Current Cancer Drug Targets - Volume 21, Issue 11, 2021

As one of the most conservative proteins in evolution, Y-box-binding protein 1 (YB-1) has long been considered as a potential cancer target. YB-1 is usually poorly expressed in normal cells and exerts cellular physiological functions such as DNA repair, pre-mRNA splicing and mRNA stabilizing. In cancer cells, the expression of YB-1 is up-regulated and undergoes nuclear translocation and contributes to tumorigenesis, angiogenesis, tumor proliferation, invasion, migration and chemotherapy drug resistance. During the past decades, a variety of pharmacological tools such as siRNA, shRNA, microRNA, circular RNA, lncRNA and various compounds have been developed to target YB-1 for cancer therapy. In this review, we describe the physiological characteristics of YB-1 in detail, highlight the role of YB-1 in tumors and summarize the current therapeutic methods for targeting YB-1 in cancer.

Triple negative breast cancer represents multiple genomic and transcriptomic heterogeneities. Genetic and epigenetic changes emerging in TNBC help it in acquiring resistance against immunological response. Distant metastasis, lack of clinically targeted therapies and prognostic markers make it the most aggressive form of breast cancer. In this review, we showed that driver alterations in targeted genes AR, ERR, TIL, TAM, miRNA, mTOR and immunosuppressive cytokines are predominantly involved in complicating TNBC by inducing cell proliferation, invasion and metastasis, and by inhibiting apoptosis. The role of node status, cathepsin-D, Ki-67 index, CD3+TIL, BRCA1 promoter methylation value and p53 as an efficient prognostic factor have also been studied to predict the disease free and overall survival rate in TNBC patients. The present review article is an attempt to gain an insight with a new vision on the etiology of TNBC, its treatment strategies and prognostic marker to identify the outcome of standard therapies and to re-design future treatment strategies to provide maximum benefit to patients.

Desmoplasia is crucial for the development, progression and treatment of immune-resistant malignancies. Targeting desmoplasia-related metabolic pathways appears to be an interesting approach to expand our stock of disposable anti-tumor agents. CXCL12/CXCR4 axis inhibition reduces fibrosis, alleviates immunosuppression and significantly enhances the efficacy of PD-1 immunotherapy. CD40L substitute therapy may increase the activity of T-cells, downregulate CD40+, prolong patients’ survival and prevent cancer progression. Although FAPα antagonists used in preclinical models did not lead to permanent cure, an alleviation of immune-resistance, modification of desmoplasia and a decrease in angiogenesis were observed. Targeting DDR2 may enhance the effect of anti-PD-1 treatment in multiple neoplasm cell lines and has the ability to overcome the adaptation to BRAF-targeted therapy in melanoma. Reprogramming desmoplasia could potentially cooperate not only with present treatment, but also other potential therapeutic targets. We present the most promising metabolic pathways related to desmoplasia and discuss the emerging strategies to improve the efficacy of immunotherapy.

The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.

Background: Fluorine-18-fluorodeoxyglucose ([18F]-FDG) Positron Emission Tomography/ Computed Tomography (PET/CT) is a useful tool that assesses glucose metabolism in tumor cells to help guide the management of cancer patients. However, the clinical relevance of glucose metabolism in healthy tissues, including hematopoietic tissues such as the spleen, has been potentially overlooked. Recent studies suggested that spleen glucose metabolism could improve the management of different cancers. Study Eligibility Criteria: Overall, the current literature includes 1,157 patients, with a wide range of tumor types. The prognostic and/or predictive value of spleen metabolism has been demonstrated in a broad spectrum of therapies, including surgery and systemic cancer therapies. Most of these studies showed that high spleen glucose metabolism at baseline is associated with a poor outcome while treatment-induce change in spleen glucose metabolism is a multi-faceted surrogate of cancer- related inflammation, which correlates with immunosuppressive tumor microenvironment as well as with immune activation. Conclusion: In this systematic review, we seek to unravel the prognostic/predictive significance of spleen glucose metabolism on [18F]-FDG PET/CT and discuss how it could potentially guide cancer patient management in the future.

Background: Gastric cancer (GC) is one of the most common gastrointestinal malignancies. According to reports, the enhancer of zeste homolog 2 (EZH2) exhibits carcinogenic function in a variety of cancers. Therefore, EZH2 may be a potential therapeutic target for the treatment of human cancer. Macromolecular Dextran Sulfate (DS) has been displayed to play a critical role in tumor inhibition. However, the molecular mechanism by which DS mediates this effect is unclear. Objectives: In this study, we explored the effects of DS on the proliferation and apoptosis of gastric cancer and the related mechanisms. Cell proliferation and counting assays, as well as cell colony formation assays, revealed that DS inhibited the proliferation and tumorigenesis of GC cells. Additionally, flow cytometry analysis displayed that DS blocked the cell cycle of GC cells in the G1/S phase and promoted their apoptosis. Methods: Bioinformatics analyses, enzyme-linked immunosorbent assays, immunohistochemistry, and other methods were applied to measure the expression of EZH2 in human GC cells and tissues. Results and Discussion: Further studies have shown that DS treatment can reduce the expression of proliferating cell nuclear antigen (PCNA) and increase the level of the ratio of Bax: Bcl-2 protein in GC cells. In addition, DS reduced EZH2 levels and increased CXXC finger protein 4 levels both in vitro and in vivo. In addition, down-regulation of EZH2 with EZH2 inhibitors reversed the inhibitory effect of DS on gastric cancer cells. Conclusion: Collectively, our work demonstrates that DS suppresses proliferation and promotes apoptosis of GC cells by regulating EZH2. Our study suggests that DS is a promising therapeutic compound for the treatment of GC.

Background: Circulating Tumor Cells (CTCs) are a potential source of metastases and relapses. The data on molecular characteristics of Ovarian Cancer (OC) CTCs are limited. Objective: This study aims to assess the TGFβ, CXCL2, VEGFA and ERCC1 expressions in two OC CTC subpopulations before and during chemotherapy (CT), and their relation to clinical characteristics. Methods: Two CTCs subpopulations (EpCAM+CK18+E-cadherin+; EpCAM+CK18+Vimentin+) were enriched using immunomagnetic separation before treatment and after 3 cycles of platinumcontaining CT. The expression of mRNA was assessed using RT-qPCR. Results: The study included 31 I-IV stage OC patients. During CT, TGFβ levels increased in both fractions (p=0.054) compared with the initial levels. ERCC1 expression in E-cadherin+ CTCs was higher during neoadjuvant than adjuvant CT (p=0.004). CXCL2 level in E-cadherin+ CTCs increased (p=0.038) during neoadjuvant CT compared with the initial. TGF-β expression in vimentin+ CTCs during CT was negatively correlated to disease stage (p=0.003). Principal component analysis before CT revealed a component combining VEGFA, TGFβ, CXCL2, and a component with ERCC1 and VEGFA; during CT, component 1 contained ERCC1 and VEGFA, and component 2 - TGFβ and CXCL2 in both fractions. Increased ERCC1 expression in E-cadherin+ CTCs during CT was associated with decreased Progression-Free Survival (PFS) (HR 1.11 (95% CI 1.03-1.21, p=0.009) in multivariate analysis. Conclusion: EpCAM+ OC CTCs are phenotypically heterogeneous, which may reflect variability in their metastatic potential. CT changes the molecular characteristics of CTCs. Expression of TGFβ in EpCAM+ CTCs increases during CT. High ERCC1 expression in EpCAM+CK18+E-cadherin+ CTCs during CT is associated with decreased PFS in OC.