LOS ANGELESIn an ongoing phase I trial in patients with solid tumors and lymphomas, the small-molecule tumor vascular disrupting agent NPI-2358 (Nereus Pharmaceuticals, San Diego, California) was dose escalated without evidence of dose-limiting toxicity, Matthew A. Spear, MD, chief medical officer at Nereus, reported at the 2007 American Association for Cancer Research annual meeting (abstract 3987).
In preclinical models, NPI-2358 interacts with soluble beta-tubulin and prevents tubulin polymerization without altering the dynamic function of formed microtubules. It destabilizes tumor vascular endothelial cells, and has an additional direct cytotoxic action on tumor cells. This profile creates a highly specific tumor cell cytotoxicity. Based on preclinical studies, NPI-2358 may have a reduced risk of side effects such as cardiotoxicity, hemodynamic changes, and neuropathies, Dr. Spear said. NPI-2358 has been shown to selectively induce tumor vascular collapse and tumor regression in multiple murine tumor models. It is particularly effective as a single agent in models of breast tumors and sarcomas, and in combination with irinotecan (Camptosar) in a colorectal model, paclitaxel in a breast cancer model, and docetaxel (Taxotere) in a non-small-cell lung cancer (NSCLC) model, he noted.
In the study reported at AACR, NPI-2358 was given to eight patients with advanced solid tumors and lymphomas refractory to standard therapies by three weekly IV infusions in 4-week cycles. The starting dose was 2 mg/m2, and escalations were conducted in cohorts of one to six patients. Good tolerability was seen up to 9 mg/m2, and the dose continues to be escalated. While no clinical responses were seen, one patient with pancreatic cancer had stable disease, Dr. Spear said.
The study was performed at the Karmanos Cancer Institute, Detroit (principal investigator Patricia LoRusso, DO), and the CTRC Institute for Drug Development, San Antonio (principal investigator Anthony Tolcher, MD).
Vascular Disruption, Not Antiangiogenesis
Tumor vascular disrupting agents, such as Nereus' NPI-2358, cut off blood flow to the tumor but work differently from antiangiogenic agents in that they attack the core of the tumor. "They work on the mature tumor blood vessels, whereas antiangiogenic agents block the formation of new vessels," G. Kenneth Lloyd, PhD, chief scientific officer at Nereus, told ONI. "The effects are different. Eventually, this could make for effective combination therapy, with agents attacking the tumor from both the inside and outside."
Dr. Lloyd added that vascular disrupting agents exhibit a profile different from taxanes and vinca alkaloids. Many vascular disrupting agents interact 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.
"Vascular disrupting agents disrupt the integrity of the tumor vasculature, which results in starvation and necrosis of tumor cells," he said.