Abstract A233: Generation of in vitro and in vivo tumor models driven by insulin‐like growth factor receptor (IGF1R) and their use in the development of OSI‐906, a selective IGF1R inhibitor

The emergence of insulin‐like growth factor‐1 receptor IGF1R as an important cancer target is evidenced by the growing number of clinical trials currently underway for both small molecule inhibitors and antibody therapeutics developed against it. In preclinical studies, perturbation in IGF1R signaling has been associated with tumor growth inhibition, blockade of metastasis, and enhanced sensitivity to therapeutic agents, including cytotoxic chemotherapeutics and molecular targeted agents. Currently agents directed against IGF1R are being evaluated in clinical trials for their therapeutic utility. Given the differential dependence on IGF1R exhibited by human tumors and xenograft lines, there is a need for additional preclinical models in which the relationship between genetic context and drug response in solid tumors can be better understood in an in vivo setting. To this end, we utilized our HER2 driven inducible breast cancer model to create a panel of genetically‐engineered mouse tumors, each driven by the human IGF1R. Some of the models were also engineered to express a cognate ligand IGF2. In these models, tumors initially driven by human HER2 expression are re‐programmed by the addition of the human IGF1R cDNA upon withdrawal of the original HER2 expression. Thus, the newly introduced IGF1R‐ IGF2 cDNA functionally maintains tumor survival by re‐directing downstream signalling effectors in a process referred to as ‘Directed Complementation’ (DC). Using this approach, introduction of IGF1R strongly complemented tumor formation across the panel, whereas introduction of the ligands, either IGF1 or IGF2, alone or in combination did not. We recently showed that treatment of IGF1R/IGF2 DC tumors with OSI‐906, a potent, selective orally active inhibitor of IGF1R, resulted in tumor regression within a week of treatment, with corresponding loss of phospho‐IGF1R signaling (AACR 2009: Abstract # 2902, Lerner, et al ). These results demonstrate the singular dependence of these tumors on IGF1R signaling, as well as the in vivo efficacy of the compound. Next, we sought to extend the utility of these validated tumor models to drug discovery by establishing IGF1R‐dependent cell lines for high‐throughput screening. Here we describe detailed molecular characterization of these cell lines derived from the IGF1R/IGF2 DC tumor models as well as their drug sensitivities. Importantly, we show that the IGF1R/IGF2 DC cell lines, like their parent tumors, retain activation of the pathway as well as sensitivity to OSI‐906. Therefore, these tumor models and derived cell lines provide an effective preclinical tool for the development of targeted anti‐IGF1R therapies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A233.