Current Cancer Drug Targets - Volume 21, Issue 9, 2021

Autophagy is a mechanism by which unwanted cellular components are degraded through a pathway that involves the lysosomes and contributes to several pathological conditions such as cancer. Gastrointestinal cancers affect the digestive organs from the esophagus to the anus and are among the most commonly diagnosed cancers globally. The modulation of autophagy using pharmacologic agents offers a great potential for cancer therapy. In this review, some commonly used compounds, together with their molecular target and the mechanism through which they stimulate or block the autophagy pathway, as well as their therapeutic benefit in treating patients with gastrointestinal cancers, are summarized.

Advances in chromosomally rearranged ALK positive non-small cell lung cancer have been dramatic in only the last few years. Survival times have improved dramatically due to the introduction of ever more efficacious ALK inhibitors. These improvements have been due largely to improvements in blood-brain barrier penetration and the breadth of ligand binding pocket mutations against which the drugs are effective. However, the advances maybe slow due to the frequency of cancers with compound resistance mutations are appearing, suggesting the need to develop multiple ALK inhibitors to target different compound mutations.Another research area that promises to provide further gains is the use of drug combinations, with an ALK inhibitor combined with a drug targeting a “second driver” to overcome resistance. In this review, the range of secondary targets for ALK+ lung cancer and the potential for their clinical success are reviewed.

Prostate cancer (PCa) is one of the leading causes of death worldwide. A variety of strategies, including surgery, chemotherapy, radiotherapy, and immunotherapy, are applied for PCa treatment. PCa cells are responsive towards therapy at early stages, but they can obtain resistance in the advanced stage. Furthermore, their migratory ability is high in advanced stages. It seems that genetic and epigenetic factors play an important role in this case. Zinc finger E-box-binding homeobox (ZEB) is a family of transcription with two key members, including ZEB1 and ZEB2. ZEB family members are known due to their involvement in promoting cancer metastasis via EMT induction. Recent studies have shown their role in cancer proliferation and inducing therapy resistance. In the current review, we focus on revealing the role of ZEB1 and ZEB2 in PCa. ZEB family members are able to significantly promote the proliferation and viability of cancer cells. ZEB1 and ZEB2 enhance migration and invasion of PCa cells via EMT induction. Overexpression of ZEB1 and ZEB2 is associated with a poor prognosis of PCa. ZEB1 and ZEB2 upregulation occurs during PCa progression and can provide therapy resistance to cancer cells. PRMT1, Smad2, and non-coding RNAs can function as upstream mediators of the ZEB family. Besides, Bax, Bcl-2, MRP1, Ncadherin, and E-cadherin can be considered as downstream targets of the ZEB family in PCa.

Background: Breast cancer (BC) is known as the most common malignancy in women. Environmental and genetic factors are associated with BC progression. Genetic polymorphisms have been reported as important risk factors for BC prognosis and drug response. Main Body: In the present review, we have summarized all of the single nucleotide polymorphisms (SNPs) which have been significantly associated with drug response in BC patients in the world. We have also categorized the reported SNPs based on their related gene functions to clarify the molecular biology of drug responses in BC. Conclusion: The majority of SNPs were reported in detoxifying enzymes which introduced such genes as the main genetic risk factors during BC drug responses. This review paves the way for introducing a prognostic panel of SNPs for the BC patients in the world.

Background: Little is known about the efficacy of programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors in patients with central nervous system (CNS) metastases. Objective: This study aimed to assess the difference in efficacy of PD-1 or PD-L1 inhibitors in patients with and without CNS metastases. Methods: From inception to March 2020, PubMed and Embase were searched for randomized controlled trials (RCTs) about PD-1 or PD-L1 inhibitors. Only trails with available hazard ratios (HRs) for overall survival (OS) of patients with and without CNS metastases simultaneously would be included. Overall survival hazard ratios and their 95% confidence interval (CI) were calculated, and the efficacy difference between these two groups was assessed in the meantime. Results: A total of 4988 patients (559 patients with CNS metastases and 4429 patients without CNS metastases) from 8 RCTs were included. In patients with CNS metastases, the pooled HR was 0.76 (95%CI, 0.62 to 0.93), while in patients without CNS metastases, the pooled HR was 0.74 (95%CI, 0.68 to 0.79). There was no significant difference in efficacy between these two groups (χ²=0.06 P=0.80). Conclusion: With no significant heterogeneity observed between patients with or without CNS metastases, patients with CNS metastases should not be excluded in the PD-1 or PD-L1 blockade therapy. Future research should permit more patients with CNS metastases to engage in PD-1 or PDL1 blockade therapy and explore the safety of PD-1 or PD-L1 inhibitors in patients with CNS metastases.

Background: Most children with recurrent metastatic solid tumors have high mortality rates. Recent studies have shown that proteasome inhibition leads to effective tumor killing in cells that have acquired treatment resistance and metastatic properties. Objective: The purpose of this study was to test the potential of Carfilzomib (CFZ), a proteasome inhibitor, in refractory pediatric solid tumors which is currently unknown. Methods: A panel of pediatric solid tumor cell lines, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma and atypical teratoid rhabdoid tumor (ATRT), was used to evaluate the cytotoxic and proteasomal inhibitory effects of CFZ. A drug scheduling experiment was performed to determine the optimal dose and time to obtain effective cell killing. Combination studies of CFZ with chemotherapeutic drugs of different classes were performed to determine the extent of synergy. Results: CFZ showed effective cytotoxicity against all cell lines tested (mean IC50 = 7nM, range = 1-20nM) and activity in a fluorophore-tagged cell-based proteasome assay. Drug scheduling experiments showed that the minimum exposure of 4-8 hours/day is needed for effective cumulative killing. CFZ, when combined with chemotherapeutic drugs of different classes, synergistically enhanced the extent of cell death. Conclusion: CFZ showed cytotoxic activity against all the solid pediatric cancer cell lines tested. This study provides initial in vitro data on the potential of CFZ to treat pediatric solid tumors and supports further investigations into the components of drug scheduling, biological correlates and drug combinations for future early phase clinical trials in children.