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Aim: The semisynthetic derivatives MePip-SF5 and isogarcinol, which are aligned with the natural products curcumin and garcinol, were tested for their antitumor effects in a preclinical model of pulmonary melanoma metastasis. Methods and results: MePip-SF5 was almost five times more effective in inhibiting B16F10 melanoma cell proliferation than its original substance of curcumin (IC50 MePip-SF5 2.8 vs. 13.8 µM). Similarly, the melanoma cytotoxicity of isogarcinol was increased by 40% compared to garcinol (IC50 3.1 vs. 2.1 µM). The in vivo toxicity of both drugs was assessed in healthy C57BL/6 mice challenged with escalating doses. Isogarcinol induced toxicity above a dose of 15 mg/kg, while MePip-SF5 showed no in vivo toxicity up to 60 mg/kg. Both drugs were tested in murine pulmonary metastatic melanoma. C57BL/6 mice (n = 10) received 500,000 B16F10 melanoma cells intravenously. After intraperitoneal injection of MePip-SF5 (60 mg/kg) or isorgarcinol (15 mg/kg) at days 8, 11 and 14 and sacrifice at day 16, the MePip-SF5-treated mice showed a significantly (p < 0.05) lower pulmonary macroscopic and microscopic tumor load than the vehicle-treated controls, whereas isogarcinol was ineffective. The pulmonary RNA levels of the mitosis marker Bub1 and the inflammatory markers TNFα and Ccl3 were significantly (p < 0.05) reduced in the MePip-SF5-treated mice. Both drugs were well tolerated, as shown by an organ inspection and normal liver- and kidney-related serum parameters. Conclusions: The novel curcuminoid MePip-SF5 showed a convincing antimetastatic effect and a lack of systemic toxicity in a relevant preclinical model of metastasized melanoma.

Background: The recommended booster third dose of vaccination against COVID-19 in cancer patients seems reasonable to protect them against a severe disease course. A prospective study was designed to assess the immunogenicity, efficacy, and safety of COVID-19 vaccination in this cohort. Methods: Patients with solid malignancies on active treatment were followed up after the primary course and booster third dose of vaccination to assess their anti-SARS-CoV-2 S1 IgG levels, efficacy in the case of SARS-CoV-2 infection, and safety. Results: Out of 125 patients receiving the primary course of vaccination, 66 patients received a booster third dose of mRNA vaccine, with a 20-fold increase in median anti-SARS-CoV-2 S1 IgG levels compared to Ab levels six months post-primary course of vaccination (p < 0.0001). After the booster third dose, anti-SARS-CoV-2 S1 IgG levels were comparable to healthy controls (p = 0.113). There was a decline in Ab levels 3 (p = 0.0003) and 6 months (p < 0.0001) post-third booster dose. No patients had either a severe disease course or a lethal outcome in the case of SARS-CoV-2 infection after the third booster dose. Conclusion: The third booster vaccination dose against COVID-19 in solid cancer patients triggers substantial immunogenicity and is safe and effective for preventing a severe COVID-19 disease course.

New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.

Next-generation sequencing-based comprehensive genome profiling (CGP) testing, OncoGuide NCC Oncopanel System, and FoundationOne CDx Cancer Genomic Profile have been covered by the Japanese national health insurance system since June 2019. Because CGP was initially developed to enroll patients into an early-phase clinical trial for solid tumors, its approved indications have been limited to patients who have completed the standard chemotherapy treatment. Approximately 14,000 cases have been registered with the Center for Cancer Genomics and Advanced Therapeutics as of March 2021. Measuring the drug access rate is not enough due to patients’ deteriorating condition during CGP analysis and due to the limited number of ongoing clinical trials available, although tumor-agnostic therapies, such as the use of pembrolizumab in high microsatellite-instable solid tumors and in conditions with a high tumor mutational burden (≥10 mut/Mb) as well as the use of entrectinib and larotrectinib in NTRK fusion-positive tumors have been approved in Japan. Moreover, since this analysis is performed using DNA derived from tumor tissue, it is difficult to perform CGP in cases in which an insufficient amount of tissue exists. Thus, noninvasive blood-based assays have been developed, and CGP panels using circulating tumor DNA from blood were approved in March 2021. However, cost, timing, and the number of tests allowed by the health system have not yet been determined. Therefore, in this review, we outline the current status and issues of CGP testing using tumor tissues as well as the expectations and limitations of liquid biopsy for use in Japanese clinical practice.

Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and checkpoint blockade has meaningfully changed the oncology landscape. While remarkable clinical advances in adaptive immunity are occurring, modulation of innate immunity has proven more difficult. The myeloid compartment, including macrophages, neutrophils, and dendritic cells, has a significant impact on the persistence or elimination of tumors. Myeloid cells, specifically in the tumor microenvironment, have direct contact with tumor tissue and coordinate with tumor-reactive T cells to either stimulate or antagonize cancer immunity. However, the myeloid compartment comprises a broad array of cells in various stages of development. In addition, hematopoietic stem and progenitor cells at various stages of myelopoiesis in distant sites undergo significant modulation by tumors. Understanding how tumors exert their influence on myeloid progenitors is critical to making clinically meaningful improvements in these pathways. Therefore, this review will cover recent developments in our understanding of how solid tumors modulate myelopoiesis to promote the formation of pro-tumor immature myeloid cells. Then, it will cover some of the potential avenues for capitalizing on these mechanisms to generate antitumor immunity.

MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.

Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment—such as surgery, chemotherapy, and/or radiation therapy—is selected. A new assay has been developed that detects circulating tumor cells (CTCs). Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics.

Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases.

Background: The recommended booster third dose of vaccination against COVID-19 in cancer patients seems reasonable to protect them against a severe disease course. A prospective study was designed to assess the immunogenicity, efficacy, and safety of COVID-19 vaccination in this cohort., Methods: Patients with solid malignancies on active treatment were followed up after the primary course and booster third dose of vaccination to assess their anti-SARS-CoV-2 S1 IgG levels, efficacy in the case of SARS-CoV-2 infection, and safety., Results: Out of 125 patients receiving the primary course of vaccination, 66 patients received a booster third dose of mRNA vaccine, with a 20-fold increase in median anti-SARS-CoV-2 S1 IgG levels compared to Ab levels six months post-primary course of vaccination ( p < 0.0001). After the booster third dose, anti-SARS-CoV-2 S1 IgG levels were comparable to healthy controls ( p = 0.113). There was a decline in Ab levels 3 ( p = 0.0003) and 6 months ( p < 0.0001) post-third booster dose. No patients had either a severe disease course or a lethal outcome in the case of SARS-CoV-2 infection after the third booster dose., Conclusion: The third booster vaccination dose against COVID-19 in solid cancer patients triggers substantial immunogenicity and is safe and effective for preventing a severe COVID-19 disease course.

Next-generation sequencing-based comprehensive genome profiling (CGP) testing, OncoGuide NCC Oncopanel System, and FoundationOne CDx Cancer Genomic Profile have been covered by the Japanese national health insurance system since June 2019. Because CGP was initially developed to enroll patients into an early-phase clinical trial for solid tumors, its approved indications have been limited to patients who have completed the standard chemotherapy treatment. Approximately 14,000 cases have been registered with the Center for Cancer Genomics and Advanced Therapeutics as of March 2021. Measuring the drug access rate is not enough due to patients' deteriorating condition during CGP analysis and due to the limited number of ongoing clinical trials available, although tumor-agnostic therapies, such as the use of pembrolizumab in high microsatellite-instable solid tumors and in conditions with a high tumor mutational burden (≥10 mut/Mb) as well as the use of entrectinib and larotrectinib in NTRK fusion-positive tumors have been approved in Japan. Moreover, since this analysis is performed using DNA derived from tumor tissue, it is difficult to perform CGP in cases in which an insufficient amount of tissue exists. Thus, noninvasive blood-based assays have been developed, and CGP panels using circulating tumor DNA from blood were approved in March 2021. However, cost, timing, and the number of tests allowed by the health system have not yet been determined. Therefore, in this review, we outline the current status and issues of CGP testing using tumor tissues as well as the expectations and limitations of liquid biopsy for use in Japanese clinical practice.

To selectively and continuously produce anti-cancer molecules specifically in malignant tumors, we have established an in situ delivery and production system ( i DPS) with Bifidobacterium as a micro-factory of various anti-cancer agents. By focusing on the characteristic hypoxia in cancer tissue for a tumor-specific target, we employed a gene-engineered obligate anaerobic and non-pathogenic bacterium, Bifidobacterium , as a tool for systemic drug administration. This review presents and discusses the anti-tumor effects and safety of the i DPS production of numerous anti-cancer molecules and addresses the problems to be improved by directing attention mainly to the hallmark vasculature and so-called enhanced permeability and retention effect of tumors.

MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.

Although the use of oral administration of pharmacological all- trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9- cis retinoic acid, and 13- cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance., Competing Interests: The authors declare no conflict of interest.

Resistance to therapy in patients with solid cancers represents a daunting challenge that must be addressed. Indeed, current strategies are still not effective in the majority of patients; which has resulted in the need for novel therapeutic approaches. Cancer stem cells (CSCs), a subset of tumor cells that possess self-renewal and multilineage differentiation potential, are known to be intrinsically resistant to anticancer treatments. In this review, we analyzed the implications for CSCs in drug resistance and described that multiple alterations in morphogenetic pathways (i.e. Hippo, Wnt, JAK/STAT, TGF-, Notch, Hedgehog pathways) were suggested to be critical for CSC plasticity. By interrogating The Cancer Genome Atlas (TCGA) datasets, we first analyzed the prevalence of morphogenetic pathways alterations in solid tumors with associated outcomes. Then, by highlighting epigenetic relevance in CSC development and maintenance, we selected histone deacetylase inhibitors (HDACi) as potential agents of interest to target this subpopulation based on the pleiotropic effects exerted specifically on altered morphogenetic pathways. In detail, we highlighted the role of HDACi in solid cancers and,specifically,in the CSC subpopulation and we pointed out some mechanisms by which HDACi are able to overcome drug resistance and to modulate stemness. Although, further clinical and preclinical investigations should be conducted to disclose the unclear mechanisms by which HDACi modulate several signaling pathways in different tumors. To date, several lines of evidence support the testing of novel combinatorial therapeutic strategies based on the combination of drugs commonly used in clinical practice and HDACi to improve therapeutic efficacy in solid cancer patients., Competing Interests: The authors declare no conflict of interest.

Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment-such as surgery, chemotherapy, and/or radiation therapy-is selected. A new assay has been developed that detects circulating tumor cells (CTCs). Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics., Competing Interests: The authors declare no conflict of interest.

Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases., Competing Interests: Conflicts of Interest: Z.H. is co-inventor of the first-generation tissue factor-targeting “neovascular-targeted immunoconjugates” (ICON) and is the inventor of the second- and third-generation tissue factor-targeting ICONs (U.S. patents pending).