Plocabulin

Hepatocellular carcinoma (HCC) has high associated morbidity and mortality rates. Although chemical medication represents a primary HCC treatment strategy, low response rates and therapeutic resistance serve to reduce its efficacy. Hence, identifying novel effective drugs is urgently needed, and many researchers have sought to identify new anti-cancer drugs from marine organisms. The marine population is considered a "blue drug bank" of unique anti-cancer compounds with diverse groups of chemical structures. Here, we discuss marine-derived compounds, including PM060184 and bryostatin-1, with demonstrated anti-cancer activity in vitro or in vivo. Based on the marine source (sponges, algae, coral, bacteria, and fungi), we introduce pharmacological parameters, compound-induced cytotoxicity, effects on apoptosis and metastasis, and potential molecular mechanisms. Cumulatively, this review provides insights into anti-HCC research conducted to date in the field of marine natural products and marine-derived compounds, as well as the potential pharmacological mechanisms of these compounds and their status in drug development.

The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype.