A small molecule that inhibits the insulin-like growth factor 1 receptor (IGF-1R) has blocked the development of human colorectal tumors in mice, according to researchers from OSI Pharmaceuticals, Melville, New York.
WASHINGTONA small molecule that inhibits the insulin-like growth factor 1 receptor (IGF-1R) has blocked the development of human colorectal tumors in mice, according to researchers from OSI Pharmaceuticals, Melville, New York. An optimized version of the molecule is now in development for clinical trials, Jonathan Pachter, PhD, OSI's senior director of cancer biology, said at the 97th Annual Meeting of the American Association of Cancer Research (abstract LB-281).
The small molecule, identified through a structure-based drug design approach and dubbed compound 1, blocked activation of the IGF-1 receptor in cell lines. It also blocked IGF-stimulated activation of downstream signaling pathways, including AKT and MAP kinase pathways, which are important for tumor growth. In mouse xenograft models, it also showed strong efficacy.
"Really the most important finding is that when the drug was given orally to mice once per day, it completely blocked the growth of human colon cancer cell tumors during the dosing period," Dr. Pachter said.
The proteins that activate the IGF-1 receptor, IGF-I and especially IGF-II, are overexpressed in a variety of human cancers, including non-small-cell lung cancer (NSCLC) and ovarian cancer, in addition to colorectal cancer, he said.
Avoiding a Pitfall
The receptor is considered an important therapeutic target but has posed challenges because it is closely related to the insulin receptor. Other researchers who have attempted to design small molecules that target the IGF-1 receptor have found that they also block the insulin receptor with similar potency and thus interfere with glucose metabolism. The OSI researchers believe that compound 1 has avoided that pitfall. No substantial rise in blood sugar occurred in the test animals at dose levels that maximally block tumor growth, and the molecule was about 15 times more potent in blocking the IGF-1 receptor than the insulin receptor. It also had little effect on a panel of about 30 other protein kinases.
"This selectivity we feel is important because it may enable our compound to block tumor growth without significant unwanted effects on metabolism," Dr. Pachter said.
In a related study presented at the same meeting (abstract LB-282), OSI's Qun-sheng Ji, PhD, reported that compound 1 was also effective against NSCLC in combination with erlotinib (Tarceva). In both NSCLC cell lines and mice, the compound further enhanced the effect of erlotinib, Dr. Ji said.
OSI906 in Development
Based on this research, a closely related compound, called OSI906, is now in development in preparation for clinical trial use, Dr. Pachter said. Toxicological studies required for filing an investigational new drug (IND) application are in progress. He said that the company anticipates filing an IND with the US Food and Drug Administration (FDA) by the end of this year.