two drugs could help prioritize the use of the most effective drug in stage IV patients. Previous research efforts aimed to predict therapeutic responses to these two drugs using organoids. While irinotecan showed promising predictability, predicting the response to oxaliplatin remained challenging. In this study, new drug screening conditions were identified to address this issue. Through additional research using CRC organoids, this paper contributes to the prediction of drug responses in CRC patients. Colorectal cancer is the third most common cancer in the world, with an annual incidence of 2 million cases. The success of first-line chemotherapy plays a crucial role in determining the disease outcome. Therefore, there is an increasing demand for precision medicine to predict drug responses and optimize chemotherapy in order to increase patient survival and reduce the related side effects. Patient-derived organoids have become a popular in vitro screening model for drug-response prediction for precision medicine. However, there is no established correlation between oxaliplatin and drug-response prediction. Here, we suggest that organoid culture conditions can increase resistance to oxaliplatin during drug screening, and we developed a modified medium condition to address this issue. Notably, while previous studies have shown that survivin is a mechanism for drug resistance, our study observed consistent survivin expression irrespective of the culture conditions and oxaliplatin treatment. However, clusterin induced apoptosis inhibition and cell survival, demonstrating a significant correlation with drug resistance. This study's findings are expected to contribute to increasing the accuracy of drug-response prediction in patient-derived APC mutant colorectal cancer organoids, thereby providing reliable precision medicine and improving patient survival rates. [ABSTRACT FROM AUTHOR]

Simple Summary: The Clonogenic Survival Assay (CSA) is pivotal in gauging cell survival and proliferative capacity in oncology research. However, it's limited by its binary output and its time- and labor-intensive nature. We developed LeGO-CSA, a refined version of CSA, utilizing imaging of cell nuclei tagged with fluorescent markers which encode red, green, blue fluorescent proteins and their variations. This facilitates both high-content and high-throughput analysis, delivering a potent tool for cancer research, promising heightened accuracy and efficiency, with the potential to expedite drug discovery and offer deeper insights into cellular dynamics in cancer. This transformative approach can revolutionize cancer research methodologies, making them more efficient and insightful. The Clonogenic Survival Assay (CSA) is a fundamental tool employed to assess cell survival and proliferative potential in cancer research. Despite its importance, CSA faces limitations, primarily its time- and labor-intensive nature and its binary output. To overcome these limitations and enhance CSA's utility, several approaches have been developed, focusing on increasing the throughput. However, achieving both high-content and high-throughput analyses simultaneously has remained a challenge. In this paper, we introduce LeGO-CSA, an extension of the classical CSA that employs the imaging of cell nuclei barcoded with fluorescent lentiviral gene ontology markers, enabling both high-content and high-throughput analysis. To validate our approach, we contrasted it with results from a classical assay and conducted a proof-of-concept screen of small-molecule inhibitors targeting various pathways relevant to cancer treatment. Notably, our results indicate that the classical CSA may underestimate clonogenicity and unveil intriguing aspects of clonal cell growth. We demonstrate the potential of LeGO-CSA to offer a robust approach for assessing cell survival and proliferation with enhanced precision and throughput, with promising implications for accelerating drug discovery and contributing to a more comprehensive understanding of cellular behavior in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This review of several recent developments and findings in molecular and radiation biology and medical physics was put together to improve the treatment of cancer. An improved understanding of the effect of radiation on tumors and normal tissue responses makes it possible to treat tumors more effectively and with less damage to normal tissues. This paper is based on a new, improved understanding of the cellular damage and repair processes and the associated internal cellular program to eliminate itself when critically damaged (apoptosis) to avoid severe mutations of the hereditary material of the individual. An improved radiation dose–time fractionation method is proposed to more effectively cure cancer without damaging the surrounding normal tissues. Furthermore, the best possible radiation beams of intensity-modulated electrons, photons, and the lightest ions from lithium to boron are proposed to obtain the best possible treatment results, increasing the tumor cure probability by about 20%. The new biological interaction cross-section-based repairable–homologically repairable (RHR) damage formulation for radiation-induced cellular inactivation, repair, misrepair, and apoptosis was applied to optimize radiation therapy. This new formulation implies renewed thinking about biologically optimized radiation therapy, suggesting that most TP53 intact normal tissues are low-dose hypersensitive (LDHS) and low-dose apoptotic (LDA). This generates a fractionation window in LDHS normal tissues, indicating that the maximum dose to organs at risk should be ≤2.3 Gy/Fr, preferably of low LET. This calls for biologically optimized treatments using a few high tumor dose-intensity-modulated light ion beams, thereby avoiding secondary cancer risks and generating a real tumor cure without a caspase-3-induced accelerated tumor cell repopulation. Light ions with the lowest possible LET in normal tissues and high LET only in the tumor imply the use of the lightest ions, from lithium to boron. The high microscopic heterogeneity in the tumor will cause local microscopic cold spots; thus, in the last week of curative ion therapy, when there are few remaining viable tumor clonogens randomly spread in the target volume, the patient should preferably receive the last 10 GyE via low LET, ensuring perfect tumor coverage, a high cure probability, and a reduced risk for adverse normal tissue reactions. Interestingly, such an approach would also ensure a steeper rise in tumor cure probability and a higher complication-free cure, as the few remaining clonogens are often fairly well oxygenated, eliminating a shallower tumor response due to inherent ion beam heterogeneity. With the improved fractionation proposal, these approaches may improve the complication-free cure probability by about 10–25% or even more. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper, we report on the inhibition of glioblastoma (GBM) cell growth and migration by the putative S1PR1 modulator ACT-2009905, using appropriate in vitro models. This work is based on our previously published finding that S1PR1 expression is strongly up-regulated in human glioblastoma samples and the fact that there is an association between S1PR1 with patients' survival times. We now show that pharmacological modulation by the putative S1PR1 modulator ACT-209905 inhibits GBM cell growth and migration. Furthermore, we investigated the influence of co-culture of GBM cells with THP-1 cells as a model for human monocytes, showing pro-tumoral effects and arguing for a complex interplay between GBM cells, immune cells and underlying signaling pathways. We believe that this manuscript fits the interests of the readership of the journal Cancers as it addresses the impact of alternative therapeutic options using ACT-209905 for improving GBM therapy. Glioblastoma (GBM) is still a deadly tumor due to its highly infiltrative growth behavior and its resistance to therapy. Evidence is accumulating that sphingosine-1-phosphate (S1P) acts as an important tumor-promoting molecule that is involved in the activation of the S1P receptor subtype 1 (S1PR1). Therefore, we investigated the effect of ACT-209905 (a putative S1PR1 modulator) on the growth of human (primary cells, LN-18) and murine (GL261) GBM cells. The viability and migration of GBM cells were both reduced by ACT-209905. Furthermore, co-culture with monocytic THP-1 cells or conditioned medium enhanced the viability and migration of GBM cells, suggesting that THP-1 cells secrete factors which stimulate GBM cell growth. ACT-209905 inhibited the THP-1-induced enhancement of GBM cell growth and migration. Immunoblot analyses showed that ACT-209905 reduced the activation of growth-promoting kinases (p38, AKT1 and ERK1/2), whereas THP-1 cells and conditioned medium caused an activation of these kinases. In addition, ACT-209905 diminished the surface expression of pro-migratory molecules and reduced CD62P-positive GBM cells. In contrast, THP-1 cells increased the ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905. In conclusion, our study suggests the role of S1PR1 signaling in the growth of GBM cells and gives a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with acute myeloid leukemia (AML), genetic mutations can cause cells to evade regulated cell death (RCD), resulting in excessive cell proliferation. The best-known form of RCD is apoptosis, which prevents the emergence of cancer cells; disturbances in this process are an important factor in the development and progression of AML. Clearly, it is essential to understand the mechanisms of apoptosis to establish a personalized, patient-specific approach in AML therapy. Therefore, this paper comprehensively reviews the current range of AML treatment approaches related to apoptosis and highlights other promising concepts such as neddylation. More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Oesophageal adenocarcinoma (OAC) is a leading cause of cancer mortality in the United Kingdom with a 5-year survival rate of approximately 15%. Major contributors to poor outcome are late diagnosis and chemotherapy resistance, and while targeted therapies have benefitted certain cancer settings, they have had limited success in OAC. An understanding of the mechanisms mediating chemotherapy resistance could identify novel targets with the potential to improve standard treatments. This paper aimed to identify mediators of both OAC cancer cell pro-survival signalling and chemotherapy resistance, as well as determine potential small molecular compounds to counteract this. Gene set enrichment analysis of transcriptional data generated a gene-list with significant differential expression between responder and non-responder OAC patients. Gene functionality assessment using siRNA screening showed that targeting SRC had an anti-tumour effect in OAC cells with the potential to enhance chemotherapy treatment. In parallel to this, a compound screen showed the Src inihibitor dasatinib sensitised OAC cells to chemotherapy. Together, these findings suggest targeting SRC as a novel therapeutic strategy in OAC. Drug resistance limits the effectiveness of oesophageal adenocarcinoma (OAC) chemotherapies, leading to a poor prognosis for this disease. Elucidation of the underlying resistance mechanisms is key to enabling the identification of more effective treatments. This study, therefore, aims to identify novel therapeutic and/or chemotherapy sensitising drug targets in OAC. Transcriptional data from a cohort of 273 pre-treatment OAC biopsies, from patients who received neoadjuvant chemotherapy followed by surgical resection, were analysed using gene set enrichment analysis (GSEA) to determine differential gene expression between responding and non-responding OAC tumours. From this, 80 genes were selected for high-throughput siRNA screening in OAC cell lines with or without standard chemotherapy treatment. In parallel, cell viability assays were performed using a panel of FDA-approved drugs and combination index (CI) values were calculated to evaluate drug synergy with standard chemotherapy. Mechanisms of synergy were investigated using western blot, propidium iodide flow cytometry, and proliferation assays. Taken together, the screens identified that targeting Src, using either siRNA or the small molecule inhibitor dasatinib, enhanced the efficacy of chemotherapy in OAC cells. Further in vitro functional analysis confirmed Src inhibition to be synergistic with standard OAC chemotherapies, 5-fluorouracil (5-FU), and cisplatin (CDDP). In conclusion, a compound screen together with a functional genomic approach identified Src as a potential chemosensitising target in OAC, which could be assessed in a clinical study for poor prognosis OAC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Monumental therapeutic advances have been made over the past two decades for the treatment of multiple myeloma. Anti-apoptotic proteins, such as Bcl-2, Bcl-xL, and Mcl-1, have been found to be upregulated in multiple myeloma cell lines, and small molecule inhibitors that target these proteins are in clinical development with the goal of enhancing apoptosis, reversing drug resistance, and improving the survival outcomes of patients with relapsed/refractory multiple myeloma. In this paper, we review the available clinical data for the Bcl-2-family protein inhibitors currently in clinical development for relapsed/refractory multiple myeloma. Despite considerable advances in the treatment of multiple myeloma over the past decade, progression of disease is inevitable, and patients ultimately succumb to relapsed and refractory disease. Efficacious therapeutic regimens that target the key biological pathways that are essential for malignant plasma cell survival are necessary in the efforts to improve patient survival outcomes. The Bcl-2 family of proteins comprise oncogenes that promote myeloma cell survival by conferring resistance to apoptosis. These proteins are frequently upregulated in myeloma cells, thus making them attractive therapeutic targets. Several small molecule inhibitors of Bcl-2-family proteins are currently in clinical development for the treatment of relapsed/refractory multiple myeloma. Venetoclax, a Bcl-2-specific inhibitor, has generated the most clinical data and has shown promising results in patients with multiple myeloma harboring the t (11;14) translocation. Venetoclax has shown efficacy when combined with anti-CD38 monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors. Several other Bcl-2 inhibitors are in clinical development, as are inhibitors of Mcl-1, a Bcl-2-family oncoprotein that is perhaps more critical for myeloma cell survival than Bcl-2. This review will summarize the latest clinical data regarding the clinical development of Bcl-2-family protein inhibitors in the treatment of relapsed/refractory multiple myeloma. [ABSTRACT FROM AUTHOR]

Simple Summary: Blood malignancies account for 6.9% of all cancer deaths. Inositol-requiring enzyme 1 alpha (IRE1α), a part of the unfolded protein response (UPR), has been shown to be pivotal for cancer cell development and progression, including blood cancers. Furthermore, IRE1α levels are often elevated in blood cancer cells, and they correspond with cell survival, response to treatment, and prognosis. The aim of our study is to summarize the current knowledge on IRE1α in blood cancers and to evaluate the potential utility of IRE1α inhibitors in the treatment of blood malignancies. The introduction of new therapies based on IRE1α inhibition may increase treatment efficacy and reduce the side effects of blood cancer therapy. Synthesis, folding, and structural maturation of proteins occur in the endoplasmic reticulum (ER). Accumulation of misfolded or unfolded proteins in the ER lumen contributes to the induction of ER stress and activation of the unfolded protein response (UPR) signaling pathway. Under ER stress, the UPR tries to maintain cellular homeostasis through different pathways, including the inositol-requiring enzyme 1 alpha (IRE1α)-dependent ones. IRE1α is located in an ER membrane, and it is evolutionarily the oldest UPR sensor. Activation of IRE1α via ER stress triggers the formation of the spliced form of XBP1 (XBP1s), which has been linked to a pro-survival effect in cancer cells. The role of IRE1α is critical for blood cancer cells, and it was found that the levels of IRE1α and XBP1s are elevated in various hematological malignancies. This review paper is focused on summarizing the latest knowledge about the role of IRE1α and on the assessment of the potential utility of IRE1α inhibitors in blood cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most malignant cancer of the glioma series, and it is highly invasive. The progression and recurrence of glioblastoma remain common due to the development of drug resistance. Of the current disease models and strategies used in pre-clinical studies for drug testing, three-dimensional (3D) bioprinting is an emerging technology in constructing a glioblastoma model. In this paper, 19 out of 304 articles yielded from the database search were selected and analysed through a systematic process. The selected studies present the effectiveness of different bioinks, which were used to mimic the tumour microenvironment of glioblastoma in bioprinting. The clinical value of the 3D bioprinted glioblastoma models on the efficacy of treatments or drug response was evaluated. Many medical applications have arisen from the technological advancement of three-dimensional (3D) bioprinting, including the printing of cancer models for better therapeutic practice whilst imitating the human system more accurately than animal and conventional in vitro systems. The objective of this systematic review is to comprehensively summarise information from existing studies on the effectiveness of bioinks in mimicking the tumour microenvironment of glioblastoma and their clinical value. Based on predetermined eligibility criteria, relevant studies were identified from PubMed, Medline Ovid, Web of Science, Scopus, and ScienceDirect databases. Nineteen articles fulfilled the inclusion criteria and were included in this study. Alginate hydrogels were the most widely used bioinks in bioprinting. The majority of research found that alginate bioinks had excellent biocompatibility and maintained high cell viability. Advanced structural design, as well as the use of multicomponent bioinks, recapitulated the native in vivo morphology more closely and resulted in bioprinted glioblastoma models with higher drug resistance. In addition, 3D cell cultures were superior to monolayer or two-dimensional (2D) cell cultures for the simulation of an optimal tumour microenvironment. To more precisely mimic the heterogenous niche of tumours, future research should focus on bioprinting multicellular and multicomponent tumour models that are suitable for drug screening. [ABSTRACT FROM AUTHOR]

Simple Summary: In the era of precision medicine and immunotherapy, the isolation and characterization of exosomes from the peripheral blood mononuclear cells (PBMC-EXs) of SCLC patients may represent a new tool to define responder (BR) from non-responder (NR) patients undergoing chemoimmunotherapy treatment. In this proof-of-concept study, we isolated PBMC-EXs from the peripheral blood of SCLC patients and investigated the potential role of such extracellular vesicles (EVs) in monitoring tumor response to drug stimuli. Interestingly, we found increased exosome levels of c-Myc and Snail along with reduced levels of the immune markers MAVS and STING in NR patients. Also, we showed that PBMC-EXs from BR patients induced an increase in apoptosis and a reduction in the cell viability of SCLC cells compared to PBMC-EXs from NR SCLC patients. Thus, we suggest that PBMC-EXs may represent an innovative strategy to be further explored for the therapy and selection of immune-responsive SCLC patients. Small cell lung cancer (SCLC) is a highly invasive and rapidly proliferating lung tumor subtype. Most patients respond well to a combination of platinum-based chemotherapy and PD-1/PDL-1 inhibitors. Unfortunately, not all patients benefit from this treatment regimen, and few alternative therapies are available. In this scenario, the identification of new biomarkers and differential therapeutic strategies to improve tumor response becomes urgent. Here, we investigated the role of exosomes (EXs) released from the peripheral blood mononuclear cells (PBMCs) of SCLC patients in mediating the functional crosstalk between the immune system and tumors in response to treatments. In this study, we showed that PBMC-EXs from SCLC patients with different responses to chemoimmunotherapy showed different levels of immune (STING and MAVS) and EMT (Snail and c-Myc) markers. We demonstrated that PBMC-EXs derived from best responder (BR) patients were able to induce a significant increase in apoptosis in SCLC cell lines in vitro compared to PBMC-EXs derived from non-responder (NR) SCLC patients. PBMC-EXs were able to affect cell viability and modulate apoptotic markers, DNA damage and the replication stress pathway, as well as the occurrence of EMT. Our work provides proof of concept that PBMC-EXs can be used as a tool to study the crosstalk between cancer cells and immune cells and that PBMC-EXs exhibit an in vitro ability to promote cancer cell death and reduce tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Aquaporins (AQPs) have emerged as potential predictors of response to cancer therapy and as targets for increasing sensitivity to treatment. However, systemic therapeutic inhibition using pan-AQP or AQP-specific inhibitors has not been characterized for efficacy in treating breast cancer or as a component of combination treatment. We evaluated AQP inhibition using established AQP inhibitors in cytotoxicity and pharmacologic assays. This study identified AQPs as a targetable vulnerability in breast cancer. AQP inhibitors can increase therapeutic efficacy, both as single agents and in a combination therapy strategy, in treating breast cancer progression and metastasis. These results provide significant insights that support the future development of improved AQP inhibitors. AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focused on finding effective anticancer peptides (ACPs) from induced tumor-suppressing cells (iTSCs) to combat breast cancer metastasis to the skeletal system. This study identified P18 as the most potent ACP from a pool of candidates, derived from a protein called Arhgdia. P18 showed significant inhibitory effects on breast cancer cell viability, migration, and invasion, as well as interfering with certain cancer-promoting proteins and GTPase signaling. Importantly, P18 demonstrated enhanced effectiveness when combined with traditional chemotherapy drugs, without significantly affecting healthy cells. Moreover, it mitigated the bone loss associated with breast cancer spread to bones. This study suggests that P18, especially in its modified form (Ac-P18-NH2), could be a promising candidate for breast cancer treatment and preventing bone destruction by regulating specific cellular signaling pathways. Background: The skeletal system is a common site for metastasis from breast cancer. In our prior work, we developed induced tumor-suppressing cells (iTSCs) capable of secreting a set of tumor-suppressing proteins. In this study, we examined the possibility of identifying anticancer peptides (ACPs) from trypsin-digested protein fragments derived from iTSC proteomes. Methods: The efficacy of ACPs was examined using an MTT-based cell viability assay, a Scratch-based motility assay, an EdU-based proliferation assay, and a transwell invasion assay. To evaluate the mechanism of inhibitory action, a fluorescence resonance energy transfer (FRET)-based GTPase activity assay and a molecular docking analysis were conducted. The efficacy of ACPs was also tested using an ex vivo cancer tissue assay and a bone microenvironment assay. Results: Among the 12 ACP candidates, P18 (TDYMVGSYGPR) demonstrated the most effective anticancer activity. P18 was derived from Arhgdia, a Rho GDP dissociation inhibitor alpha, and exhibited inhibitory effects on the viability, migration, and invasion of breast cancer cells. It also hindered the GTPase activity of RhoA and Cdc42 and downregulated the expression of oncoproteins such as Snail and Src. The inhibitory impact of P18 was additive when it was combined with chemotherapeutic drugs such as Cisplatin and Taxol in both breast cancer cells and patient-derived tissues. P18 had no inhibitory effect on mesenchymal stem cells but suppressed the maturation of RANKL-stimulated osteoclasts and mitigated the bone loss associated with breast cancer. Furthermore, the P18 analog modified by N-terminal acetylation and C-terminal amidation (Ac-P18-NH2) exhibited stronger tumor-suppressor effects. Conclusions: This study introduced a unique methodology for selecting an effective ACP from the iTSC secretome. P18 holds promise for the treatment of breast cancer and the prevention of bone destruction by regulating GTPase signaling. [ABSTRACT FROM AUTHOR]

Simple Summary: High-Z gold nanoparticles show potential as radiosensitizers in the radiotherapy of cancer. In this paper, we introduce the benefits and procedures for the application of gold nanoparticles in targeted cancer radiotherapy. Based on microscopic images of the distribution of antibody-conjugated nanoparticles, we established pharmacokinetic models simulating the biodistribution of nanoparticle conjugates in the tumor and tumor environment in preclinical models. This information has been implemented in radiation transport Monte Carlo simulation codes for further investigating physical and chemical enhancement and radiobiological effects, such as DNA strand breaks and cell survival. Future perspectives and challenges of translating this promising gold nanoparticle-aided radiotherapy into clinical practice are also discussed. High-Z gold nanoparticles (AuNPs) conjugated to a targeting antibody can help to improve tumor control in radiotherapy while simultaneously minimizing radiotoxicity to adjacent healthy tissue. This paper summarizes the main findings of a joint research program which applied AuNP-conjugates in preclinical modeling of radiotherapy at the Klinikum rechts der Isar, Technical University of Munich and Helmholtz Zentrum München. A pharmacokinetic model of superparamagnetic iron oxide nanoparticles was developed in preparation for a model simulating the uptake and distribution of AuNPs in mice. Multi-scale Monte Carlo simulations were performed on a single AuNP and multiple AuNPs in tumor cells at cellular and molecular levels to determine enhancements in the radiation dose and generation of chemical radicals in close proximity to AuNPs. A biologically based mathematical model was developed to predict the biological response of AuNPs in radiation enhancement. Although simulations of a single AuNP demonstrated a clear dose enhancement, simulations relating to the generation of chemical radicals and the induction of DNA strand breaks induced by multiple AuNPs showed only a minor dose enhancement. The differences in the simulated enhancements at molecular and cellular levels indicate that further investigations are necessary to better understand the impact of the physical, chemical, and biological parameters in preclinical experimental settings prior to a translation of these AuNPs models into targeted cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular directed therapy for hepatocellular carcinoma (HCC) involves targeting specific signaling pathways that normally promote cancer cell growth and survival. Accordingly, a blockage of these pathways leads to tumor shrinkage and improves the patient outcome. Recent advancements in molecular directed therapies have focused on tyrosine kinase and angiogenesis inhibition, thus targeting pathways involved in the molecular pathogenesis of HCC. Especially the vascular endothelial growth factor (VEGF) signaling pathway is one of the most prominent pathways involved in HCC progression. The combination of inhibiting VEGF signaling and immune-directed therapy or double immunocheckpoint inhibition are the mainstay of contemporary treatment strategies and promising agents for future combination treatment regimens. However, the effectiveness of these therapies may vary among patients, highlighting the need to identify the specific molecular alterations for tailored therapeutic approaches. Additionally, in modern systemic therapy of patients with HCC, the underlying pathology of the liver has always been encountered to identify population subgroups in terms of pathophysiology and underlying liver function to predict response to different therapeutic regimens. We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of antiretroviral therapy has shown promising antineoplastic effects in multiple cancers; however, its efficacy in glioblastoma is unknown. We conducted an unbiased screen of 16 antiretroviral medications in 40 glioma cell lines and validated their efficacy in patient-derived glioma neurospheres and established cell lines. Our study provides the first mechanistic and functional insight into the utility of drug repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, antiretroviral therapy may be a promising adjuvant treatment for glioblastoma. Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Retinoblastoma (RB) is a malignant childhood eye cancer. In search for new or adjuvant treatment options, the gastric inhibitory polypeptide receptor (GIPR), upregulated upon the overexpression of trefoil factor family peptide 1 (TFF1), a diagnostic and prognostic biomarker for advanced RBs, came into our focus of interest. The overexpression of GIPR, found to be co-expressed with TFF1 in RB tumors, significantly reduced RB cell viability and growth and increased apoptosis levels. Moreover, GIPR-overexpressing RB cells developed significantly smaller tumors in vivo, indicating a tumor suppressor role of GIPR in RB. Although our data revealed that GIPR is not a direct TFF1 receptor, TFF1 and GIPR seem to be involved in the same signaling cascades. GIPR expression in RB cells seems to be regulated by miR-542-5p, and p53 is involved in GIPR downstream signaling, together providing potential targets for novel retinoblastoma treatment approaches. Retinoblastoma (RB) is the most common malignant intraocular tumor in early childhood. Gene expression profiling revealed that the gastric inhibitory polypeptide receptor (GIPR) is upregulated following trefoil factor family peptide 1 (TFF1) overexpression in RB cells. In the study presented, we found this G protein-coupled transmembrane receptor to be co-expressed with TFF1, a new diagnostic and prognostic RB biomarker for advanced subtype 2 RBs. Functional analyses in two RB cell lines revealed a significant reduction in cell viability and growth and a concomitant increase in apoptosis following stable, lentiviral GIPR overexpression, matching the effects seen after TFF1 overexpression. In chicken chorioallantoic membrane (CAM) assays, GIPR-overexpressing RB cells developed significantly smaller CAM tumors. The effect of GIPR overexpression in RB cells was reversed by the GIPR inhibitor MK0893. The administration of recombinant TFF1 did not augment GIPR overexpression effects, suggesting that GIPR does not serve as a TFF1 receptor. Investigations of potential GIPR up- and downstream mediators suggest the involvement of miR-542-5p and p53 in GIPR signaling. Our results indicate a tumor suppressor role of GIPR in RB, suggesting its pathway as a new potential target for future retinoblastoma therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Radium-223 is used for the management of metastatic castration-resistant prostate cancer. However, the response to this treatment is poor. Targeting the DNA damage response pathway through pharmacological inhibition has the ability to enhance the radiation response. In this study, we investigated the radiosensitising effects of three different DNA damage response inhibitors targeting ATM, ATR, and PARP in combination with X-rays and radium-223 on human prostate cancer cell lines. Their effects on cell survival, DNA double-strand break repair, cell cycle distribution, and apoptosis were evaluated. We determined that these inhibitors increase the ability of X-rays and radium-223 to kill prostate cells to varying degrees. Moreover, inhibition of the DNA damage response pathways impeded the repair of radiation-induced DNA double-strand breaks and induced changes in cell cycle distribution. Altogether, our study determined DDR inhibition as a promising strategy to increase the effectiveness of treatments utilising X-rays and/or 223Ra for localised and metastatic castration-resistant prostate cancer. Radium-223 (223Ra) and Lutetium-177-labelled-PSMA-617 (177Lu-PSMA) are currently the only radiopharmaceutical treatments to prolong survival for patients with metastatic-castration-resistant prostate cancer (mCRPC); however, mCRPC remains an aggressive disease. Recent clinical evidence suggests patients with mutations in DNA repair genes associated with homologous recombination have a greater clinical benefit from 223Ra. In this study, we aimed to determine the utility of combining DNA damage response (DDR) inhibitors to increase the therapeutic efficacy of X-rays, or 223Ra. Radiobiological responses were characterised by in vitro assessment of clonogenic survival, repair of double strand breaks, cell cycle distribution, and apoptosis via PARP-1 cleavage. Here, we show that DDR inhibitors increase the therapeutic efficacy of both radiation qualities examined, which is associated with greater levels of residual DNA damage. Co-treatment of ATM or PARP inhibition with 223Ra increased cell cycle arrest in the G2/M phase. In comparison, combined ATR inhibition and radiation qualities caused G2/M checkpoint abrogation. Additionally, greater levels of apoptosis were observed after the combination of DDR inhibitors with 223Ra. This study identified the ATR inhibitor as the most synergistic inhibitor for both radiation qualities, supporting further pre-clinical evaluation of DDR inhibitors in combination with 223Ra for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Anthracycline-induced cardiomyopathies and sarcopenia are often seen in cancer patients, affecting their quality of life and overall survival. Translational research aimed to find new cardioprotective strategies is strictly needed in cardioncology. Soluble guanylate cyclase activator vericiguat reduces heart failure rates in patients with reduced ejection fraction. In this study, we highlighted the cardioprotective and anti-inflammatory properties of vericiguat during exposure to anthracyclines and demonstrated its preventive properties of sarcopenia induced by doxorubicin (DOXO), which can be exploited for potential cardioprotective strategies in cancer patients. Furthermore, vericiguat reduces chemokines and cytokines involved in cardiomyopathies through NLR family pyrin domain containing 3 (NLRP-3) pathways in human cardiomyocytes and skeletal muscle cells. The findings that emerged from this study could provide the rationale for further preclinical and clinical investigations aimed at reducing anthracycline cardiotoxicity and sarcopenia in cancer patients. Anthracycline-induced cardiomyopathies and sarcopenia are frequently seen in cancer patients, affecting their overall survival and quality of life; therefore, new cardioprotective and anti-sarcopenic strategies are needed. Vericiguat is a new oral guanylate cyclase activator that reduces heart failure hospitalizations or cardiovascular death. This study highlighted the potential cardioprotective and anti-sarcopenic properties of vericiguat during anthracycline therapy. Human cardiomyocytes and primary skeletal muscle cells were exposed to doxorubicin (DOXO) with or without a pre-treatment with vericiguat. Mitochondrial cell viability, LDH, and Cytochrome C release were performed to study cytoprotective properties. Intracellular Ca++ content, TUNEL assay, cGMP, NLRP-3, Myd-88, and cytokine intracellular levels were quantified through colorimetric and selective ELISA methods. Vericiguat exerts significant cytoprotective and anti-apoptotic effects during exposure to doxorubicin. A drastic increase in cGMP expression and reduction in NLRP-3, MyD-88 levels were also seen in Vericiguat-DOXO groups vs. DOXO groups (p < 0.001) in both cardiomyocytes and human muscle cells. GCa vericiguat reduces cytokines and chemokines involved in heart failure and sarcopenia. The findings that emerged from this study could provide the rationale for further preclinical and clinical investigations aimed at reducing anthracycline cardiotoxicity and sarcopenia in cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, much research has focused on how exercise improves cancer prognosis and how the protein myokine, which is associated with exercise, inhibits cancer progression. However, there have been few detailed studies on oral cancer. This study is the first to show that exercise inhibits the progression of oral cancer. While other studies have shown that exercise suppresses growth, decreases the tumor formation rate, or improves survival in patients with other organ cancers, this study showed that exercise inhibits tumor formation and growth in oral cancer and prolongs survival. Furthermore, while many studies have demonstrated an indirect immune-mediated mechanism by which exercise suppresses cancer, this study suggests the additional possibility that myokines released by exercise directly affect oral cancer cells. This study has the above novelties. Major advances have been made in cancer treatment, but the prognosis for elderly cancer patients with sarcopenia and frailty remains poor. Myokines, which are thought to exert preventive effects against sarcopenia, have been reported to be associated with the prognosis of various cancers, but their effect on head and neck squamous cell carcinoma (HNSCC) is unknown. The aim of this study was to clarify the influence of exercise on the control of HNSCC and to examine the underlying mechanism involved. Mice were injected with HSC-3-M3 cells, a human cell line of highly metastatic and poorly differentiated tongue cancer, at the beginning of the study. Just prior to transplantation, blood was collected from the mice, and the levels of myokines were measured by ELISA. Oncostatin M (OSM), a selected myokine, was added to HSC-3-M3 cells, after which the cell proliferation ability, cell cycle, and protein expression were analyzed in vitro. Tumor cell viability was lower (control: 100%, exercise: 75%), tumors were smaller (control: 26.2 mm3, exercise: 6.4 mm3), and survival was longer in the exercise group than in the control group in vivo. OSM inhibited HSC-3-M3 cell proliferation in a concentration-dependent manner in vitro. The addition of OSM increased the proportion of cells in the G0/G1 phase, decreased the proportion of cells in the G2/M phase, and increased the expression of the CDK inhibitors p21 and p27. These results indicate that exercise may directly inhibit the proliferation of HNSCC cell lines via OSM. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinoma (CCA) accounts for approximately 15% of primary liver cancers. CCA has a poor prognosis and, thus, more effective systemic treatments are needed. We tested opaganib and upamostat, drugs that target sphingosine kinase 2 and multiple serine proteases, primarily trypsins, which are highly expressed in CCA tumors. This study demonstrates the results of inhibiting these novel targets with these drugs individually and in combination in a patient-derived CCA xenograft mouse model. Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group. [ABSTRACT FROM AUTHOR]

Simple Summary: The objective of drug repurposing is to discover novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a commonly prescribed antidepressant, has demonstrated promising anticancer properties in experimental studies. Nevertheless, its precise role and mechanisms of action in triple-negative breast cancer (TNBC) remain incompletely elucidated. Our research findings propose that PX may impact TNBC by modulating critical molecular pathways, providing significant implications for enhancing chemosensitivity and identifying potential therapeutic synergies in clinical practice. These findings provide a basis for the creation of individualized treatment plans and the identification of the most effective therapeutic interventions to enhance treatment precision and effectiveness in patients with TNBC. The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use. [ABSTRACT FROM AUTHOR]

Simple Summary: The interaction between the highly aggressive triple-negative breast cancer, and the neutrophils is connected to the poor outcomes of this tumor. Using a wide array of cellular and molecular essays, we found that triple-negative breast cancer cells stressed out the neutrophil-like cells and reduced their viability in cell culture conditions. Furthermore, growing neutrophil-like cells with breast cancer cells enhanced the inflammatory activity of the neutrophil-like cells through the release and expression of chemical or structural inflammatory mediators. Given that cancer cells can exploit the active inflammatory milieu to the advantage of their growth and spread, targeting the crosstalk mechanisms that we illustrated here could help in defining potential therapeutic options in breast cancer management. Breast cancer (BC) is one of the most common types of cancer in women in the United Arab Emirates. Immunogenic tumours, such as triple-negative breast cancer (TNBC), show increased neutrophil infiltration, which is associated with poor prognosis and limited efficacy of immunotherapy. This study aims to investigate in vitro the bidirectional effect of neutrophils on metastatic TNBC (MDA-MB-231) compared to less-metastatic luminal breast cancer (MCF-7) cell lines. We found that BC cells or their conditioned medium (CM) reduced the viability of neutrophil-like cells (HL60). This was supported by increased cellular stress and NETosis in differentiated HL60 cells (dHL60) upon exposure to MDA-MB-231 compared to MCF-7-CM using nucleic acid staining essays. Flow cytometry showed comparable expression of inflammatory markers by polymorphonuclear cells (PMN) when treated with MDA-MB-231-CM and standard polarizing cocktails. Furthermore, MDA-MB-231-CM triggered an inflammatory pattern with evidence of stronger adhesion (CD62L) and degranulation (CD11b and CD66b) phenotypes. The proinflammatory polarization of dHL60 by MDA-MB-231-CM was additionally confirmed by the elevated CD54 expression, myeloperoxidase, and CD11b protein levels, which matched an increased transwell migratory capacity. In conclusion, BC might use neutrophils to their benefit through NETosis and complement system activation, which makes this crosstalk a potential mechanism for understanding tumour progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer accounts for 11.4% of all cancer cases and 18.0% of all cancer deaths. Understanding the molecular mechanisms underlying lung adenocarcinoma (LUAD), one of the most common lung cancers, is imperative to enhance diagnostic accuracy, drug development, and prognostic evaluation. The present study explored the interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4), as well as the influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on the glycolysis, proliferation, and metastasis ability in LUAD cell lines and their effects on the tumor growth in xenograft animal models. GPC4 promotes HS3ST1-mediated glycolysis, and the hypoxia-derived exosomal lncRNA OIP5-AS1 promotes glycolysis via the miR-200c-3p axis in LUAD cells. The hypoxia-derived exosomal lncRNA OIP5-AS1 enhances LUAD cell proliferation and metastasis in vitro and promotes LUAD tumor growth and metastasis via miR-200c-3p in vivo. These findings highlight that the hypoxia-derived exosomal lncRNA OIP5-AS1 may participate in LUAD progression. Objective: The diagnosis of lung adenocarcinoma (LUAD) is often delayed due to the typically asymptomatic nature of the early-stage disease, causing advanced-stage LUAD diagnosis in most patients. Hypoxia is widely recognized as a driving force in cancer progression. Exosomes originating from hypoxic tumor cells promote tumorigenesis by influencing glycolysis, migration, invasion, and immune infiltration. Given these insights, our study aimed to explore the role of hypoxia-derived exosomal long non-coding RNA (lncRNA) OIP5-AS1 in LUAD cell lines and mouse models. Materials and Methods: Exosomes were meticulously isolated and authenticated based on their morphology and biomarkers. The interaction between heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1) and Glypican 4 (GPC4) was examined using immunoprecipitation. The influence of the hypoxia-derived exosomal lncRNA OIP5-AS1 on glycolysis was assessed in LUAD cell lines. The effect of the hypoxia-derived exosomal lncRNA OIP5-AS1 on cell proliferation and metastasis was evaluated using colony formation, cell viability, cell cycle, and apoptosis analyses. Its effects on tumor size were confirmed in xenograft animal models. Results: Our study revealed the mechanism of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. We discovered that GPC4 promotes HS3ST1-mediated glycolysis and that the hypoxia-derived exosomal lncRNA OIP5-AS1 enhances glycolysis by regulating miR-200c-3p in LUAD cells. Notably, this lncRNA stimulates LUAD cell proliferation and metastasis and fosters LUAD tumor size via miR-200c-3p. Our findings underscore the potential role of the hypoxia-derived exosomal lncRNA OIP5-AS1 in LUAD progression. Conclusions: The hypoxia-derived exosomal lncRNA OIP5-AS1 promotes LUAD by regulating HS3ST1-GPC4-mediated glycolysis via miR-200c-3p. [ABSTRACT FROM AUTHOR]

Simple Summary: This research explores how the low-molecular microphthalmia-associated transcription factor (MITF) specific inhibitor ML329 affects malignant melanoma (MM) cells' biology. ML329 significantly reduced cell viability in specific melanoma cell lines and differently influenced their metabolic functions. ML329 also substantially and differently affected the ability to form 3D spheroids and altered the expression of genes related to regulatory and signaling factors among various MM cell lines. These diverse effects across different melanoma types underscore the complexity of MITF-related activities among various types of MM, aiding the development of a more effective understanding of MMs' pathophysiology as well as their targeted therapies. To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM cell lines including SK-mel-24, A375, dabrafenib- and trametinib-resistant A375 (A375DT), and WM266-4. Upon exposure to 2 or 10 μM of ML329, cell viability was significantly decreased in WM266-4, SK-mel-24, and A375DT cells, but not A375 cells, in a dose-dependent manner, and these toxic effects of ML329 were most evident in WM266-4 cells. Extracellular flux assays conducted using a Seahorse bioanalyzer revealed that treatment with ML329 increased basal respiration, ATP-linked respiration, proton leakage, and non-mitochondrial respiration in WM266-4 cells and decreased glycolytic function in SK-mel-24 cells, whereas there were no marked effects of ML329 on A375 and A375DT cells. A glycolytic stress assay under conditions of high glucose concentrations also demonstrated that the inhibitory effect of ML329 on the glycolytic function of WM266-4 cells was dose-dependent. In addition, ML329 significantly decreased 3D-spheroid-forming ability, though the effects of ML329 were variable among the MM cell lines. Furthermore, the mRNA expression levels of selected genes, including STAT3 as a possible regulator of 3D spheroid formation, KRAS and SOX2 as oncogenic-signaling-related factors, PCG1a as the main regulator of mitochondrial biogenesis, and HIF1a as a major hypoxia transcriptional regulator, fluctuated among the MM cell lines, possibly supporting the diverse ML329 effects mentioned above. The findings of diverse ML329 effects on various MM cell lines suggest that MITF-associated biological activities are different among various types of MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor cells shed pieces of DNA that circulate in biofluids like blood and urine. The amount of circulating tumor DNA is related to the amount of cancer in the body. Knowing the amount of cancer helps doctors predict outcomes and decide treatments for patients. Tumor DNA has methylation patterns that makes it distinct from non-cancer DNA. In this study, we describe a new method called tumor methylated fraction (TMeF) that quantifies the cancer-indicative methylation patterns within circulating tumor DNA from blood samples. This method is non-invasive because it does not need tumor tissue to estimate the amount of cancer in the body. In the future, doctors could use TMeF to supplement current cancer screening methods. Estimating the abundance of cell-free DNA (cfDNA) fragments shed from a tumor (i.e., circulating tumor DNA (ctDNA)) can approximate tumor burden, which has numerous clinical applications. We derived a novel, broadly applicable statistical method to quantify cancer-indicative methylation patterns within cfDNA to estimate ctDNA abundance, even at low levels. Our algorithm identified differentially methylated regions (DMRs) between a reference database of cancer tissue biopsy samples and cfDNA from individuals without cancer. Then, without utilizing matched tissue biopsy, counts of fragments matching the cancer-indicative hyper/hypo-methylated patterns within DMRs were used to determine a tumor methylated fraction (TMeF; a methylation-based quantification of the circulating tumor allele fraction and estimate of ctDNA abundance) for plasma samples. TMeF and small variant allele fraction (SVAF) estimates of the same cancer plasma samples were correlated (Spearman's correlation coefficient: 0.73), and synthetic dilutions to expected TMeF of 10−3 and 10−4 had estimated TMeF within two-fold for 95% and 77% of samples, respectively. TMeF increased with cancer stage and tumor size and inversely correlated with survival probability. Therefore, tumor-derived fragments in the cfDNA of patients with cancer can be leveraged to estimate ctDNA abundance without the need for a tumor biopsy, which may provide non-invasive clinical approximations of tumor burden. [ABSTRACT FROM AUTHOR]

Simple Summary: Elevated expression of BIRC5/survivin, a protein crucial for cell division, is linked to unfavorable outcomes in neuroblastoma (NB), a prevalent pediatric tumor. Novel therapeutic approaches are consequently warranted. Therefore, we examined the effects of S12 and LQZ-7I, small molecules that disrupt survivin's interaction with itself and other proteins, on NB cells in vitro and in vivo. We demonstrate that these drugs effectively suppress the growth of NB cells, partly by hindering cell division. In contrast, incomplete inhibition of BIRC5 transcription did not diminish NB growth. We conclude that inhibitors of survivin protein interaction hold promise as a novel therapeutic class against NB and should be further investigated. Increased expression of BIRC5/survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB), the most common extracranial tumor of childhood. Transcriptional inhibitors of survivin have been tested in adult cancers and inhibitors of survivin homodimerization are emerging. We compared genetic inhibition of survivin transcription with the inhibition of survivin homodimerization by S12 and LQZ-7I, chosen from a larger panel of survivin dimerization inhibitors with activity against NB cells. Mice hemizygous for Birc5 were crossed with NB-prone TH-MYCN mice to generate Birc5+/-/MYCNtg/+ mice. The marked decrease of survivin transcription in these mice did not suffice to attenuate the aggressiveness of NB, even when tumors were transplanted into wild-type mice to assure that immune cell function was not compromised by the lack of survivin. In contrast, viability, clonogenicity and anchorage-independent growth of NB cells were markedly decreased by S12. S12 administered systemically to mice with subcutaneous NB xenotransplants decreased intratumoral hemorrhage, albeit not tumor growth. LQZ-7I, which directly targets the survivin dimerization interface, was efficacious in controlling NB cell growth in vitro at markedly lower concentrations compared to S12. LQZ-7I abrogated viability, clonogenicity and anchorage-independent growth, associated with massively distorted mitotic spindle formation. In vivo, LQZ-7I effectively reduced tumor size and cell proliferation of NB cells in CAM assays without apparent toxicity to the developing chick embryo. Collectively, these findings show that inhibiting survivin homodimerization with LQZ-7I holds promise for the treatment of NB and merits further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: We show that breast cancer gene 2 (BRCA2) is highly expressed in cultured olaparib-resistant colorectal cancer (CRC) cells and that CRC cells become more sensitive to olaparib with reduced BRCA2 expression. Importantly, inhibiting lysine acetyltransferase 2B (KAT2B) expression also decreases the resistance of CRC cells towards olaparib treatment. Mechanistically, a lack of KAT2B reduces the acetylation of histone H3 lysine 27 (H3K27), thus binding the latter to BRCA2 promotors, which affects BRCA2 expression. Our research suggests the critical role of a KAT2B-BRCA2 axis, which is also valid for BRCA2 wildtype phenotypes, opening interesting new perspectives for better-predicting olaparib sensitivity in CRC. Olaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers with BRCA1/2 mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib. The recovery of the wildtype BRCA is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors, but additional molecular features of olaparib resistance remain poorly understood. The objective of our study was to find molecular parameters that contribute to olaparib response or resistance in CRC. We report that histone acetyltransferase KAT2B decreases BRCA2 expression by reducing the acetylation of the 27th amino acid in histone H3 (H3K27) at the promoter of the BRCA2 gene in colorectal cancer (CRC). This increases the sensitivity of CRC cells toward olaparib treatment. The H3K27ac binding domain of BRCA2 may be required for its transcription. Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) is one of the most common malignancies with limited therapeutic targets available. CDR1as, an endogenous circular RNA with a closed loop structure, has been reported to be a crucial regulator and promising biomarker in various tumors. However, whether and how CDR1as participates in GC progression remains not well characterized. In this study, we explored the biological roles, the downstream molecular mechanism and the upstream regulator of CDR1as in GC. We found that CDR1as mediated by human antigen R (HuR) promotes GC growth through the miR-299-3p/TGIF1 axis, which provides new insights into GC pathogenesis and brings a new potential target for clinical GC therapy. Background: Gastric cancer (GC) remains a common malignancy worldwide with a limited understanding of the disease mechanisms. A novel circular RNA CDR1as has been recently reported to be a crucial regulator of human cancer. However, its biological role and mechanism in the GC growth are still far from clear. Methods: Small interfering RNAs (siRNAs), lentivirus or plasmid vectors were applied for gene manipulation. The CDR1as effects on the GC growth were evaluated in CCK8 and colony formation assays, a flow cytometry analysis and mouse xenograft tumor models. A bioinformatics analysis combined with RNA immunoprecipitation (RIP), RNA pull-down assays, dual-luciferase reporter gene assays, Western blot, reverse transcription–quantitative polymerase chain reaction (RT-qPCR) and functional rescue experiments were used to identify the CDR1as target miRNA, the downstream target gene and its interaction with human antigen R (HuR). Results: The CDR1as overexpression promoted the GC growth in vitro and in vivo and reduced the apoptotic rate of GC cells. Its knockdown inhibited the GC cell proliferation and viability and increased the cell apoptotic rate. Proliferation-related proteins PCNA and Cyclin D1 and apoptosis-related proteins Bax, Bcl-2, Caspase-3 and Caspase-9 were regulated. Mechanically, the cytoplasmic CDR1as acted as a miR-299-3p sponge to relieve its suppressive effects on the GC cell growth. Oncogenic TGIF1 was a miR-299-3p downstream target gene that mediated the promotive effects of CDR1as and regulated the PCNA and Bax levels. HuR interacted with CDR1as via the RRM2 domain and positively regulated the CDR1as level and its oncogenic role as well as downstream target TGIF1. Conclusions: CDR1as promotes the GC growth through the HuR/CDR1as/miR-299-3p/TGIF1 axis and could be used as a new therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Simple Summary: Nicotine, a highly addictive component in cigarette smoke, facilitates tumorigenesis and the accelerated development of non-small cell lung cancer (NSCLC), which is known to account for ~80% of all lung cancer cases. This study sheds light on how the nicotine treatment of NSCLC cells regulates vascular endothelial growth factor (VEGF) signaling, known to be important in the progression of vascular disease and cancer, by acting through nicotinic acetylcholine receptors and by leading to the activation of β-adrenergic receptors through increased levels of the stress neurotransmitters, norepinephrine/noradrenaline, and epinephrine/adrenaline. Nicotine-induced activation of VEGF promoted the function of proteins involved in increased cell survival and suppressed the function of a crucial tumor suppressor, blocking cell death. This work expands our scientific knowledge of mechanisms employed by nicotine in regulating VEGF signaling in a manner dependent on the acetylcholine and/or β-adrenergic receptors, leading to lung cancer cell survival, and also provides significant insights into novel future therapeutic strategies to combat lung cancer. In addition to binding to nicotinic acetylcholine receptors (nAChRs), nicotine is known to regulate the β-adrenergic receptors (β-ARs) promoting oncogenic signaling. Using A549 (p53 wild-type) and H1299 (p53-null) lung cancer cells, we show that nicotine treatment led to: increased adrenaline/noradrenaline levels, an effect blocked by treatment with the α7nAChR inhibitor (α-BTX) but not by the β-blocker (propranolol) or the α4β2nAChR antagonist (DhβE); decreased GABA levels in A549 and H1299 cell media, an effect blocked by treatment with DhβE; increased VEGF levels and PI3K/AKT activities, an effect diminished by cell co-treatment with α-BTX, propranolol, and/or DhβE; and inhibited p53 activity in A549 cells, that was reversed, upon cell co-treatment with α-BTX, propranolol, and/or DhβE or by VEGF immunodepletion. VEGF levels increased upon cell treatment with nicotine, adrenaline/noradrenaline, and decreased with GABA treatment. On the other hand, the p53 activity decreased in A549 cells treated with nicotine, adrenaline/noradrenaline and increased upon cell incubation with GABA. Knockdown of p53 led to increased VEGF levels in the media of A549 cells. The addition of anti-VEGF antibodies to A549 and H1299 cells decreased cell viability and increased apoptosis; blocked the activities of PI3K, AKT, and NFκB in the absence or presence of nicotine; and resulted in increased p53 activation in A549 cells. We conclude that VEGF can be upregulated via α7nAChR and/or β-ARs and downregulated via GABA and/or p53 in response to the nicotine treatment of NSCLC cells. [ABSTRACT FROM AUTHOR]

Simple Summary: ASCT2 is an attractive tumour metabolism target based on its critical role in cancer cell growth. The potential mechanisms of microtubule protein inhibitor C118P in breast cancer remain unknown. Identification of the potential target of C118P is essential. We evaluated the inhibitory effects of C118P on breast cancer. C118P restrained the tumour growth of MDA-MB-231 cells by inducing apoptosis, G2/M phase arrest, and autophagy. Furthermore, ASCT2 was confirmed to be a target of C118P. This is the first report to provide evidence that ASCT2 might be a candidate target of C118P in breast cancer treatment. Remarkably, this study will provide an opportunity for ASCT2 inhibition as a therapeutic strategy. Background: The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown. Methods: Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip. Results: C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte–breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures. Conclusion: C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2. [ABSTRACT FROM AUTHOR]

Simple Summary: The PTEN gene is an important and well-characterised tumour suppressor, known to be altered in many cancer types. Interestingly, the effect of the loss or mutation of PTEN is not dichotomous, and small changes in PTEN cellular levels can promote cancer development. Less well-known mechanisms regulating PTEN, with emerging importance, include the PTEN–miRNA–PTENP1 axis, which has been shown to play a critical role in the fine tuning of PTEN cellular levels. This mechanism, working at the post-transcriptional level, involves the interplay and competition between the PTEN transcript, its pseudogene long non-coding RNA transcripts, PTENP1, and microRNAs. Our growing knowledge of this mechanism has opened avenues for the development of strategies to alter the cellular levels of PTEN, miRNAs, and PTENP1 as a new frontier in cancer therapy. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a well characterised tumour suppressor, playing a critical role in the maintenance of fundamental cellular processes including cell proliferation, migration, metabolism, and survival. Subtle decreases in cellular levels of PTEN result in the development and progression of cancer, hence there is tight regulation of the expression, activity, and cellular half-life of PTEN at the transcriptional, post-transcriptional, and post-translational levels. PTENP1, the processed pseudogene of PTEN, is an important transcriptional and post-transcriptional regulator of PTEN. PTENP1 expression produces sense and antisense transcripts modulating PTEN expression, in conjunction with miRNAs. Due to the high sequence similarity between PTEN and the PTENP1 sense transcript, the transcripts possess common miRNA binding sites with the potential for PTENP1 to compete for the binding, or 'sponging', of miRNAs that would otherwise target the PTEN transcript. PTENP1 therefore acts as a competitive endogenous RNA (ceRNA), competing with PTEN for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (PTENP1-AS-α and PTENP1-AS-β), which can regulate PTEN transcription. In this review, we provide an overview of the post-transcriptional regulation of PTEN through interaction with its pseudogene, the cellular miRNA milieu and operation of the ceRNA network. Furthermore, its importance in maintaining cellular integrity and how disruption of this PTEN–miRNA–PTENP1 axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of PTENP1-miRNA mediated regulation of PTEN may present as a viable alternative therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Paclitaxel-based chemotherapy is the standard front-line therapy for advanced or metastatic endometrial cancer. However, paclitaxel resistance eternally develops. Based on the high prevalence of PIK3CA mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a PI3K inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. Based on our in vitro and in vivo results, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial–mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondria are well known for being the powerhouses of the cell—whether the cell is normal or cancerous. Moreover, they can move, split, fuse themselves, or be eliminated via mitophagy with the help of the interplay between motor proteins and the cell scaffold—especially microtubules. The relationship between mitochondria, microtubules, and motor proteins is altered in cancer, and targeting this molecular machinery can offer a novel weapon in its treatment. In this paper, we review and summarize the state of the art of this approach. Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton—particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin—the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes. [ABSTRACT FROM AUTHOR]

Simple Summary: MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11 and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins respectively. This is first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation. Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis (c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC50 in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation. [ABSTRACT FROM AUTHOR]

Simple Summary: The 5-year survival rate for women with metastatic breast cancer is 29%. Potential biomarker identification is important for new treatment modalities in affected patients. Previous studies have shown that Parathyroid hormone-related peptide (PTHrP) plays a critical role in breast cancer growth and metastasis. Our study aimed to use a genetically modified breast cancer mouse model to precisely examine the role of PTHrP from early primary breast cancer initiation to late progression. We identified a novel long non-coding RNA (lncRNA), a new target for fatty acid metabolism that can be regulated via PTHrP in our unique mouse breast cancer model. We confirmed that a potential human lncRNA, OLMALINC, plays a similar role in fatty acid metabolism that can be regulated via PTHrP and validated our mouse findings in human breast cancer cell lines. Genetically engineered mouse models provide valuable tools to study the molecular metabolism for breast cancer progression. Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling mechanisms using lineage tracing have not yet been carefully analyzed. Here, we generated Pthrpflox/flox; Cre+ mT/mG mice (KO) and Pthrpwt/wt; Cre+ mT/mG tumor mice (WT) to examine the signaling pathways under the control of PTHrP from the early to late stages of tumorigenesis. GFP+ mammary epithelial cells were further enriched for subsequent RNA sequencing (RNAseq) analyses. We observed significant upregulation of cell cycle signaling and fatty acid metabolism in PTHrP WT tumors, which are linked to tumor initiation and progression. Next, we observed that the expression levels of a novel lncRNA, GM50337, along with stearoyl-Coenzyme A desaturase 1 (Scd1) are significantly upregulated in PTHrP WT but not in KO tumors. We further validated a potential human orthologue lncRNA, OLMALINC, together with SCD1 that can be regulated via PTHrP in human BC cell lines. In conclusion, these novel findings could be used to develop targeted strategies for the treatment of BC and its metastatic complications. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is one of the most common cancers in the world, and despite improvements in treatment, it remains a significant health burden. B7-H3 is a member of the B7 immune checkpoint family of membrane proteins and shows increased expression in lung cancers; however, the functional consequences of this to cancer cell signalling remain unclear. Here, we show that B7-H3 forms a complex with the metabolic enzyme IMPDH2, and this protects cancer cells from oxidative stress and resulting apoptosis triggered by chemotherapy. The removal of B7-H3 from cancer cells in 2D results in sensitisation to chemotherapeutic stress and reduces cell viability in an IMPDH2-dependent manner. However, the loss of B7-H3 in 3D spheroid models results in enhanced IMPDH2-dependent spheroid growth, likely due to the weakening of cell–cell adhesion. These findings demonstrate that B7-H3 functionally contributes to metabolic signalling in lung cancer cells in the absence of immune cell interactions. Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Moderate loco-regional hyperthermia (40–45 °C) is a therapeutic modality that can improve the effects of chemotherapy and radiotherapy and, in addition, improve our immune response against cancer. However, the effects of these combinations on many different cancers are modest. The use of much higher temperatures (>60 °C, thermal ablation) can cause severe damage to healthy tissues. In fact, our results show that cancer cells show extraordinary resistance to moderate hyperthermia. However, we found that the combination of hyperthermia (not higher than 52 °C) with low-strength electromagnetic fields acts synergistically, causing irreversible damage to different cancer cells. Moreover, these externally applied energies can be combined with chemotherapy and/or targeted therapies to achieve complete cancer eradication. In vivo, the energy causing focal hyperthermia can be distributed in multiple beams that can be concentrated in the tumor, thus avoiding damaging the healthy tissues that it passes through. At present, the applications and efficacy of non-ionizing radiations (NIR) in oncotherapy are limited. In terms of potential combinations, the use of biocompatible magnetic nanoparticles as heat mediators has been extensively investigated. Nevertheless, developing more efficient heat nanomediators that may exhibit high specific absorption rates is still an unsolved problem. Our aim was to investigate if externally applied magnetic fields and a heat-inducing NIR affect tumor cell viability. To this end, under in vitro conditions, different human cancer cells (A2058 melanoma, AsPC1 pancreas carcinoma, MDA-MB-231 breast carcinoma) were treated with the combination of electromagnetic fields (EMFs, using solenoids) and hyperthermia (HT, using a thermostated bath). The effect of NIR was also studied in combination with standard chemotherapy and targeted therapy. An experimental device combining EMFs and high-intensity focused ultrasounds (HIFU)-induced HT was tested in vivo. EMFs (25 µT, 4 h) or HT (52 °C, 40 min) showed a limited effect on cancer cell viability in vitro. However, their combination decreased viability to approximately 16%, 50%, and 21% of control values in A2058, AsPC1, and MDA-MB-231 cells, respectively. Increased lysosomal permeability, release of cathepsins into the cytosol, and mitochondria-dependent activation of cell death are the underlying mechanisms. Cancer cells could be completely eliminated by combining EMFs, HT, and standard chemotherapy or EMFs, HT, and anti-Hsp70-targeted therapy. As a proof of concept, in vivo experiments performed in AsPC1 xenografts showed that a combination of EMFs, HIFU-induced HT, standard chemotherapy, and a lysosomal permeabilizer induces a complete cancer regression. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytological approaches have long been used in the diagnosis, prognosis, and management of acute myeloid leukemia (AML) and myelodysplastic neoplasms. Technological advances in molecular biology, in particular next-generation sequencing (NGS), have made it possible to establish a molecular list of several gene mutations in AML and MDS, within a matter of days. The combination of cytological approaches and NGS makes it possible to pinpoint genetic mutations and cancer cell survival and proliferation pathways, enabling better clinical management and improved prognosis of patients with acute leukemia and myelodysplastic neoplasms. For decades, the diagnosis, prognosis and thus, the treatment of acute myeloblastic leukemias and myelodysplastic neoplasms has been mainly based on morphological aspects, as evidenced by the French-American-British classification. The morphological aspects correspond quite well, in a certain number of particular cases, to particular evolutionary properties, such as acute myelomonoblastic leukemias with eosinophils or acute promyelocytic leukemias. Advances in biology, particularly "classical" cytogenetics (karyotype) and molecular cytogenetics (in situ hybridization), have made it possible to associate certain morphological features with particular molecular abnormalities, such as the pericentric inversion of chromosome 16 and translocation t(15;17) in the two preceding examples. Polymerase chain reaction techniques have made it possible to go further in these analyses by associating these karyotype abnormalities with their molecular causes, CBFbeta fusion with MYH11 and PML-RAR fusion in the previous cases. In these two examples, the molecular abnormality allows us to better define the pathophysiology of leukemia, to adapt certain treatments (all-transretinoic acid, for example), and to follow up the residual disease of strong prognostic value beyond the simple threshold of less than 5% of marrow blasts, signaling the complete remission. However, the new sequencing techniques of the next generation open up broader perspectives by being able to analyze several dozens of molecular abnormalities, improving all levels of management, from diagnosis to prognosis and treatment, even if it means that morphological aspects are increasingly relegated to the background. [ABSTRACT FROM AUTHOR]

Simple Summary: A variety of anticancer therapeutic targets have been identified over the decades. Nevertheless, the complexity of biological regulation dictates the necessity of knowledge about mechanisms specific to a particular tumor type. Using the DepMap CRISPR/Cas9 knockout database, we performed a comprehensive search for genes critical for tumor survival. Both established and novel markers of tumor viability were identified, many of which are transcriptional regulators. Our results substantiate new therapeutic strategies applicable to individual tumors. The identification of mechanisms that underlie the biology of individual tumors is aimed at the development of personalized treatment strategies. Herein, we performed a comprehensive search of genes (termed Supertargets) vital for tumors of particular tissue origin. In so doing, we used the DepMap database portal that encompasses a broad panel of cell lines with individual genes knocked out by CRISPR/Cas9 technology. For each of the 27 tumor types, we revealed the top five genes whose deletion was lethal in the particular case, indicating both known and unknown Supertargets. Most importantly, the majority of Supertargets (41%) were represented by DNA-binding transcription factors. RNAseq data analysis demonstrated that a subset of Supertargets was deregulated in clinical tumor samples but not in the respective non-malignant tissues. These results point to transcriptional mechanisms as key regulators of cell survival in specific tumors. Targeted inactivation of these factors emerges as a straightforward approach to optimize therapeutic regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Estrogen receptor-positive (ER+) breast cancer is the most prevalent breast cancer subtype, accounting for 70–85% of all cases. The combination of endocrine therapy, such as aromatase inhibitors (AIs), with target therapy is one of the most recent approaches, but its effectiveness is not optimal. Cannabidiol (CBD) has demonstrated important anti-tumor effects on ER+ breast cancer cells. Considering this, our goal was to evaluate the effects of combining CBD with the AIs currently in use in the clinical context. Our results revealed that CBD may be particularly beneficial when combined with the AI exemestane (Exe), since it potentiates the anti-tumor effects of Exe through the modulation of cell death and specific targets, including ERα and androgen receptor (AR). This reinforces the beneficial potential of cannabinoids in breast cancer and points to the possibility of improving Exe effects through an adjuvant therapy with CBD. Background: Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER+ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness. Methods: MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated. Results: CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER+ breast tumors. Conclusions: Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids. [ABSTRACT FROM AUTHOR]

Simple Summary: PRMT5 is overexpressed and activated in various human cancers, including breast cancer. This study aims to dissect the mechanism underlying how PRMT5 is dysregulated in cancers. Our results demonstrate that TRAF6-mediated ubiquitination plays an important role in the regulation of PRMT5 activity and cell proliferation. Thus, inhibition of TRAF6 is a possible strategy for improving PRMT5 targeted therapy. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and associated with poor prognosis and survival. However, the regulatory mechanisms of PRMT5 remain poorly understood. Here, we report that TRAF6 serves as an upstream E3 ubiquitin ligase to promote PRMT5 ubiquitination and activation. We find that TRAF6 catalyzes K63-linked ubiquitination of PRMT5 and interacts with PRMT5 in a TRAF6-binding-motif-dependent manner. Moreover, we identify six lysine residues located at the N-terminus as the primarily ubiquitinated sites. Disruption of TRAF6-mediated ubiquitination decreases PRMT5 methyltransferase activity towards H4R3 in part by impairing PRMT5 interaction with its co-factor MEP50. As a result, mutating the TRAF6-binding motifs or the six lysine residues significantly suppresses cell proliferation and tumor growth. Lastly, we show that TRAF6 inhibitor enhances cellular sensitivity to PRMT5 inhibitor. Therefore, our study reveals a critical regulatory mechanism of PRMT5 in cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Despite efficient control of the primary tumor by radiation or surgery, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. Today, most of the tested treatments including inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MEK) or immune checkpoint blockade have been largely ineffective in patients with metastatic UM. Given that single-agent targeted therapies often activate compensatory mechanisms, combination strategies are relevant to evaluate in UM in preclinical and clinical settings. Our study confirms the previously described synergy of the dual inhibition of focal adhesion kinase (FAK) and MEK, and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM. Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. The most recurrent event in UM is the activation of Gαq signaling induced by mutations in GNAQ/11. These mutations activate downstream effectors including protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Clinical trials with inhibitors of these targets have not demonstrated a survival benefit for patients with UM metastasis. Recently, it has been shown that GNAQ promotes YAP activation through the focal adhesion kinase (FAK). Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM both in vitro and in vivo. In this study, we have evaluated the synergy of the FAK inhibitor with a series of inhibitors targeting recognized UM deregulated pathways in a panel of cell lines. The combined inhibition of FAK and MEK or PKC had highly synergistic effects by reducing cell viability and inducing apoptosis. Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic prostate cancer (mPCa) results in high mortality and there are no effective treatments. The molecular mechanisms mediating the transition of early-stage PCa cells into malignant, metastatic cells are not clearly understood. Whereas the TGFβ pathway has been demonstrated to induce the epithelial-to-mesenchymal transition of prostate cancer cells, it necessitates the activation of the Rac-p21-activated kinase (PAK) signaling in this process. Identifying the role of PAK in mPCa, and compounds targeting its activity may lead to novel therapeutic applications for preventing and treating mPCa. Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of our study is to use E-selectin-binding peptide (ESBP) to actively recognize E-selectin, so allowing a drug delivery system to actively recognize the cells and inhibit ovarian cancer cells by targeting adhesion molecules of E-selectin. A drug-loaded nanoparticle with a special structure was designed as the drug carrier. Based on the fact that tumors often occur together with inflammation, the drug could be delivered to and more concentrated in ovarian tumor sites as well as tumor-associated inflammatory cells by using this drug-delivery system targeting selectins. Through recognition and binding with E-selectin in ovarian cancer cells and utilizing the steric hindrance effect of macromolecules that nanoparticles possess, paclitaxel was delivered and released, thus inducing ovarian cancer cell apoptosis and cell migration and decreasing myeloid-derived suppressor cells related to drug-resistance in a mouse model. It also had higher drug efficacy, extended the survival of tumor-bearing mice and had relatively lower in vivo toxicity than paclitaxel treatment. All results in this study provided potent proof of its potential to be applied to clinical use. Objective: The aim is to use E-selectin-binding peptide (ESBP) to actively recognize E-selectin, so allowing a drug delivery system to actively recognize the cells and inhibit the tumor growth of ovarian cancer by targeting adhesion molecules of E-selectin. An ovarian-cancer-directed drug delivery system was designed based on the high affinity of E-selectin-binding peptide (ESBP) to E-selectin. The effects and mechanisms of ESBP-bovine serum albumin (BSA) polymerized nanoparticles were investigated. Methods: BSA polymerized nanoparticles (BSANPs) and ESBP-BSANPs-paclitaxel (PTX) were prepared and their characteristics were measured. The in vitro targetability and cytotoxicity of ESBP-BSANPs-PTX were evaluated through in vitro drug uptake and MTT experiments. The mechanisms of ESBP-BSANPs-PTX were investigated via apoptosis, wound healing and immunohistochemistry assays. The in vivo targeting properties and drug effects were observed in a mouse tumor-bearing model. Results: In vitro experiments revealed an increase in the uptake of ESBP-BSANPs-FITC. The cytotoxicity of ESBP-BSANPs-PTX in A2780/CP70, HUVEC, RAW264.7 and ID8 cells was higher than that of PTX alone. ESBP-BSANPs-PTX increased cell apoptosis in a dose-dependent manner and exhibited a greater ability to inhibit cell migration than BSANPs-PTX. In vivo experiments demonstrated the targetability and good effects of ESBP-BSANPs. Conclusions: ESBP-BSANPs-PTX improve PTX targetability, provide tumor-specific and potent therapeutic activities, and show promise for the development of agents in preclinical epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic reprogramming is one of tumor and immune cells' most significant metabolic alterations. Moreover, metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), the mammalian target of rapamycin (mTOR), can induce growth, proliferation, and angiogenesis of tumor cells. Therefore, inhibiting these metabolic pathways can be considered a potential therapeutic strategy in human malignancies. On the other hand, according to previous studies, pharmacological inhibiting of metabolic pathways using dual-pathway inhibitors can considerably inhibit tumor growth and progression, more than suppressing each pathway separately. This review aims to summarize the latest metabolic interventions by dual pathway inhibitors and discuss the achievements and limitations of this therapeutic tactic. The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach. [ABSTRACT FROM AUTHOR]