Marine-based Oncology Drugs
NPI-2358 is one of 200 synthetic analogues made from the parent compound halimide isolated from a marine fungus (Aspergillus) that grows on sea grass. A Phase I trial of patients with advanced solid tumors started in June 2006, and the drug is advancing through dose-escalation protocols. In preclinical models of breast, sarcoma, colon, and prostate cancer, NPI-2358 disrupts tumor blood vessels by interacting with microtubules, resulting in their rapid collapse in the center of tumors and tumor cell death. This mechanism of action targets only the vasculature of tumor cells but not healthy cells, thereby potentially reducing side effects of cardiotoxicity and neurotoxicity.
NPI-2358 also acts synergistically with other chemotherapeutic agents in animal models. In one study, the company reports that lung tumor growth was reduced 74% when treated with NPI-2358 in combination with taxotere, compared to 26% when taxotere was used alone.
Similar reductions in tumor growth are observed in animal models for colon cancer when NPI-2358 is added to irinotecan, for breast tumors in a paclitaxel combination, and for sarcomas when combined with radiation. Moreover, compared to other vascular disrupting drugs, NPI-2358 has a longer duration of action and inhibits multidrug-resistant tumor cells, according to the company.
For the proteasome inhibitor NPI-0052, Nereus uses the natural compound in the clinic. NPI-0052 comes from Salinispora tropica, a new marine actinomycete identified in sediment from the ocean floor. Nereus produces a supply of NPI-0052 through an industrial, scalable saline fermentation process.
Since Millennium Pharmaceutical’s (www.mlnm.com) Velcade® was approved to treat multiple myeloma and mantle cell lymphoma, pharmaceutical companies have intensified their search for other proteasome inhibitors. Nereus is conducting two Phase I trials of NPI-0052, one on patients with solid tumors and lymphomas and the other on patients with relapsed/refractory multiple myeloma. If the drug proves effective in treating diverse types of cancer, it will have broad commercial appeal.
“We see advantages of NPI-0052 over Velcade in preclinical studies,” comments Sethna, “that we hope will be realized in humans. For example, NPI-0052 is active against multiple myeloma cells taken from patients who have become resistant to Velcade, steroid therapy, thalidomide, and lenalidomide.”
The company reports that in preclinical settings, NPI-0052 inhibits three key protease functions, is less cytotoxic to normal cells, shows a faster onset of action, and is six times more potent than Velcade. In addition, the compound can be given once weekly and is active orally or intravenously.