rrx-001 and entinostat

Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific "driver" mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, "elephant in the room", is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and 'tame the beast of resistance', thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to "prime" tumors and reverse resistance.

Topics: Antibodies, Monoclonal; Azacitidine; Azetidines; Benzamides; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; CpG Islands; Disease Progression; DNA Methylation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Histones; Humans; Hydralazine; Immunotherapy; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Nitro Compounds; Nivolumab; Prognosis; Pyridines; Treatment Outcome; Valproic Acid

Resistance to chemotherapy, biological and targeted therapies is an important clinical problem. Resistance can arise and/or be selected for multiple mechanisms of action. Unfortunately, acquired resistance to antitumor agents or regimens is nearly inevitable in all patients with metastatic disease. Until recently, it was believed that this resistance was unalterable and irreversible, rendering retreatment with the same or similar drugs futile in most cases. However, the introduction of epigenetic therapies, including HDAC inhibitors and DNA methyltransferase inhibitors (DNMTIs), has provided oncologists with new strategies to potentially overcome this resistance. For example, if chemoresistance is the product of multiple non-genetic alterations, which develop and accumulate over time in response to treatment, then the ability to epigenetically modify the tumor to reconfigure it back to its baseline non-resistant state, holds tremendous promise for the treatment of advanced, metastatic cancer. This minireview aims (1) to explore the potential mechanisms by which a group of small molecule agents including HDACs (entinostat and vorinostat), DNA hypomethylating agents such as the DNMTIs (decitabine (DEC), 5-azacytidine (5-AZA)) and redox modulators (RRx-001) may reprogram the tumors from a refractory to non-refractory state, (2) highlight some recent findings in this area, and (3) discuss the therapeutic potential of resensitization approaches with formerly failed chemotherapies.

Topics: Animals; Antineoplastic Agents; Azacitidine; Azetidines; Benzamides; Decitabine; DNA Modification Methylases; Drug Resistance, Neoplasm; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neoplasms; Nitro Compounds; Oxidative Stress; Pyridines; Vorinostat