elisidepsin and Carcinoma--Non-Small-Cell-Lung

Because of the poor results observed after platinum-based first-line chemotherapy, research on new strategies for second-line treatment of advanced non-small-cell lung cancer (NSCLC) is warranted. Current research focuses on the development of new agents and the assessment of a combination of therapies, especially those with different mechanisms of action. PM02734 (elisidepsin, Irvalec) is a compound related to Kahalalide F (KF), a moderately soluble marine product that belongs to a family of dehydro aminobutyric acid-containing peptides isolated from the herbivorous marine mollusk Elysia rufescens. Preclinical and clinical studies showed that KF induces strong cytotoxic activity against different solid tumors, including NSCLC, particularly in patients with squamous histology; in fact, almost 40% of patients treated in the second line were still alive at 1 year after beginning treatment with KF. Analysis of data collected during clinical development has revealed that KF has a predictable and manageable toxicity profile. The toxicities most commonly associated with KF are generally transient and mild or moderate. The absence of hematologic toxicity and cumulative toxic effects suggests that KF may be suitable for combination trials with other anticancer agents. The development of KF could stopped because of the unavailability of a natural source of the compound. PM02734 is a closely related derivative of KF with similar activity and characteristics. Herein, we summarize the studies of PM02734 and future clinical perspectives.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Depsipeptides; Humans; Injections, Intravenous; Lung Neoplasms; Mollusk Venoms; Randomized Controlled Trials as Topic

PM02734 (elisidepsin) is a synthetic marine-derived cyclic peptide of the kahalalide family currently in phase II clinical development. The mechanisms of cell death induced by PM02734 remain unknown.. Human non-small-cell lung cancer (NSCLC) cell lines H322 and A549 were used to evaluate PM02734-induced cytotoxicity, apoptosis, and autophagy, as well as effects on cell death-related signaling pathways.. PM02734 at clinically achievable concentrations (0.5-1 μmol/L) was cytotoxic to H322 and A549 cells but did not cause nuclear fragmentation, PARP cleavage, or caspase activation, suggesting that classical apoptosis is not its main mechanism of cell death. In contrast, PM02734-induced cell death was associated with several characteristics of autophagy, including an increase in acidic vesicular organelle content, levels of GFP-LC3-positive puncta, elevation of the levels of Atg-5/12 and LC3-II, and an associated compromise of the autophagic flux resulting in increased number of autophagosomes and/or autolysosomes. Cotreatment with 3-methyladenine (3-MA) and downregulation of Atg-5 gene expression by siRNA partially inhibited PM02734-induced cell death. PM02734 caused inhibition of Akt/mTOR signaling pathways and cotreatment with the Akt inhibitor wortmannin or with the mTOR inhibitor rapamycin led to a significant increase in PM02734-induced cell death. Furthermore, PM02734 caused the activation of death-associated protein kinase (DAPK) by dephosphorylation at Ser308, and downregulation of DAPK expression with siRNA caused also a partial but significant reduction of PM02734-induced cell death. In vivo, PM02734 significantly inhibited subcutaneous A549 tumor growth in nude mice (P < 0.05) in association with induction of autophagy.. Our data indicate that PM02734 causes cell death by a complex mechanism that involves increased autophagosome content, due for the most part to impairment of autophagic flux, inhibition of the Akt/mTOR pathway, and activation of DAPK. This unique mechanism of action justifies the continued development of this agent for the treatment of NSCLC.

Topics: Adenine; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Death-Associated Protein Kinases; Depsipeptides; Enzyme Activation; Green Fluorescent Proteins; Humans; Immunoblotting; Lung Neoplasms; Mice; Mice, Nude; Microscopy, Fluorescence; Microtubule-Associated Proteins; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

PM02734 (elisidepsin) is a novel marine-derived cyclic peptide belonging to the Kahalalide family of compounds currently under phase I development with early evidence of a positive therapeutic index. The cytotoxicity of PM02734 has been determined in a panel of human NSCLC (non-small cell lung cancer) cell lines. Western blot analysis showed a direct correlation between ErbB3 expression and cell sensitivity to PM02734. Furthermore, PM02734 was more effective in the induction of ErbB3 degradation and dephosphorylation than in that of ErbB2 and ErbB1 in human NSCLC cell lines. The combination of PM02734 and erlotinib was synergistic in all NSCLC cell lines tested, including erlotinib resistant cell lines, with combination indexes ranging between 0.59 and 0.81. The combination of PM02734 and erlotinib was more effective than either drug alone in mice inoculated intravenously (i.v.) with A549 cells. The combination of PM02734 and erlotinib was more effective in inhibiting AKT than either single agent alone in H322 cells. These results have provided a rational basis for an ongoing clinical trial to explore this combination in patients with advanced malignant solid tumours.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Survival; Depsipeptides; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Mice; Mice, Nude; Oncogene Proteins v-erbB; Protein Kinase Inhibitors; Quinazolines; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays