Current Cancer Drug Targets - Volume 20, Issue 10, 2020

Alternative splicing (AS) plays a significant role in the hallmarks of cancer and can provide neoantigens for immunotherapy. Here, we summarize recent advances in immune system associated tumor specific-antigens (TSAs) produced by AS. We further discuss the regulating mechanisms involved in AS-mediated innate and adaptive immune responses and the anti-tumoral and protumoral roles in different types of cancer. For example, ULBP1_RI, MLL5Δ21spe, NKp44-1Δ5, MHC-IΔ7, CD200SΔ1, 2, PVR α/β/γ/δ and IL-33 variants 1/2/3 act as regulators in solid tumors and IPAK4-L and, FOXP1ΔN100 exhibit functions in hematological cancers.

Several subtypes of T cells are located in a tumor environment, each of which supplies their energy using different metabolic mechanisms. Since the cancer cells require high levels of glucose, the conditions of food poverty in the tumor environment can cause inactivation of immune cells, especially the T-effector cells, due to the need for glucose in the early stages of these cells activity. Different signaling pathways, such as PI3K-AKt-mTOR, MAPK, HIF-1α, etc., are activated or inactivated by the amount and type of energy source or oxygen levels that determine the fate of T cells in a cancerous environment. This review describes the metabolites in the tumor environment and their effects on the function of T cells. It also explains the signaling pathway of T cells in the tumor and normal conditions, due to the level of access to available metabolites and subtypes of T cells in the tumor environment.

Background: Breast cancer (BC) is the cardinal cause of cancer-related deaths among women across the globe. Our understanding of the molecular mechanisms underlying BC invasion and metastasis remains insufficient. Recent studies provide compelling evidence on the prospective contribution of noncoding RNAs (ncRNAs) and the association of different interactive mechanisms between these ncRNAs with breast carcinogenesis. MicroRNAs (small ncRNAs) and lncRNAs (long ncRNAs) have been explored extensively as classes of ncRNAs in the pathogenesis of several malignancies, including BC. Objective: In this review, we aim to provide a better understanding of the involvement of miRNAs and lncRNAs and their underlying mechanisms in BC development and progression that may assist the development of monitoring biomarkers and therapeutic strategies to effectively combat BC. Conclusion: These ncRNAs play critical roles in cell growth, cell cycle regulation, epithelialmesenchymal transition (EMT), invasion, migration, and apoptosis among others, and were observed to be highly dysregulated in several cancers. The miRNAs and lncRNAs were observed to interact with each other through several mechanisms that governed the expression of their respective targets and could act either as tumor suppressors or as oncogenes, playing a crucial part in breast carcinogenesis.

NUPR1 is a transcription factor that has attracted great attention because of its various roles in cancer. Several studies were carried out to determine its molecular targets and mechanism of action to develop novel therapies against cancer. Here, we shed light on the role of NUPR1 in different types of cancer. NUPR1 regulates a complex network of pathways that may be affected by its silencing, which can cause varying effects. Its role in some types of cancer has been reported but remains incompletely understood, whereas its roles in other types of cancers have not been reported yet. Therefore, targeting NUPR1 for cancer treatment remains challenging and risky.

The clinical pathology of various human malignancies is supported by tropomyosin receptor kinase (Trk) B TrkB which is a specific binding receptor of the brain-derived neurotrophic factor (BDNF). TrkB and TrkB fusion proteins have been observed to be over-expressed in many cancer patients. Moreover, these proteins have been observed in multiple types of cells. A few signaling pathways can be modulated by the abnormal activation of the BDNF/TrkB pathway. These signaling pathways include PI3K/Akt pathway, transactivation of EGFR, phospholipase C-gamma (PLCγ) pathway, Ras-Raf-MEK-ERK pathway, Jak/STAT pathway, and nuclear factor kappalight- chain-enhancer of activated B cells (NF-kB) pathway. The BDNF/TrkB pathway, when overexpressed in tumors, is correlated with reduced clinical prognosis and short survival time of patients. Targeting the BDNF/TrkB pathway and the use of Trk inhibitors, such as entrectinib, larotrectinib, etc. are promising methods for targeted therapy of tumors. The present review provides an overview of the role of the TrkB pathway in the pathogenesis of cancer and its value as a potential therapeutic target.

Esophageal adenocarcinoma (EAC) is one of the fastest-growing cancers in the world. It occurs primarily due to the chronic gastroesophageal reflux disease (GERD), during which the esophageal epithelium is frequently exposed to the acidic fluid coming up from the stomach. This triggers gene mutations in the esophageal cells, which may lead to EAC development. While p53 is activated to get rid of the mutated cells, NFΚB orchestrates the remaining cells to heal the wound. However, if the mutations happen to TP53 (a common occasion), the mutant product turns to support tumorigenesis. In this case, NFΚB goes along with the mutant p53 to facilitate cancer progression. TRAIL is one of the cytokines produced in response to GERD episodes and it can kill cancer cells selectively, but its clinical use has not been as successful as expected, because some highly sophisticated defense mechanisms against TRAIL have developed during the malignancy. To clear the obstacles for TRAIL action, using a second agent to disarm the cancer cells is required. CCN1 appears to be such a molecule. While supporting normal esophageal cell growth, CCN1 suppresses malignant transformation by inhibiting NFΚB and kills the EAC cell through TRAIL-mediated apoptosis.

Background: Many studies have explored the relationship between the expression level of miRNAs and the prognosis of patients with laryngeal cancer (LC). However, the prognostic value of miRNA in LC patients has not been comprehensively evaluated. Methods: PubMed, Web of Science, Embase, and Cochrane Database of Systematic Reviews were extensively searched for all studies published before the end of February 2020 that investigated the correlation between miRNA expression level and clinical prognosis in patients with LC. Results: Twenty-one studies involving 1784 patients were included in our meta-analysis. The survival endpoints of OS and DFS were 1.69 (95% CI 1.45-1.98; p < 0.05) and 3.62 (95% CI 2.34–5.62; p < 0.05), respectively. Both OS and DFS results were statistically significant. Subgroup analyses were performed by evaluating the effects of miR-196b, miR-375, and miR-21 on OS and the effects of miR-34c-5p on DFS. The results obtained for miR-196b and miR-34c-5p were statistically significant. Conclusion: The results indicate that miRNAs, as prognostic biomarkers for LC, play an important role in clinical value. In particular, miR-196b and miR-34c-5p have the potential to be used as prognostic biomarkers. However, further large-scale cohort studies based on these miRNAs are urgently needed to validate their clinical value and help determine the direction of future clinical work in the area.

Background: Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1. Objective: To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients. Methods: In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival. Results: Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed. Conclusion: In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.