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Simple Summary: Blood clots are formed when blood vessels are injured. They help stop bleeding and heal wounds, but can also cause serious problems if they block blood flow or break off and travel to other organs. This study investigates how blood clots differ in people with cancer compared to healthy or non-cancerous individuals. This study found that cancer patients have higher levels of histones in their blood, which make their clots stiffer and resistant to lysis. Further, clots formed in cancer patients have higher viscoelastic properties, and hence are harder to break down. These findings suggest that cancer patients have abnormal clotting properties that may increase their risk of developing thrombosis, and evaluating these properties can be helpful in detecting cancer. Background: Blood viscoelasticity and plasma protein levels can play an important role in the diagnosis and prognosis of cancer. However, the role of histones and DNA in modulating blood clot properties remains to be investigated. This study investigates the differences in blood viscoelasticity and plasma protein levels among cancer patients, individuals with other diseases, and healthy individuals. Methods: Blood samples were collected from 101 participants, including 45 cancer patients, 22 healthy individuals, and 34 individuals with other diseases. Rheological properties of clots formed in vitro by reconstituted elements of fibrinogen or plasma were analyzed with an Anton Paar Rheometer, USA. Plasma protein levels of D-dimer, TPA, EPCR, fibrinogen, and histone H3 were measured through ELISA. Blood clots were formed with or without DNA and histones (H3) by adding thrombin and calcium to plasma samples, and were evaluated for viscoelasticity, permeability, and degradation. Results: Cancer patients show higher blood viscoelasticity and plasma D-dimer levels compared to healthy individuals and individuals with other diseases. Our in vitro analysis showed that the addition of histone to the plasma results in a significant decrease in viscoelasticity and mean fiber thickness of the clot formed thereafter. In parallel studies, using plasma from patients, DNA and histones were detected in fibrin clots and were associated with less degradation by t-PA. Moreover, our results show that the presence of DNA and histones not only increases clots' permeability, but also makes them more prone to degradation. Conclusions: Plasma histones and DNA affect the structure of the clot formed and induce defective fibrinolysis. Moreover, the increased viscoelastic properties of plasma from cancer patients can be used as potential biomarkers in cancer prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Biliary tract malignancies, including cholangiocarcinoma (CCA) and gallbladder neoplasms, present intricate challenges in diagnosis and treatment. This comprehensive overview highlights the diversity of CCA subtypes, their genetic underpinnings, and the pivotal role of etiological factors. Despite diagnostic complexities, advancements in genomic sequencing reveal promising therapeutic targets, such as FGFR2 alterations and IDH1 mutations. Dr. James Cleary's insights underscore the potential of these targets in reshaping the treatment landscape. This paper provides insights into the conventional understanding of biliary tract malignancies and emphasizes the critical need for ongoing research to optimize outcomes in this challenging cancer subtype. By elucidating diverse FGFR2 alterations and the potential of IDH1 inhibition, the aim is to pave the way for targeted therapeutic interventions. As we delve deeper into understanding the intricate complexities of biliary tract malignancies, this research seeks to drive precision medicine forward, offering hope for improved treatment strategies and outcomes in the face of this formidable cancer. This paper provides insights into the conventional understanding of biliary tract malignancies, with a specific focus on cholangiocarcinoma (CCA). We then delve into the groundbreaking ideas presented by Dr. James Cleary. CCA, originating from biliary tree cells, manifests diverse subtypes contingent upon anatomical localization and differentiation status. These variants exhibit discrete genetic aberrations, yielding disparate clinical phenotypes and therapeutic modalities. Intrahepatic, perihilar, and distal CCAs intricately involve distinct segments of the biliary tree, further categorized as well-differentiated, moderately differentiated, or poorly differentiated adenocarcinomas based on their histological differentiation. Understanding the etiological factors contributing to CCA development assumes paramount importance. Stratifying these factors into two groups, those unrelated to fluke infestations (e.g., viral hepatitis and fatty liver conditions) and those associated with fluke infestations (e.g., chronic liver inflammation), facilitates predictive modeling. The epidemiology of CCA exhibits global variability, with Southeast Asia notably displaying higher incidences attributed primarily to liver fluke infestations. Jaundice resulting from bile duct obstruction constitutes a prevalent clinical manifestation of CCA, alongside symptoms like malaise, weight loss, and abdominal pain. Diagnostic challenges arise due to the symptomatic overlap with other biliary disorders. Employing comprehensive liver function tests and imaging modalities such as computed tomography assumes a pivotal role in ensuring accurate diagnosis and staging. However, the definitive confirmation of CCA necessitates a biopsy. Treatment modalities, predominantly encompassing surgical resection and radiation therapy, hold curative potential, although a considerable subset of patients is deemed unresectable upon exploration. Challenges intensify, particularly in cases classified as cancer of unknown origin, underscoring the imperative for early intervention. Advancements in genomic sequencing have revolutionized precision medicine in CCA. Distinct genomic markers, including fibroblast growth factor receptor 2 (FGFR2) alterations and isocitrate dehydrogenase 1 (IDH1) mutations, have emerged as promising therapeutic targets. FGFR2 alterations, encompassing mutations and rearrangements, play pivotal roles in oncogenesis, with FGFR inhibitors demonstrating promise despite identified resistance mechanisms. Similarly, IDH1 inhibitors face challenges with resistance, despite encouraging early clinical trial results, prompting exploration of novel irreversible inhibitors. Dr. James Cleary's illuminating discourse underscores the significance of diverse FGFR2 alterations and the potential of IDH1 inhibition in reshaping the treatment landscape for CCA. These findings unveil critical avenues for targeted therapeutic interventions, emphasizing the critical need for ongoing research to optimize outcomes in this challenging cancer subtype, incorporating innovative insights from Dr. Cleary. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent advances in diagnosis and therapy, malignant melanoma poses a significant problem both to clinicians and cancer researchers due to its resistance to therapy and unpredictable behavior. In this review, we discuss etiology, risk factors, diagnosis, prognosis, and therapy of melanoma, with a focus on new developments in these areas including bioinformatics. These are analyzed in the context of its unique metabolic characteristics and of recent advances in vitamin D biology with implications for melanoma. Active forms of vitamin D can prevent or inhibit melanoma development and progression, and can be used in therapy of this disease. Knowledge of patient vitamin D status and vitamin D signaling in the tumoral tissue can help in predicting the progression of the disease and in primary or adjuvant therapy. Therefore, vitamin D signaling represents a realistic target for the prevention or therapy of malignant melanoma. Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem. [ABSTRACT FROM AUTHOR]

Simple Summary: Androgen receptor-negative prostate cancer is one of the important mechanisms of castration resistant prostate cancer. The application of next generation androgen receptor signaling pathway inhibitors (ARPIs) has led to a gradual increase of AR-negative prostate cancer in the clinic. In this paper, we demonstrated the potential promotional role of ID2 in androgen receptor-negative prostate cancer through extensive bioinformatics analysis and experimental studies. Through transcriptome sequencing and downstream functional enrichment analysis, we found that ID2 can activate neuroendocrine or stemness-related pathways and inhibit androgen receptor signaling pathways. ID2 can activate JAK/STAT signaling pathway as well as FGFR signaling pathway to promote the acquisition of prostate cancer lineage plasticity, which in turn leads to androgen receptor-negative prostate cancer. Through cell function experiments and mouse experiments, we reveal that ID2 can promote prostate cancer evolution. Using transcriptome sequencing and publicly available clinical data, we generated ID2-related gene signatures to help determine clinical prognosis. The use of androgen receptor pathway inhibitors (ARPIs) has led to an increase in the proportion of AR-null prostate cancer, including neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC), but the mechanism underlying this lineage transition has not been elucidated. We found that ID2 expression was increased in AR-null prostate cancer. In vitro and in vivo studies confirmed that ID2 promotes PCa malignancy and can confer resistance to enzalutamide in PCa cells. We generated an ID2 UP50 signature, which is capable of determining resistance to enzalutamide and is valuable for predicting patient prognosis. Functional experiments showed that ID2 could activate stemness-associated JAK/STAT and FGFR signaling while inhibiting the AR signaling pathway. Our study indicates a potentially strong association between ID2 and the acquisition of a stem-like phenotype in adenocarcinoma cells, leading to resistance to androgen deprivation therapy (ADT) and next-generation ARPIs in prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Colon cancer is a solid tumor that is a prominent contributor to global mortality. Immune cells genetically engineered with a chimeric antigen receptor (CAR) that can recognize cancer-specific targets is a new innovative therapy approach that has had success in treating blood cancers but is still in development for treating solid tumors such as colon cancer. Part of the reason for the added difficulty in targeting solid tumors is the tumor microenvironment that acts as a protective barrier around a solid tumor. In this research paper, we have developed a new cellular approach for the targeted treatment of colon cancer that is designed to overcome the tumor microenvironment. We tested this new CAR cell therapy against multiple solid colon cancer models, and confirmed its efficacy and functionality in finding and eliminating solid tumors. Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen (CEA), given its widespread expression and role in tumorigenesis and metastasis. CEA is known to be prolifically shed from tumor cells in a soluble form, thus hindering CAR recognition of tumors and migration through the TME. We have developed a next-generation CAR construct exclusively targeting cell-associated CEA, incorporating a PD1-checkpoint inhibitor and a CCR4 chemokine receptor to enhance homing and infiltration of the CAR-NK-92 cell line through the TME, and which does not induce fratricidal killing of CAR-NK-92-cells. To evaluate this therapeutic approach, we harnessed intricate 3D multicellular tumor spheroid models (MCTS), which emulate key elements of the TME. Our results demonstrate the effective cytotoxicity of CEA-CAR-NK-92 cells against CRC in colorectal cell lines and MCTS models. Importantly, minimal off-target activity against non-cancerous cell lines underscores the precision of this therapy. Furthermore, the integration of the CCR4 migration receptor augments homing by recognizing target ligands, CCL17 and CCL22. Notably, our CAR design results in no significant trogocytosis-induced fratricide. In summary, the proposed CEA-targeting CAR-NK cell therapy could offer a promising solution for CRC treatment, combining precision and efficacy in a tailored approach. [ABSTRACT FROM AUTHOR]

Simple Summary: The literature aims to explore anti-androgenic particulars against luminal androgen receptor-specific triple-negative breast cancer, thus providing a concise report on the clinical profile of anti-androgens. This review summarizes the types of triple-negative cancer cells, along with the brief involvement of androgen receptors in the luminal type. The paper intricately describes the evidence obtained from the clinical trials and confers the conclusions, in an attempt to help clinicians set forth the optimal strategies in mitigating LAR-TNBC and creating a steadfast foundation for patient care. Triple-negative tumors are progressively delineating their existence over the extended spectrum of breast cancers, marked by intricate molecular heterogeneity, a low overall survival rate, and an unexplored therapeutic approach. Although the basal subtype transcends the group and contributes approximately 80% to triple-negative breast cancer (TNBC) cases, the exceptionally appearing mesenchymal and luminal androgen receptor (LAR) subtypes portray an unfathomable clinical course. LAR with a distinct generic profile frequently metastasizes to regional lymph nodes and bones. This subtype is minimally affected by chemotherapy and shows the lowest pathologic complete response. The androgen receptor is the only sex steroid receptor that plays a cardinal role in the progression of breast cancers and is typically overexpressed in LAR. The partial AR antagonist bicalutamide and the next-generation AR inhibitor enzalutamide are being assessed in standard protocols for the mitigation of TNBC. There arises an inevitable need to probe into the strategies that could neutralize these androgen receptors and alleviate the trajectory of concerning cancer. This paper thus focuses on reviewing literature that provides insights into the anti-androgenic elements against LAR typical TNBC that could pave the way for clinical advancements in this dynamic sphere of oncology. [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: Natural killer cells are a part of the native immune response to cancer. NK cell-based immunotherapies are an emerging strategy to kill tumor cells. This paper reviews the role of NK cells, their mechanism of action for killing tumor cells, and the receptors which could serve as potential targets for signaling. In this review, the role of nanoparticles in NK cell activation and increased cytotoxicity of NK cells against cancer are highlighted. Natural killer (NK) cells are one of the first lines of defense against infections and malignancies. NK cell-based immunotherapies are emerging as an alternative to T cell-based immunotherapies. Preclinical and clinical studies of NK cell-based immunotherapies have given promising results in the past few decades for hematologic malignancies. Despite these achievements, NK cell-based immunotherapies have limitations, such as limited performance/low therapeutic efficiency in solid tumors, the short lifespan of NK cells, limited specificity of adoptive transfer and genetic modification, NK cell rejection by the patient's immune system, insignificant infiltration of NK cells into the tumor microenvironment (TME), and the expensive nature of the treatment. Nanotechnology could potentially assist with the activation, proliferation, near-real time imaging, and enhancement of NK cell cytotoxic activity by guiding their function, analyzing their performance in near-real time, and improving immunotherapeutic efficiency. This paper reviews the role of NK cells, their mechanism of action in killing tumor cells, and the receptors which could serve as potential targets for signaling. Specifically, we have reviewed five different areas of nanotechnology that could enhance immunotherapy efficiency: nanoparticle-assisted immunomodulation to enhance NK cell activity, nanoparticles enhancing homing of NK cells, nanoparticle delivery of RNAi to enhance NK cell activity, genetic modulation of NK cells based on nanoparticles, and nanoparticle activation of NKG2D, which is the master regulator of all NK cell responses. [ABSTRACT FROM AUTHOR]

Simple Summary: The integrin family of cell surface proteins plays an important role in the development and spread of cancers. Therefore, drugs which inhibit integrins should make effective cancer treatments. Most potential drugs developed so far target a single integrin and have not proved effective at treating cancer in human studies. Our research aims to develop more effective drugs by targeting two related integrins. This paper describes how these potential drug molecules are made, allowing chemists to make better compounds in the future, and describes the anti-integrin effects of the new compounds. Together this information will lead to the future design and development of better anticancer drugs. The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the β3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvβ3 and αIIbβ3 are important anticancer targets, most integrin antagonists developed to target the β3 integrins are highly selective for αvβ3 or αIIbβ3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic β3 integrin antagonist. These new antagonists combine a high activity against αvβ3 with a moderate affinity for αIIbβ3, providing the first evidence for a new approach to integrin targeting in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with multiple myeloma (MM) who become refractory to three or more lines of therapy (RRMM patients) have few valid therapeutic alternatives. Among them, drugs directed against the BCMA antigen expressed in plasma cells are very appealing. Belantamab-mafodotin (belamaf) is the first antibody-drug conjugate against BCMA ready for clinical use. In this paper, we report the Spanish experience of belamaf monotherapy in 156 patients with RRMM. The overall response rate was 41.8%, with 39.8% of patients achieving a partial response or better. Median progression-free survival was 3.61 months, but interestingly, it increased to 14.47 months in patients achieving a minimal response or better. Treatment was well tolerated, ocular events being the most reported toxicity (87.9%; grade ≥ 3, 33.7%), but only two patients discontinued treatment due to side effects. Overall, our results confirm the safety and efficacy of belamaf in this poor prognosis subset of patients. Belantamab-mafodotin (belamaf) is a novel antibody-drug conjugate targeting B-cell maturation antigen that showed anti-myeloma activity in patients with relapsed and refractory multiple myeloma (RRMM). We performed an observational, retrospective, and multicenter study aimed to assess the efficacy and safety of single-agent belamaf in 156 Spanish patients with RRMM. The median number of prior therapy lines was 5 (range, 1–10), and 88% of patients were triple-class refractory. Median follow-up was 10.9 months (range, 1–28.6). The overall response rate was 41.8% (≥CR 13.5%, VGPR 9%, PR 17.3%, MR 2%). The median progression-free survival was 3.61 months (95% CI, 2.1–5.1) and 14.47 months (95% CI, 7.91–21.04) in patients achieving at least MR (p < 0.001). Median overall survival in the entire cohort and in patients with MR or better was 11.05 months (95% CI, 8.7–13.3) and 23.35 (NA-NA) months, respectively (p < 0.001). Corneal events (87.9%; grade ≥ 3, 33.7%) were the most commonly adverse events, while thrombocytopenia and infections occurred in 15.4% and 15% of patients, respectively. Two (1.3%) patients discontinued treatment permanently due to ocular toxicity. Belamaf showed a noticeably anti-myeloma activity in this real-life series of patients, particularly among those achieving MR or better. The safety profile was manageable and consistent with prior studies. [ABSTRACT FROM AUTHOR]

Simple Summary: As a result of FDA approval of CAR-T cell treatments in the last few years, this immunotherapy has provided further direction to precision medicine through its combination with other therapeutic approaches. In the past year, several review articles have been published focusing on advances in this fast-developing field, especially with respect to efforts to overcome hurdles associated with applying CAR-T cells in solid tumors. This review paper focuses on combining CAR-T cell therapy with small molecule drugs, up-to-date progress in CAR-T cell therapy research, and advances in combined CAR-T immunotherapy with other treatments targeting solid tumors. Chimeric antigen receptors (CAR) T cells are T cells engineered to express membrane receptors with high specificity to recognize specific target antigens presented by cancer cells and are co-stimulated with intracellular signals to increase the T cell response. CAR-T cell therapy is emerging as a novel therapeutic approach to improve T cell specificity that will lead to advances in precision medicine. CAR-T cells have had impressive outcomes in hematological malignancies. However, there continue to be significant limitations of these therapeutic responses in targeting solid malignancies such as heterogeneous antigens in solid tumors, tumor immunosuppressive microenvironment, risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. This review paper summarizes recent approaches and innovations through combination therapies of CAR-T cells and other immunotherapy or small molecule drugs to counter the above disadvantages to potentiate the activity of CAR-T cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most prevalent cerebral cancer in adults without proven therapy. Chimeric antigen receptor T cell treatment has demonstrated good clinical success in hematologic cancers. The application of chimeric antigen receptor T cell therapy to solid tumors, such as glioblastoma, is currently the subject of scientific investigation. The creation of chimeric antigen receptor T cells and its iterations are briefly described in this article. Specifically, this study addresses the obstacles and hurdles faced and glioblastoma targets studied in recent years. This review provides the reader with a comprehensive understanding of the current state of chimeric antigen receptor T cell therapy for glioblastoma and a clear understanding of each therapeutic target. Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Although progress has been made in the treatment and survival of patients with a range of malignancies, the prognosis for patients harboring metastatic osteosarcoma (bone cancer) remains dismal due to the limited therapeutic options available. Endothelial progenitor cells (EPCs) mediate the angiogenic (blood vessel formation) switch in several cancers. Spatial proximity between EPCs and osteosarcoma in the bone led to the hypothesis that EPCs-osteosarcoma interactions may possibly promote osteosarcoma (OS) progression and aggressiveness. In the current paper, we demonstrate the non-physical role that EPCs play in OS migration and invasion, along with deciphering a potential underlying molecular mechanism. Our findings may pave the way toward the development of new EPCs-targeted therapies to inhibit OS metastasis and hence enhance the therapeutic efficacy of this devastating bone cancer. Background: Osteosarcoma (OS) mortality is attributed to lung metastases. Endothelial progenitor cells (EPCs) mediate the angiogenic switch in several cancers. The spatial proximity between EPCs and OS in the bone led to the hypothesis that EPCs-osteosarcoma interactions may possibly promote OS progression and aggressiveness. Methods: A PI3K inhibitor, Bevacizumab (an anti-VEGF-A antibody), and an anti-FGF2 antibody were added to the EPCs' conditioned medium (EPC-CM), and their impacts on OS cell (U2-OS and 143B) proliferation, migration, invasion, MMP9 expression, and AKT phosphorylation were determined. The autocrine role of VEGF-A was assessed using Bevacizumab treatment and VEGF-A silencing in OS cells. Toward this end, an orthotopic mouse OS model was established. Mouse and human tumors were immunolabeled with antibodies to the abovementioned factors. Results: EPC-CM enhanced osteosarcoma MMP9 expression, invasiveness, and migration via the PI3K/AKT pathway. The addition of Bevacizumab and an anti-FGF2 antibody to the EPC-CM diminished OS cell migration. The autocrine role of VEGF-A was assessed using Bevacizumab and VEGF-A silencing in OS cells, resulting in decreased AKT phosphorylation and, consequently, diminished invasiveness and migration. Consistently, OS xenografts in mice displayed high VEGF-A and FGF2 levels. Remarkably, lung metastasis specimens derived from OS patients exhibited marked immunolabeling of CD31, VEGF-A, and FGF2. Conclusions: EPCs promote OS progression not only by physically incorporating into blood vessels, but also by secreting cytokines, which act via paracrine signaling. EPCs induced in vitro MMP9 overexpression, invasion, and migration. Additional animal studies are warranted to further expand these results. These findings may pave the way toward the development of novel EPCs-targeted therapeutics aimed at blocking OS metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: For many types of cancer, chemotherapy is still widely used, but it can cause serious side effects because it kills all rapidly growing cells, not just the cancerous ones. In this paper, a nanoparticle-based drug delivery system has been designed to selectively deliver a highly cytotoxic drug to tumor cells. The nanoparticles, obtained from a protein called silk fibroin, have been loaded with a naphthalene diimide derivative, namely NDI-1, which kills cells by affecting their DNA. The surface of the silk fibroin nanoparticles has been decorated with cyclopentapeptides incorporating the Arg-Gly-Asp sequence (cRGDs) to specifically target the tumor cells, thus reducing the harm to healthy cells and minimizing side effects. Developing drug delivery systems to target cytotoxic drugs directly into tumor cells is still a compelling need with regard to reducing side effects and improving the efficacy of cancer chemotherapy. In this work, silk fibroin nanoparticles (SFNs) have been designed to load a previously described cytotoxic compound (NDI-1) that disrupts the cell cycle by specifically interacting with non-canonical secondary structures of DNA. SFNs were then functionalized on their surface with cyclic pentapeptides incorporating the Arg-Gly-Asp sequence (cRGDs) to provide active targeting toward glioma cell lines that abundantly express ανβ3 and ανβ5 integrin receptors. Cytotoxicity and selective targeting were assessed by in vitro tests on human glioma cell lines U373 (highly-expressing integrin subunits) and D384 cell lines (low-expressing integrin subunits in comparison to U373). SFNs were of nanometric size (d50 less than 100 nm), round shaped with a smooth surface, and with a negative surface charge; overall, these characteristics made them very likely to be taken up by cells. The active NDI-1 was loaded into SFNs with high encapsulation efficiency and was not released before the internalization and degradation by cells. Functionalization with cRGDs provided selectivity in cell uptake and thus cytotoxicity, with a significantly higher cytotoxic effect of NDI-1 delivered by cRGD-SFNs on U373 cells than on D384 cells. This manuscript provides an in vitro proof-of-concept of cRGD-silk fibroin nanoparticles' active site-specific targeting of tumors, paving the way for further in vivo efficacy tests. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review paper, we focused on the discussion of various important aspects of hormone receptor (HR)-positive breast cancer, including HR structure and signaling, genetics (epigenetics and gene mutations), gene expression-based assays, traditional and new drugs for treatment, and new technological uses in diagnosis and treatment. Particularly, we summarized the commonly mutated genes and abnormally methylated genes in HR-positive breast cancer and compared the common gene expression-based assays that are used in breast cancer as prognostic and/or predictive tools in detail. All of these topic discussions have not been fully described and summarized within other research or review articles. The current molecular classification divides breast cancer into four major subtypes, including luminal A, luminal B, HER2-positive, and basal-like, based on receptor gene expression profiling. Luminal A and luminal B are hormone receptor (HR, estrogen, and/or progesterone receptor)-positive and are the most common subtypes, accounting for around 50–60% and 15–20% of the total breast cancer cases, respectively. The drug treatment for HR-positive breast cancer includes endocrine therapy, HER2-targeted therapy (depending on the HER2 status), and chemotherapy (depending on the risk of recurrence). In this review, in addition to classification, we focused on discussing the important aspects of HR-positive breast cancer, including HR structure and signaling, genetics, including epigenetics and gene mutations, gene expression-based assays, the traditional and new drugs for treatment, and novel or new uses of technology in diagnosis and treatment. Particularly, we have summarized the commonly mutated genes and abnormally methylated genes in HR-positive breast cancer and compared four common gene expression-based assays that are used in breast cancer as prognostic and/or predictive tools in detail, including their clinical use, the factors being evaluated, patient demographics, and the scoring systems. All these topic discussions have not been fully described and summarized within other research or review articles. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite increasing knowledge of the biological mechanisms leading to neoplastic transformation, the identification of various molecular targets for innovative drugs, refinements in supportive care, and the wider use of allogeneic transplants, the prognosis of acute myeloid leukemia (AML) remains dismal. In the last years, the role of the bone marrow microenvironment and of the immune system in favoring leukemic cell persistence has emerged both as a cause of treatment failure but also as a potential setting for novel therapies. The aim of the present paper is to review the biological evidence and clinical trials of immune-based treatments for AML. It is now well known that the bone marrow (BM) cell niche contributes to leukemogenesis, but emerging data support the role of the complex crosstalk between AML cells and the BM microenvironment to induce a permissive immune setting that protects leukemic stem cells (LSCs) from therapy-induced death, thus favoring disease persistence and eventual relapse. The identification of potential immune targets on AML cells and the modulation of the BM environment could lead to enhanced anti-leukemic effects of drugs, immune system reactivation, and the restoration of AML surveillance. Potential targets and effectors of this immune-based therapy could be monoclonal antibodies directed against LSC antigens such as CD33, CD123, and CLL-1 (either as direct targets or via several bispecific T-cell engagers), immune checkpoint inhibitors acting on different co-inhibitory axes (alone or in combination with conventional AML drugs), and novel cellular therapies such as chimeric antigen receptor (CAR) T-cells designed against AML-specific antigens. Though dozens of clinical trials, mostly in phases I and II, are ongoing worldwide, results have still been negatively affected by difficulties in the identification of the optimal targets on LSCs. [ABSTRACT FROM AUTHOR]

Simple Summary: The aryl hydrocarbon receptor (AhR) is expressed in breast cancer cells and tumors and in some studies, the AhR is a negative prognostic factor for patient survival. Structurally diverse AhR ligands have been extensively investigated as anticancer agents in breast cancer cells and tumors and show efficacy in both estrogen receptor (ER)-positive and ER -negative breast cancer cells. Moreover, synthetic AhR ligands are being developed and have been in clinical trials for treating breast cancer. In contrast, other reports show that AhR ligands enhance mammary carcinogenesis and in a few studies opposite results are observed for the same AhR ligands in comparable breast cancer cells lines. This paper attempts to provide an extensive, unbiased review of the contrasting effects of AhR ligands in breast cancer and points out that future research will be required to resolve these conflicting results. Breast cancer is a complex disease which is defined by numerous cellular and molecular markers that can be used to develop more targeted and successful therapies. The aryl hydrocarbon receptor (AhR) is overexpressed in many breast tumor sub-types, including estrogen receptor -positive (ER+) tumors; however, the prognostic value of the AhR for breast cancer patient survival is not consistent between studies. Moreover, the functional role of the AhR in various breast cancer cell lines is also variable and exhibits both tumor promoter- and tumor suppressor- like activity and the AhR is expressed in both ER-positive and ER-negative cells/tumors. There is strong evidence demonstrating inhibitory AhR-Rα crosstalk where various AhR ligands induce ER degradation. It has also been reported that different structural classes of AhR ligands, including halogenated aromatics, polynuclear aromatics, synthetic drugs and other pharmaceuticals, health promoting phytochemical-derived natural products and endogenous AhR-active compounds inhibit one or more of breast cancer cell proliferation, survival, migration/invasion, and metastasis. AhR–dependent mechanisms for the inhibition of breast cancer by AhR agonists are variable and include the downregulation of multiple genes/gene products such as CXCR4, MMPs, CXCL12, SOX4 and the modulation of microRNA levels. Some AhR ligands, such as aminoflavone, have been investigated in clinical trials for their anticancer activity against breast cancer. In contrast, several publications have reported that AhR agonists and antagonists enhance and inhibit mammary carcinogenesis, respectively, and differences between the anticancer activities of AhR agonists in breast cancer may be due in part to cell context and ligand structure. However, there are reports showing that the same AhR ligand in the same breast cancer cell line gives opposite results. These differences need to be resolved in order to further develop and take advantage of promising agents that inhibit mammary carcinogenesis by targeting the AhR. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is one of the most problematic issues worldwide, as it still requires effective therapy. Unfortunately, clinically available cancer-specific medications result in serious side effects. This is also true for pancreatic cancer which additionally is well-known for difficulties in the treatment. Therefore, the aim of the study was to evaluate the biological activity, in terms of anticancer effects, of ranatensin (RAN), a naturally existing bombesin-like peptide. For the first time, we characterized the peptide as a dopaminergic system ligand. However, despite the presence of dopamine receptors in pancreatic cancer cell lines used, RAN was found to affect cancer cells possibly through different receptors since RAN's impact on pancreatic cancer cells was not correlated with their expression level of DRD2. Nevertheless, this peptide may serve as a potential useful agent with therapeutic efficacy in cancers expressing DRD2 receptors, for which DRD2 antagonism is crucial to produce antitumor effects. Despite the progress in early diagnostic and available treatments, pancreatic cancer remains one of the deadliest cancers. Therefore, there is an urgent need for novel anticancer agents with a good safety profile, particularly in terms of possible side-effects. Recently dopaminergic receptors have been widely studied as they were proven to play an important role in cancer progression. Although various synthetic compounds are known for their interactions with the dopaminergic system, peptides have recently made a great comeback. This is because peptides are relatively safe, easy to correct in terms of the improvement of their physicochemical and biological properties, and easy to predict. This paper aims to evaluate the anticancer activity of a naturally existing peptide—ranatensin, toward three different pancreatic cancer cell lines. Additionally, since there is no sufficient information confirming the exact character of the interaction between ranatensin and dopaminergic receptors, we provide, for the first time, binding properties of the compound to such receptors. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma of the vulva and vagina is a relatively rare neoplasm, unlike melanoma of the skin. Its prognosis is poor, and its pathogenesis is not fully understood. Immunotherapy is one of the rapidly developing cancer treatment methods. In this article, we focus on the pathogenesis of lower genital tract melanomas and related risk factors and compare the effectiveness of two groups of drugs—anti-PD-L1 and anti-CTLA4 antibodies—in the treatment of this condition. This type of immunotherapy is a relatively common treatment method for cutaneous melanoma but not for the rare vulvovaginal melanoma. For vulvovaginal melanoma, the effects of these treatments appear to be limited; however, this requires further research. Cutaneous melanoma is a relatively common neoplasm, with fairly well understood pathogenesis, risk factors, prognosis and therapeutic protocols. The incidence of this disease is increasing every year. The situation is different for rare malignancies such as vulvar melanomas and for the even rarer vaginal melanomas. The risk factors for vulvovaginal tumors are not fully understood. The basis of treatment in both cases is surgical resection; however, other types of treatments such as immunotherapy are available. This paper focuses on comparing the pathogenesis and risk factors associated with these neoplasms as well as the efficacy of two groups of drugs—anti-PD-L1 and anti-CTLA4 inhibitors—against both cutaneous melanoma and melanoma of the lower genital tract (vulva and vagina). In the case of cutaneous melanoma, the situation looks more optimistic than for vulvovaginal melanoma, which has a much worse prognosis and, as it turns out, shows a poorer response to immune therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the most common and lethal malignancy worldwide. Musashi-2 (MSI2) is an RNA-binding protein that is overexpressed in advanced NSCLC. VEGFR2 protein expression contributes to NSCLC progression and several FDA-approved drugs are used to target it in the clinic. Here, we show that MSI2 is a strong positive regulator of VEGFR2 protein levels in murine and human NSCLC cell lines. Furthermore, we found that MSI2 protein directly binds to VEGFR2 and PTEN mRNAs and impacts VEGFR2 downstream signaling, in part via PTEN regulation. Lung cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents most of the diagnoses of lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR2) is a member of the VEGF family of receptor tyrosine kinase proteins, which are expressed on both endothelial and tumor cells, are one of the key proteins contributing to cancer development, and are involved in drug resistance. We previously showed that Musashi-2 (MSI2) RNA-binding protein is associated with NSCLC progression by regulating several signaling pathways relevant to NSCLC. In this study, we performed Reverse Protein Phase Array (RPPA) analysis of murine lung cancer, which suggests that VEGFR2 protein is strongly positively regulated by MSI2. Next, we validated VEGFR2 protein regulation by MSI2 in several human lung adenocarcinoma cell line models. Additionally, we found that MSI2 affected AKT signaling via negative PTEN mRNA translation regulation. In silico prediction analysis suggested that both VEGFR2 and PTEN mRNAs have predicted binding sites for MSI2. We next performed RNA immunoprecipitation coupled with quantitative PCR, which confirmed that MSI2 directly binds to VEGFR2 and PTEN mRNAs, suggesting a direct regulation mechanism. Finally, MSI2 expression positively correlated with VEGFR2 and VEGF-A protein levels in human lung adenocarcinoma samples. We conclude that the MSI2/VEGFR2 axis contributes to lung adenocarcinoma progression and is worth further investigations and therapeutic targeting. [ABSTRACT FROM AUTHOR]

Simple Summary: Roughly 430,000 new cases of renal cell carcinoma (RCC) occurred worldwide in 2022, and about one-third of RCC cases are diagnosed at an advanced stage of disease (aRCC). When patients with aRCC fail first-line treatment, they commonly receive one of the recommended second-line treatments, i.e., axitinib, cabozantinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib. Axitinib is a second-generation tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor tyrosine kinases 1, 2, and 3. It has been available since 2011 for the treatment of aRCC after the failure of prior therapy with sunitinib or cytokines. The aim of our research was to understand how axitinib compares with other treatment options considering data from clinical trials and observational studies that reflect real-world clinical practice. Therefore, we conducted a systematic literature review to summarise evidence on commonly used and recommended treatments in aRCC after the failure of prior therapy with sunitinib or cytokines. Background: We conducted a systematic literature review (SLR) to identify clinical evidence on treatments in advanced renal cell carcinoma (aRCC) after the failure of prior therapy with cytokines, tyrosine kinase inhibitors, or immune checkpoint inhibitors. Herein, we summarise the evidence for axitinib in aRCC after the failure of prior therapy with cytokines or sunitinib. Methods: This SLR was registered with PROSPERO (CRD42023492931) and followed the 2020 PRISMA statement and the Cochrane guidelines. Comprehensive searches were conducted in MEDLINE and Embase as well as for conference proceedings. Study eligibility was defined according to population, intervention, comparator, outcome, and study design. Results: Of 1252 titles/abstracts screened, 266 peer-reviewed publications were reviewed, of which 182 were included. In addition, 28 conference abstracts were eligible. Data on axitinib were reported in 55 publications, of which 16 provided efficacy and/or safety outcomes on axitinib after therapy with sunitinib or cytokines. In these patients, median progression-free and overall survival ranged between 5.5 and 8.7 months and 11.0 and 69.5 months, respectively. Conclusions: Axitinib is commonly used in clinical practice and has a well-characterised safety and efficacy profile in the treatment of patients with aRCC after the failure of prior therapy with sunitinib or cytokines. [ABSTRACT FROM AUTHOR]

Simple Summary: Sufferers of neuroendocrine neoplasms (NENs) of unknown primary origin are a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, treatment should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. The aim of this review is to explore the evidence relating to available treatment options for NENs of unknown primary and to offer insights into future perspectives. Particular attention is given to molecular characterization and genomic profiling of NENs with potential therapeutic implications, mainly through the identification of druggable targets for agnostic treatments. Moreover, a treatment algorithm for both well-differentiated and poorly differentiated NENs of unknown primary is proposed. Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Folate receptors can serve to increase folate uptake in cancer cells through significant overexpression, which is ultimately critical for cell proliferation and tumor growth. Therefore, the characterization of folate receptor expression in cancer presents exciting opportunities in multiple dimensions. On the one hand, the folate receptor can be used as a target for selective transfer of therapeutic agents. On the other hand, it can be used for risk stratification. We found that in prostate cancer (PCa), activation and membrane integration by GPI–transamidase exhibit significant changes. By image analysis, we could demonstrate these differences to healthy control cells and tissues, and we expect high potential in this approach to identify biological subtypes and allow risk stratification based on these alterations in PCa. Due to the proliferation-induced high demand of cancer cells for folic acid (FA), significant overexpression of folate receptors 1 (FR1) is detected in most cancers. To our knowledge, a detailed characterization of FR1 expression and regulation regarding therapeutic and diagnostic feasibilities in prostate cancer (PCa) has not been described. In the present study, cell cultures, as well as tissue sections, were analyzed using Western blot, qRT-PCR and immunofluorescence. In addition, we utilized FA-functionalized lipoplexes to characterize the potential of FR1-targeted delivery into PCa cells. Interestingly, we detected a high level of FR1-mRNA in healthy prostate epithelial cells and healthy prostate tissue. However, we were able to show that PCa cells in vitro and PCa tissue showed a massively enhanced FR1 membrane localization where the receptor can finally gain its function. We were able to link these changes to the overexpression of GPI–transamidase (GPI-T) by image analysis. PCa cells in vitro and PCa tissue show the strongest overexpression of GPI-T and thereby induce FR1 membrane localization. Finally, we utilized FA-functionalized lipoplexes to selectively transfer pDNA into PCa cells and demonstrate the therapeutic potential of FR1. Thus, FR1 represents a very promising candidate for targeted therapeutic transfer pathways in PCa and in combination with GPI-T, may provide predictive imaging in addition to established diagnostics. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer has remained the leading cause of death among gynecologic malignancies. The current standard of treatment, in most cases, is a combination of surgery and chemotherapy, based on platinum agents and taxanes. Despite the increasing usage of newer drug groups, such as bevacizumab and PARP inhibitors, and the expansion of patient groups for these drugs, ovarian cancer is characterized by recurrences, particularly in the form of peritoneal implants. This review focuses on immunotherapy for ovarian cancer. It considers the current state of knowledge in areas such as cancer vaccines, adoptive cell therapy, CAR-T therapy, and anti-CTLA-4 monotherapy. The paper specifically considers PD-1/PDL-1 as drug targets. Anti-PD-1/PD-L1 monotherapy, and anti-PD-1/PD-L1 immunotherapy in combination with other agents, are analyzed. Ovarian cancer is one of the most fatal cancers in women worldwide. Cytoreductive surgery combined with platinum-based chemotherapy has been the current first-line treatment standard. Nevertheless, ovarian cancer appears to have a high recurrence rate and mortality. Immunological processes play a significant role in tumorigenesis. The production of ligands for checkpoint receptors can be a very effective, and undesirable, immunosuppressive mechanism for cancers. The CTLA-4 protein, as well as the PD-1 receptor and its PD-L1 ligand, are among the better-known components of the control points. The aim of this paper was to review current research on immunotherapy in the treatment of ovarian cancer. The authors specifically considered immune checkpoints molecules such as PD-1/PDL-1 as targets for immunotherapy. We found that immune checkpoint-inhibitor therapy does not have an improved prognosis in ovarian cancer; although early trials showed that a combination of anti-PD-1/PD-L1 therapy with targeted therapy might have the potential to improve responses and outcomes in selected patients. However, we must wait for the final results of the trials. It seems important to identify a group of patients who could benefit significantly from treatment with immune checkpoints inhibitors. However, despite numerous trials, ICIs have not become part of routine clinical practice for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the advancement of molecular biology and Next-Generation Sequencing (NGS), the study of the tumor microenvironment continues to have paradigmatic importance in research applied to malignant melanoma, and neoangiogenesis continues to exert a significant influence. In this review, we discuss the most updated knowledge about neoangiogenesis in melanoma, address the role of the TME in progression, and outline future therapeutic perspectives. Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone cancer-related chronic pain is mediated by central sensitization involving neuroinflammation via glial cell activation in the spinal dorsal horn, but not the capsaicin-sensitive sensory neuronal system. Bone cancer and its related chronic pain are huge clinical problems since the available drugs are often ineffective or cannot be used long term due to a broad range of side effects. The mechanisms, mediators and targets need to be identified to determine potential novel therapies. Here, we characterize a mouse bone cancer model induced by intratibial injection of K7M2 osteosarcoma cells using an integrative approach and investigate the role of capsaicin-sensitive peptidergic sensory nerves. The mechanical pain threshold was assessed by dynamic plantar aesthesiometry, limb loading by dynamic weight bearing, spontaneous pain-related behaviors via observation, knee diameter with a digital caliper, and structural changes by micro-CT and glia cell activation by immunohistochemistry in BALB/c mice of both sexes. Capsaicin-sensitive peptidergic sensory neurons were defunctionalized by systemic pretreatment with a high dose of the transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX). During the 14- and 28-day experiments, weight bearing on the affected limb and the paw mechanonociceptive thresholds significantly decreased, demonstrating secondary mechanical hyperalgesia. Signs of spontaneous pain and osteoplastic bone remodeling were detected both in male and female mice without any sex differences. Microglia activation was shown by the increased ionized calcium-binding adapter molecule 1 (Iba1) immunopositivity on day 14 and astrocyte activation by the enhanced glial fibrillary acidic protein (GFAP)-positive cell density on day 28 in the ipsilateral spinal dorsal horn. Interestingly, defunctionalization of the capsaicin-sensitive afferents representing approximately 2/3 of the nociceptive fibers did not alter any functional parameters. Here, we provide the first complex functional and morphological characterization of the K7M2 mouse osteosarcoma model. Bone-cancer-related chronic pain and hyperalgesia are likely to be mediated by central sensitization involving neuroinflammation via glial cell activation in the spinal dorsal horn, but not the capsaicin-sensitive sensory neuronal system. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript systematically reviews the role of positron emission tomography (PET) in the assessment of toxicity associated with chimeric antigen receptor T-cell therapy (CAR T-cell therapy). CAR T-cell therapy, a revolutionary form of immunotherapy, activates immune mechanisms against malignant cells. By doing so, it can also provoke immune-mediated responses against healthy tissues. These responses exhibit diverse clinical, radiological, and functional manifestations across multiple physiological systems. Adverse events include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Both can cause life-threatening complications. Given the critical imperative of timely identification and vigilant monitoring of these adverse events to enable targeted interventions, PET has emerged as an indispensable imaging biomarker facilitating their detection, prediction, and surveillance. Hence, our investigation is specifically tailored to examine the utility of PET in evaluating adverse events induced by CAR T-cell therapy. The utilization of chimeric antigen receptor (CAR) T-cell therapy to target cluster of differentiation (CD)19 in cancer immunotherapy has been a recent and significant advancement. Although this approach is highly specific and selective, it is not without complications. Therefore, a systematic review was conducted to assess the current state of positron emission tomography (PET) in evaluating the adverse effects induced by CAR T-cell therapy. A thorough search of relevant articles was performed in databases such as PubMed, Scopus, and Web of Science up until March 2024. Two reviewers independently selected articles and extracted data, which was then organized and categorized using Microsoft Excel. The risk of bias and methodological quality was assessed. In total, 18 articles were examined, involving a total of 753 patients, in this study. A wide range of utilities were analyzed, including predictive, correlative, and diagnostic utilities. While positive outcomes were observed in all the mentioned areas, quantitative analysis of the included studies was hindered by their heterogeneity and use of varying PET-derived parameters. This study offers a pioneering exploration of this promising field, with the goal of encouraging further and more focused research in upcoming clinical trials. [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: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers. It is considered one of the deadliest cancers due to its high metastatic potential and drug resistance. This review discusses various targets and nanoparticle-based delivery systems developed, tested, and approved for the effective diagnosis and targeted treatment of PDAC. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics. [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer, including head and neck cancer (HNC), certain key players in the body's inflammatory process, such as the interleukin (IL)-6 and IL-1 systems, are associated with outcomes. We studied some of these key players in a subgroup of HNC patients. From one blood sample measured at diagnosis, we determined high levels of molecules from members of the IL-6 and IL-1 families with their associated soluble cytokine receptors. High values indicated a lower survival rate. This prediction was to some extent better than the standard clinical predictors used. The results highlight potential new targets for immune treatment development. Additionally, these findings could contribute to the refinement of cancer treatment strategies, particularly in the context of emerging immune therapies. Activation of the acute-phase cascade (APC) has been correlated with outcomes in various cancers, including head and neck squamous cell carcinoma (HNSCC). Primary drivers of the APC are the cytokines within the interleukin-6 (IL-6) and IL-1 families. Plasma levels of IL-6 family cytokines/soluble receptors (IL-6, IL-27, IL-31, OSM, CNTF, soluble (s-)gp130, s-IL-6Rα) and IL-1 family members (IL-1RA, s-IL-33Rα) were determined at diagnosis for 87 human papillomavirus (HPV)-negative (−) HNSCC patients. We then studied the 5-year Disease-Specific Survival (DSS) and Overall Survival (OS). Increased plasma levels of IL-6 (p < 0.001/p < 0.001) (DSS/OS), IL-31 (p = 0.044/p = 0.07), IL-1RA (p = 0.004/p = 0.035), soluble (s)-IL-6Rα p = 0.022/p = 0.035), and s-gp130 (p = 0.007/p = 0.003) at diagnosis were predictors of both OS and DSS from HPV(−) HNSCC patients. The cytokine DSS/OS predictions were associated with TNM stage and smoking history, whereas the soluble receptors IL-6Rα, gp130, and IL33Rα more uniquely predicted DSS/OS. Clinically, IL-6 levels above 2.5 pg/mL yielded 75% specificity and 70% sensitivity for DSS. In conclusion, high plasma levels of IL-6, IL-31, and IL-1RA, as well as the soluble receptors IL-6Rα, gp130, and IL33Rα, predicted clinical outcome. This shows their potential as candidates for both general therapy and immune therapy stratification, as well as being future platforms for the development of new immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is common, affecting over 400,000 patients globally each year. In limited stage disease and where surgery is a feasible therapeutic option, event free survival rates are high. In contrast, locally advanced disease is associated with frequent relapse, and up to 30% of patients present with metastatic disease. Standard of care treatments for metastatic disease include tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), but clinical responses are variable and generally not durable. Novel cell-based immunotherapy approaches such as Chimeric Antigen Receptor T-cells (CAR-T) and T-cell receptor engineered T-cells (TCR-T) have shown efficacy in some blood cancers and are currently under evaluation in solid tumours including RCC. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies and outline how advanced engineering solutions may further enhance this therapeutic approach. Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space. [ABSTRACT FROM AUTHOR]

Simple Summary: Gliomas develop in the central nervous system from the glial cells that support it. Low-grade gliomas (LGGs) are characterized by a reduced number of immune cells infiltrating the tumor, requiring immune-boosting therapies to release the immunosuppressive environment of the tumor. We conducted a bioinformatics-led study to evaluate the prognostic impact of cell surface receptor markers for tumor-associated macrophages (TAMs) that produce transforming growth factor beta (TGFB) ligands and interferon-gamma receptor activation to maintain the tumor microenvironment in an immunosuppressed state. Detailed investigation of messenger RNA levels and their impact on OS in LGG patients demonstrated that low mRNA levels of a specific TGFB ligand, TGFB2, and the receptor along with the signaling molecules from interferon-gamma receptor activation (IFNGR2, IRF1, IRF5, and STAT1) result in improved survival of LGG patients. LGG patients expressing high levels of TGFB2 and IFNGR2 are over-represented in IDH wild-type tumor samples, suggesting that TGFB2 and IFNGR2 mRNA can be therapeutically targeted in these high-risk patients. Furthermore, demethylation of TFGB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 genes also results in worse survival outcomes, pointing to a molecular mechanism that increases the negative prognostic effects of increased mRNA levels of these target genes. We observed that significant upregulation of mRNA expression levels for three TAM markers, MSR1/CD204, CD86, and CD68, suggested that TGFB2 is pivotal in establishing a pro-tumorigenic TME in gliomas mediated through TAMs. Interestingly, a tumor-associated antigen CD276/B7-H3 mRNA expression increased in tumor tissue, giving further insights into the roles of macrophages and tumor cells in the immunosuppressive TME. Therefore, to improve OS in LGG patients, combination therapies must target TGFB2 and IFN-γ activation (via IRF5 inhibition) or immune therapies targeted against CD276/B7-H3. LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p < 0.0001), 8.9-fold (p < 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase, p < 0.0001) and TGFB2 (2.2-fold increase, p < 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p < 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2high HR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation in TGFB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes. [ABSTRACT FROM AUTHOR]

Simple Summary: In the past decades, the survival of ovarian malignant tumors has been largely unchanged. Treatment usually consists of a combination of systemic and surgical therapy. However, when recurrence occurs, treatment options are limited. When repeated surgery is no longer possible and chemotherapy is no longer effective, theranostics, a newly developing approach, might be of value. Theranostics will diagnose and destroy malignant tissue by binding radioactive isotopes to targets on malignant cells. To develop this approach, selection and validation of a target is necessary. For the selection of a target in ovarian tumors, the follicle-stimulating hormone (FSH) receptor appears to be suitable because it is primarily expressed in ovarian tissue, and expression is reported in malignant tumors. This review seeks to determine whether the follicle-stimulating hormone receptor is expressed in ovarian tumor types and, therefore, is suitable as a target in a future theranostic approach. Ovarian cancer mortality rates have not decreased significantly in the past years. As most women are still diagnosed in an advanced stage, there is a need for new treatment strategies for recurrent disease. A potentially new developing targeted approach, theranostics, combines diagnostics and treatment using radiopharmaceuticals. Through target receptors, imaging and treatment of malignant tissue can be achieved. For ovarian malignancy, the follicle-stimulating hormone (FSH) receptor may serve as a possible target since expression appears to be limited to ovarian cells. In this systematic review, we aim to gather all available literature on the expression of the FSH receptor in ovarian tumors. Pubmed, Embase and the Cochrane databases were searched until December 2023 for eligible studies. The search yielded 41 studies, mostly regarding serous carcinomas, sex cord–stromal tumors (SCSTs) and cell lines of serous and SCSTs. Various techniques were used to analyze the expression of the FSH receptor. For serous carcinomas, conflicting results on the expression of the FSH receptor were found. Studies on SCSTs, mainly studying the subtype of granulosa cell tumors, all showed positive expression of the FSH receptor. In the cell lines studies, the KGN cell line derived from a granulosa cell tumor shows positive expression in all studies. Available studies show that SCSTs express the FSH receptor. A theranostic approach targeting the FSH receptor may, therefore, provide a useful new approach for this malignancy with limited therapeutic options in recurrent disease. [ABSTRACT FROM AUTHOR]

Simple Summary: All patients suspected of having head and neck paragangliomas (HNPGLs) undergo magnetic resonance imaging (MRI) or computed tomography (CT) of the head and neck area as the standard imaging according to the Dutch guidelines. However, a relatively new imaging modality, [68Ga]Ga-DOTATOC PET/CT, has shown promising results in the detection of HNPGLs. In this pilot study, we aimed to compare the results of this new modality with the standard imaging. We compared both techniques in 25 patients at the University Medical Center Utrecht, The Netherlands. Twenty-eight percent of the patients had different outcomes between both modalities. In all cases, additional HNPGLs were identified using the [68Ga]Ga-DOTATOC PET/CT, suggesting the need for further prospective research to validate this finding. If confirmed, this modality could potentially be implemented as the standard of care for HNPGL detection in germline variant carriers. The Dutch guideline for patients suspected of head and neck paragangliomas (HNPGLs) recommends magnetic resonance imaging (MRI) and/or computed tomography (CT) of the head and neck area. Additionally, it suggests considering additional nuclear imaging. The aim of this study was to evaluate the outcomes of [68Ga]Ga-DOTATOC PET/CT compared to MRI in patients with suspected HNPGLs and carriers of genetic variations. Methods: In this single-center pilot study, retrospective data were obtained from consecutive patients between 2016 and 2023. Both MRI and [68Ga]Ga-DOTATOC PET/CT were performed within 12 months. The primary outcome was the location of HNPGLs. Results: A total of 25 consecutive patients were included, and 7 patients (28.0%, p = 0.5) showed differences between the imaging modalities, of whom 5 patients had unexpected localizations with additional uptake by somatostatin receptors (SSTR) on the [68Ga]Ga-DOTATOC PET/CT. Conclusions: The authors recommend performing baseline imaging with [68Ga]Ga-DOTATOC PET/CT (if available) in variant carriers and using MRI/CT for follow-up according to the regional protocol, thereby shifting the gold standard for baseline imaging from MRI/CT to [68Ga]Ga-DOTATOC PET/CT. [ABSTRACT FROM AUTHOR]

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. [ABSTRACT FROM AUTHOR]

The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Malignant meningiomas have high aggressiveness and recurrence rates and a poor prognosis, with no clear pharmacological treatment available. The study aims to investigate the progression mechanism of malignant meningiomas and the targets of intervention. RACK1 and CSNK2B have been shown to promote tumor progression but their roles in meningiomas are not clear. In this study, we will investigate the roles of RACK1-CSNK2B in meningiomas and search for targets to inhibit the progression of meningiomas. Higher-grade meningiomas (WHO grade II and III) are characterized by aggressive invasiveness and high postoperative recurrence rates. The prognosis remains inadequate even with adjuvant radiotherapy and currently there is no definitive pharmacological treatment strategy and target for malignant meningiomas. This study aims to unveil the mechanisms driving the malignant progression of meningiomas and to identify potential inhibitory targets, with significant clinical implications. Implementing techniques such as protein immunoprecipitation, mass spectrometry, RNA interference, and transcriptome sequencing, we investigated the malignancy mechanisms in meningioma cell lines IOMM-LEE and CH157-MN. Additionally, in vivo experiments were carried out on nude mice. We discovered a positive correlation between meningioma malignancy and the levels of the receptor for activated C kinase 1 (RACK1), which interacts with CSNK2B, the β subunit of casein kinase 2 (CK2), inhibiting its ubiquitination and subsequent degradation. This inhibition allows CK2 to activate the NF-κb pathway, which increases the transcription of CDK4 and cyclin D3, resulting in the transition of the cell cycle into the G2/M phase. The RACK1 inhibitor, harringtonolide (HA), significantly suppressed the malignant tendencies of meningioma cells. Our study suggests that RACK1 may play a role in the malignant progression of meningiomas, and therefore, targeting RACK1 could emerge as an effective strategy for reducing the malignancy of these tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: High-grade gliomas (HGG), both in children and adults, are rare tumors. However, due to the dismal prognosis, they constitute a significant clinical problem. Standard treatment methods (possibly complete tumor resection, radiotherapy, chemotherapy) are not optimal and it is, therefore, necessary to search for new therapeutic methods that can increase the survival rate. One possibility is the use of immune cells expressing a chimeric antigen receptor (CAR). In the following work, we present the latest results of preclinical and clinical studies evaluating the effectiveness of CAR-expressing cells in HGG therapy. Despite promising results of preclinical studies, most of the patients described in the clinical trials who received the CAR-expressing cell died of cancer. However, the transient efficacy of CAR-expressing cells was also observed, resulting in the reduction of tumor mass and prolongation of survival compared to the median survival time of HGG patients treated in a standard way. High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20–30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Protein Tyrosine Phosphatase Receptor Type D (PTPRD) plays a role in cell proliferation, differentiation, oncogenic transformation, and brain development and serves as an orexigenic asprosin receptor. This study investigates the expression of PTPRD in endometrial cancer (EC) and the placenta, as well as in glioblastoma (GBM). PTPRD is significantly upregulated at the mRNA and protein levels in patients with EC and GBM compared to healthy controls. In patients with EC, PTPRD is significantly downregulated by obesity. Using a tissue microarray, abundant PTPRD expression in low- and high-grade EC tumours is noted. Using liquid biopsies from EC patients, we show the expression of PTPRD in peripheral leukocytes. Moreover, asprosin treatment upregulates the expression of PTPRD in syncytialised placental cells in vitro, but not in EC cell lines. Collectively, our data suggest that PTPRD may have potential as a biomarker for malignancies such as EC and GBM, further implicating asprosin as a potential metabolic regulator in these cancers. Background: Protein Tyrosine Phosphatase Receptor Type D (PTPRD) is involved in the regulation of cell growth, differentiation, and oncogenic transformation, as well as in brain development. PTPRD also mediates the effects of asprosin, which is a glucogenic hormone/adipokine derived following the cleavage of the C-terminal of fibrillin 1. Since the asprosin circulating levels are elevated in certain cancers, research is now focused on the potential role of this adipokine and its receptors in cancer. As such, in this study, we investigated the expression of PTPRD in endometrial cancer (EC) and the placenta, as well as in glioblastoma (GBM). Methods: An array of in silico tools, in vitro models, tissue microarrays (TMAs), and liquid biopsies were employed to determine the gene and protein expression of PTPRD in healthy tissues/organs and in patients with EC and GBM. Results: PTPRD exhibits high expression in the occipital lobe, parietal lobe, globus pallidus, ventral thalamus, and white matter, whereas in the human placenta, it is primarily localised around the tertiary villi. PTPRD is significantly upregulated at the mRNA and protein levels in patients with EC and GBM compared to healthy controls. In patients with EC, PTPRD is significantly downregulated with obesity, whilst it is also expressed in the peripheral leukocytes. The EC TMAs revealed abundant PTPRD expression in both low- and high-grade tumours. Asprosin treatment upregulated the expression of PTPRD only in syncytialised placental cells. Conclusions: Our data indicate that PTPRD may have potential as a biomarker for malignancies such as EC and GBM, further implicating asprosin as a potential metabolic regulator in these cancers. Future studies are needed to explore the potential molecular mechanisms/signalling pathways that link PTPRD and asprosin in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptors (CARs) are used to recognize highly specific antigens ("mugshots") to target immune effectors ("policemen") against cancer cells. Whereas this new immunotherapy has already set novel standards in the treatment of some specific types of blood cancer, it has not yet been successful with most blood (and solid) cancers for different reasons. In this work, the authors investigated the possibility of using a specific antigen called CD45 as target for CAR therapies. CD45 stands out by being present on all blood cells and therefore represents a promising target in any type of blood cancer. However, immune cells themselves also harbor CD45 at their cell surface, which is expected to lead to either inactivity of the CAR or self-killing of immune cells. To avoid these problems the Hamburg group used a trick—they applied the CRISPR/Cas gene scissors and thus produced CD45-knockout (CD45ko) immune-effector cells. Even though CD45 had been supposed to be important for the functionality of immune-effector cells, the authors observed excellent survival, proliferation and killing activities of their CD45ko CAR cells, independent of the targeted cancer-cell population. Their results thus provide initial proof-of-concept for the potential usefulness of CD45ko/CD45-CAR immune cells to target blood cancer. Background: CAR-T cell therapy has shown impressive results and is now part of standard-of-care treatment of B-lineage malignancies, whereas the treatment of myeloid diseases has been limited by the lack of suitable targets. CD45 is expressed on almost all types of blood cells including myeloid leukemia cells, but not on non-hematopoietic tissue, making it a potential target for CAR-directed therapy. Because of its high expression on T and NK cells, fratricide is expected to hinder CD45CAR-mediated therapy. Due to its important roles in effector cell activation, signal transduction and cytotoxicity, CD45 knockout aimed at preventing fratricide in T and NK cells has been expected to lead to considerable functional impairment. Methods: CD45 knockout was established on T and NK cell lines using CRISPR/Cas9-RNPs and electroporation, and the successful protocol was transferred to primary T cells. A combined protocol was developed enabling CD45 knockout and retroviral transduction with a third-generation CAR targeting CD45 or CD19. The functionality of CD45ko effector cells, CD45ko/CD45CAR-T and CD45ko/CD19CAR-T cells was studied using proliferation as well as short- and long-term cytotoxicity assays. Results: As expected, the introduction of a CD45-CAR into T cells resulted in potent fratricide that can be avoided by CD45 knockout. Unexpectedly, the latter had no negative impact on T- and NK-cell proliferation in vitro. Moreover, CD45ko/CD45CAR-T cells showed potent cytotoxicity against CD45-expressing AML and lymphoma cell lines in short-term and long-term co-culture assays. A pronounced cytotoxicity of CD45ko/CD45CAR-T cells was maintained even after four weeks of culture. In a further setup, we confirmed the conserved functionality of CD45ko cells using a CD19-CAR. Again, the proliferation and cytotoxicity of CD45ko/CD19CAR-T cells showed no differences from those of their CD45-positive counterparts in vitro. Conclusions: We report the efficient production of highly and durably active CD45ko/CAR-T cells. CD45 knockout did not impair the functionality of CAR-T cells in vitro, irrespective of the target antigen. If their activity can be confirmed in vivo, CD45ko/CD45CAR-T cells might, for example, be useful as part of conditioning regimens prior to stem cell transplantation. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer stands as the predominant form of cancer identified in women, underscoring the urgent demand for innovative targeted therapies. Engineered adoptive cell therapies represent a groundbreaking approach, empowering the immune cells of patients to precisely target their tumors through cancer-specific receptors. Encouragingly, preclinical studies have illuminated the immense promise of this strategy. Nonetheless, the translation of this technique into clinical practice hinges on the accumulation of additional robust clinical data. Within this review, we offer a comprehensive examination of the current landscape surrounding engineered cell therapies for breast cancer, delving into both their limitations and the compelling prospects for enhancement. Breast cancer remains a significant health challenge, and novel treatment approaches are critically needed. This review presents an in-depth analysis of engineered adoptive T-cell therapies (E-ACTs), an innovative frontier in cancer immunotherapy, focusing on their application in breast cancer. We explore the evolving landscape of chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies, highlighting their potential and challenges in targeting breast cancer. The review addresses key obstacles such as target antigen selection, the complex breast cancer tumor microenvironment, and the persistence of engineered T-cells. We discuss the advances in overcoming these barriers, including strategies to enhance T-cell efficacy. Finally, our comprehensive analysis of the current clinical trials in this area provides insights into the future possibilities and directions of E-ACTs in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Compared to the resounding success demonstrated in the field of B-cell leukemia, lymphoma, and multiple myeloma, in the field of acute myeloid leukemia, CAR-T-cell-therapy slows down its application in clinical practice. Yet, immunotherapy and/or cell therapy could be curative in certain high-risk AML subtypes refractory to classical chemotherapy approaches. Several CAR-T constructs targeting different antigens have been tested and have shown promising results. This review illustrates the main results obtained with the use of CAR-T in AML. Chimeric antigen receptors (CAR)-T-cell therapy represents the most important innovation in onco-hematology in recent years. The progress achieved in the management of complications and the latest generations of CAR-T-cells have made it possible to anticipate in second-line the indication of this type of treatment in large B-cell lymphoma. While some types of B-cell lymphomas and B-cell acute lymphoid leukemia have shown extremely promising results, the same cannot be said for myeloid leukemias—in particular, acute myeloid leukemia (AML), which would require innovative therapies more than any other blood disease. The heterogeneities of AML cells and the immunological complexity of the interactions between the bone marrow microenvironment and leukemia cells have been found to be major obstacles to the clinical development of CAR-T in AML. In this review, we report on the main results obtained in AML clinical trials, the preclinical studies testing potential CAR-T constructs, and future perspectives. [ABSTRACT FROM AUTHOR]

Simple Summary: Growing evidence shows that the dynamic interactions between tumor-associated macrophages and lactate play an important role in sustaining a tumor niche; however, the relationship between lactate and tumor-associated macrophages in colorectal cancer has not been fully studied. In this study, we found that lactate produced by CRC could induce M2 polarization by activating the AKT-ERK pathway. After polarization, M2 macrophages secreted abundant CCL8 and accelerated tumor progression and metastasis through the CCR5/mTORC1 pathway. This mutual interaction between macrophages and tumor cells may be central to formulate the inhibitory niche of TME and maintain the malignancy of a tumor. Targeting the CCL8/CCR5/mTORC1 pathway is a promising target for future tumor treatment. Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment. Lactic acid (LA) has been identified as an influential factor in promoting immune escape and tumor progression. However, the mechanisms through which LA modulates TAMs in colorectal cancer (CRC) remain poorly understood. We used qRT-PCR to quantify the expression of LA-related genes (LDHA and LAMP2) in CRC tumor tissues and adjacent nontumor tissues (n = 64). The biological effects and mechanisms of LA on macrophages and tumors were evaluated via qRT-PCR, Western blot, RNA-seq, wound healing assay, colony formation assay in vitro, and allograft mouse tumor models in vivo. We found the expression of LDHA and LAMP2 was highly elevated in the tumor regions and positively associated with a poor clinical stage of CRC. A high concentration of LA was generated under hypoxia; it could promote tumor progression and metastasis with the involvement of macrophages. The inhibition of LA release impaired this protumor phenomenon. Mechanically, LA induced M2 macrophages through the AKT/ERK signaling pathway; subsequently, M2 macrophages secreted CCL8 and facilitated the proliferation and metastasis of CRC cells by activating the CCL8/CCR5/mTORC1 axis. This effect was inhibited by the antagonist or knockdown of CCR5. In conclusion, lactate-induced CCL8 in TAMs accelerated CRC proliferation and metastasis through the CCL8/CCR5/mTORC1 axis. [ABSTRACT FROM AUTHOR]

Simple Summary: Based on the miRNA expression signature of LUAD, we focused on miR-139-3p, a passenger strand, and clarified its tumor-suppressive function in lung adenocarcinoma (LUAD) cells. A total of the 21 target genes (KRT80, CENPM, SPC24, ORC1, MYEOV, TRIP13, GPX8, ARHGEF39, MKI67, KIF18B, CHAF1B, CP, GPRIN1, UCK2, CHEK1, HELLS, CTSV, FAM111B, SLC16A3, MELK, and CENPF) were identified as miR-139-3p targets in LUAD, and the expression of these genes was as independent prognostic factor for patient survival. Moreover, inhibition of TRIP13 using a specific inhibitor (DCZ0415) enhanced the sensitivity of LUAD cells to anticancer drugs. Analyses of our microRNA (miRNA) expression signature combined with The Cancer Genome Atlas (TCGA) data revealed that both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) are significantly downregulated in lung adenocarcinoma (LUAD) clinical specimens. Functional analyses of LUAD cells ectopically expressing miR-139-3p showed significant suppression of their aggressiveness (e.g., cancer cell proliferation, migration, and invasion). The involvement of the passenger strand, miR-139-3p, in LUAD pathogenesis, is an interesting finding contributing to the elucidation of unknown molecular networks in LUAD. Of 1108 genes identified as miR-139-3p targets in LUAD cells, 21 were significantly upregulated in LUAD tissues according to TCGA analysis, and their high expression negatively affected the prognosis of LUAD patients. We focused on thyroid hormone receptor interactor 13 (TRIP13) and investigated its cancer-promoting functions in LUAD cells. Luciferase assays showed that miR-139-3p directly regulated TRIP13. siRNA-mediated TRIP13 knockdown and TRIP13 inhibition by a specific inhibitor (DCZ0415) attenuated the malignant transformation of LUAD cells. Interestingly, when used in combination with anticancer drugs (cisplatin and carboplatin), DCZ0415 exerted synergistic effects on cell proliferation suppression. Identifying the molecular pathways regulated by tumor-suppressive miRNAs (including passenger strands) may aid in the discovery of diagnostic markers and therapeutic targets for LUAD. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastomas are the most common primary brain tumors in adults. They harbor a dismal prognosis and intrinsic resistance to treatment. Nonetheless, around 5% of glioblastomas present a unique genetic alteration, the FGFR3-TACC3 gene fusion, that drives tumor transformation and could represent a therapeutic opportunity. In this review, we discuss the state-of-the-art knowledge regarding glioblastomas with FGFR3-TACC3 gene fusions. We present their unique features and the methods for their identification. Targeted therapies aimed at inhibiting the protein resulting from the gene fusion have been developed with moderate clinical efficacy. An integrated effort is ongoing to improve the treatment results for these patients. In 2012, whole-transcriptome sequencing analysis led to the discovery of recurrent fusions involving the FGFR3 and TACC3 genes as the main oncological driver in a subset of human glioblastomas. Since then, FGFR3-TACC3 fusions have been identified in several other solid cancers. Further studies dissected the oncogenic mechanisms of the fusion protein and its complex interplay with cancer cell metabolism. FGFR3-TACC3 fusion-driven gliomas emerged as a defined subgroup with specific clinical, histological, and molecular features. Several FGFR inhibitors were tested in FGFR3-TACC3 fusion-positive gliomas and proved some efficacy, although inferior to the results seen in other FGFR3-TACC3 fusion-driven cancers. In this review, we summarize and discuss the state-of-the-art knowledge resulting from a 10-year research effort in the field, its clinical implications for glioma patients, the potential reasons for targeted therapy failures, and the perspective of emerging treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: The specific mechanisms by which tumors acquire resistance to chimeric antigen receptor (CAR) T cell therapy are not completely understood. The aim of this study was to elucidate the complex interactions between tumor cells and CAR T cells targeting epithelial cell adhesion molecule (EpCAM) in a xenograft model of gastric cancer. Using whole-body CAR T cell imaging and single-cell multiomic analyses, we noticed that within resistant tumors, CAR T cells exhibited a tendency to proliferate, but they were largely dysfunctional, losing their ability to fight cancer effectively. Specifically, most CD8 T cells became exhausted within tumors, while CD4 T cells transformed into regulatory T cells that can dampen the immune response. Additionally, the resistant tumor cells had specific gene changes that could promote cancer growth and make the disease more challenging to cure. This research provides valuable information for understanding how tumors resist CAR T cell therapy and may guide future developments in cancer treatment. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells. [ABSTRACT FROM AUTHOR]

Simple Summary: The semaphorin 6 family has emerged as a group of proteins for which substantial progress has been made in terms of comprehending the molecular events they engage in and the intricate complexities of their modus operandi within the tumor milieu. Despite the advancements and heightened scholarly attention within cancer research in the realms of targeted therapeutics and immunotherapy, there remains an imperative for continued progress in unraveling the intricacies and pathogenetic mechanisms inherent in tumor progression and in identifying discerning therapeutic targets or diagnostic biomarkers. This comprehensive review provides a nuanced overview and synthesis of the research progress dedicated to elucidating the roles played by members of the semaphorin 6 family in the trajectory of tumor progression, their intricate interplay with relevant signaling pathways, and their impact on immunological phenomena within the tumor microenvironment, positioning the potential clinical relevance of the members of the semaphorin 6 family. According to recent evidence, some groups of semaphorins (SEMAs) have been associated with cancer progression. These proteins are able to modulate the cellular signaling of particular receptor tyrosine kinases (RTKs) via the stimulation of SEMA-specific coreceptors, namely plexins (plexin-A, -B, -C, -D) and neuropilins (Np1, Np2), which share common domains with RTKs, leading to the coactivation of the latter receptors. MET, ERBB2, VEGFR2, PFGFR, and EGFR, among others, represent acknowledged targets of semaphorins that are often associated with tumor progression or poor prognosis. In particular, higher expression of SEMA6 family proteins in cancer cells and stromal cells of the cancer niche is often associated with enhanced tumor angiogenesis, metastasis, and resistance to anticancer therapy. Notably, high SEMA6 expression in malignant tumor cells such as melanoma, pleural mesothelioma, gastric cancer, lung adenocarcinoma, and glioblastoma may serve as a prognostic biomarker of tumor progression. To date, very few studies have focused on the mechanisms of transmembrane SEMA6-driven tumor progression and its underlying interplay with RTKs within the tumor microenvironment. This review presents the growing evidence in the literature on the complex and shaping role of SEMA6 family proteins in cancer responsiveness to environmental stimuli. [ABSTRACT FROM AUTHOR]

Simple Summary: (CAR)-T cell-based therapies have achieved substantial success against different haematological malignancies. However, results for solid tumours have been limited up to now, in part due to the fact that the immunosuppressive tumour microenvironment inactivates CAR-T cell clones. In this paper we study mathematically the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using computer simulations, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study in silico, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. This strategy lead in our simulations to the expansion of the CAR-T cells injected and the production of a massive army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. Thus, our proposed strategy could provide a way to develop successful CAR-T cell therapies against solid tumours. Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is one of the worst cancer types and the most common cancer originating within the brain. Patients afflicted by glioblastoma suffer from poor prognosis, a lack of specific therapies and frequent tumor recurrences. Many researchers are confident that glioblastoma cells can display traits of stem cells and that these attributes lead to an aggressive growth and high rate of recurrence. Based on our previous work that demonstrates that the "sun hormone" vitamin D3 can block these stem cell traits, we have now gained additional insights into the effects of the active form of vitamin D3, calcitriol. We can show that specific gene variants of the vitamin D3 receptor might be responsible for the sensitivity towards calcitriol and that sensitive cells are blocked in their stemness attributes as well as migratory potential. Glioblastoma is the most common primary brain cancer in adults and represents one of the worst cancer diagnoses for patients. Suffering from a poor prognosis and limited treatment options, tumor recurrences are virtually inevitable. Additionally, treatment resistance is very common for this disease and worsens the prognosis. These and other factors are hypothesized to be largely due to the fact that glioblastoma cells are known to be able to obtain stem-like traits, thereby driving these phenotypes. Recently, we have shown that the in vitro and ex vivo treatment of glioblastoma stem-like cells with the hormonally active form of vitamin D3, calcitriol (1α,25(OH)2-vitamin D3) can block stemness in a subset of cell lines and reduce tumor growth. Here, we expanded our cell panel to over 40 different cultures and can show that, while half of the tested cell lines are sensitive, a quarter can be classified as high responders. Using genetic and proteomic analysis, we further determined that treatment success can be partially explained by specific polymorphism of the vitamin D3 receptor and that high responders display a proteome suggestive of blockade of stemness, as well as migratory potential. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor (CAR)-T cells are a novel type of therapy that is becoming more prominent in the treatment of many hematological malignancies. They are associated with serious side effects including hemophagocytic lymphohistiocytosis (HLH), which can be fatal. Diagnosis of HLH can be challenging due to the lack of a uniform diagnostic criteria and the overlap with other frequent toxicities of CAR-T cells. Available treatments have been previously used for HLH but may not be as effective in this setting. The purpose of this literature review was to examine the evolution of the diagnostic criteria and treatment recommendations for HLH specifically in the setting of CAR-T cell therapy in order to facilitate prompt diagnosis and the implementation of suitable treatment to improve patient outcomes. Since CAR-T cell therapy was initially approved in 2017, its use has become more prevalent and so have its side effects. CAR-T-related HLH, also named immune effector cell-associated HLH-like syndrome (IEC-HS), is a rare but fatal toxicity if not recognized promptly. We conducted a review of the literature in order to understand the prevalence of IEC-HS as well as clarify the evolution of the diagnostic criteria and treatment recommendations. IEC-HS occurrence varies between CAR-T cell products and the type of malignancy treated. Diagnosis can be challenging as there are no standardized diagnostic criteria, and its clinical features can overlap with cytokine release syndrome and active hematological disease. Suggested treatment strategies have been extrapolated from prior experience in HLH and include anakinra, corticosteroids and ruxolitinib. IEC-HS is a potentially fatal toxicity associated with CAR-T cell therapy. Early recognition with reliable diagnostic criteria and prompt implementation of treatment specific to IEC-HS is imperative for improving patient outcomes. [ABSTRACT FROM AUTHOR]