Plinabulin (NPI-2358): A Novel Tumor Vascular Disrupting Agent

Vascular disrupting agents (VDAs) are a rapidly advancing class of oncology therapeutics that elicit anti-tumor activity by selectively disrupting established tumor vasculature. The target of tumor neovasculature has been validated through the use of a number of angiogenesis inhibitors targeted to the VEGF and EGF pathways in standard of care oncology regimens (eg. Avastin, Sutent, Nexavar, and Erbitux). VDAs target tumor vasculature in a markedly different, and perhaps complimentary mechanism, and have recently gained significant attention based on positive Phase 2 data, leading to the initiation of Phase 3 studies.

Tumor blood vessels differ from normal blood vessels in their pathophysiological characteristics, in particular structural disorganization and high dependence on endothelial cells, and lack the structural support of connective tissue, pericytes and smooth muscle as well as having high permeability (“leaky”). VDAs target the tumor vasculature through a different set of molecular targets than angiogenesis inhibitors by exploiting these characteristics. Preclinical and clinical studies indicate that the efficacy and toxicity profiles of VDAs are different from and complimentary to the VEGF targeted agents and standard cytotoxic agents. In particular myelosuppression, mucositis, prolonged hypertension and bleeding events have not appeared to be associated with VDAs. Not only do these agents differ from the angiogenesis inhibitors as well as cytotoxic agents in terms of toxicity profiles, but data suggest the potential for synergy in anti-tumor activity.

Plinabulin is a VDA of novel structure in having been derived from a marine microbial source, as opposed to terrestrial sources for other VDAs. Plinabulin binds to the colchicine binding site              of  b-tubulin preventing polymerization and disrupting the cytoplasmic microtubule network. This leads to loss of vascular endothelial cytoskeletal function, morphology and cohesion, as well as cytotoxicity in proliferating immature tumor vascular endothelial cells, resulting in vascular architectural destabilization and selective tumor vascular collapse and necrosis. This vascular collapse commences within minutes of exposure. The tumor neovasculature is particularly susceptible to these effects given the lack of supporting structure and dependence on immature proliferating endothelial cells. Plinabulin has been shown to produce anti-tumor activity in animal models as a single agent and synergistically with other chemotherapy agents including taxanes. Overall, preclinical studies indicated plinabulin had a favorable safety and activity profile leading to the initiation of clinical trials. Favorable data from early clinical studies lead to the initiation of a Phase 2 clinical trial program. Clinical page.