NPI-2358: A Novel Tumor Vascular Disrupting Agent

Solid tumors need to create and maintain new blood vessels (neovasculature) in order to support growth. In the early 1980s, it was demonstrated that occlusion of the blood supply in rodent tumors induced regression of the tumor. Drugs such as Avastin and Sutent effect significant anti-tumor activity by inhibiting the formation of these new blood vessels (anti-angiogenesis agents). There are now new generations of tumor vascular disrupting agents (VDAs), which instead selectively attack tumor blood vessels that are already formed and which are essential for tumor viability. Many of these VDAs exhibit their effects by interacting at the colchicine-binding site on tubulin, preventing the formation of new microtubules that is essential to maintaining the structure of the rapidly proliferating tumor vascular cells. This interaction induces a characteristic rapid collapse of the tumor vascular cell wall and occlusion of established vasculature in the tumor, which induces tumor cell hypoxia, leading to necrosis. This vascular collapse commences within minutes of exposure to the VDA and involves changing the shape of the proliferating immature endothelial cells present in the tumor vasculature, but not in the quiescent and mature endothelial cells in non-tumor vasculature. Because of the differences in targets and mechanism of action, it appears VDAs may be complimentary or synergistic with anti-angiogenesis agents as well as other chemotherapeutic drugs.

Nereus is developing NPI-2358, a novel VDA that exerts single agent activity in several tumor models, including lung, breast, sarcoma, colon and prostate. NPI-2358 maintains full activity in multi-drug resistant human tumor cell lines and in animal models induces a rapid vascular collapse and decreased blood flow in established tumors.

NPI-2358 is in Phase I clinical studies. The initial indication is for solid tumors refractory to current therapy and the route of administration will be intravenous.