benzofurans and Mesothelioma

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzofurans; Biomarkers; Female; GPI-Linked Proteins; Humans; Lung Neoplasms; Male; Mesothelin; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Neoplasm Staging; Organophosphates; Pleural Neoplasms; Radiography; Treatment Outcome; Tubulin Modulators; Tumor Burden

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with a poor prognosis. Thus, novel therapeutic agents need to be developed for treating it. We recently reported the isolation of the novel anti-MPM compound designated as JBIR-23 from Streptomyces sp. AK-AB27. In this study, JBIR-23 exerted its cytotoxic effect on MPM cells by promotion of tubulin polymerization and G₂/M arrest, which was followed by apoptosis induction via the caspase pathway through phosphorylation of p38 mitogen-activated protein kinase and c-jun N-terminal kinase. Furthermore, in vivo analysis demonstrated that JBIR-23 prevented tumor growth in tumor-bearing nude mice without evident side effects.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Separation; Female; Flow Cytometry; Humans; Immunoblotting; Mesothelioma; Mice; Mice, Nude; Tubulin; Tubulin Modulators; Xenograft Model Antitumor Assays

The screening for active compounds against malignant pleural mesothelioma (MPM) cells produced by Streptomyces sp. AK-AB27 resulted in the isolation of two compounds with a dodecahydrodibenzo[b,d]furan skeleton named JBIR-23 (1) and -24 (2). Their structures were established on the basis of extensive NMR and MS analyses. Compounds 1 and 2 exhibited cytotoxic effects against several MPM cell lines.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Mesothelioma; Streptomyces