Disrupting IGF signaling in breast cancer as a therapeutic strategy.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #ES-3 Disrupting endocrine signaling in breast cancer has long been a mainstay of therapy. Understanding that the estradiol and estrogen receptor-α (ERα) play and important role in breast cancer has led to important advances in risk reduction, adjuvant therapy, and management of metastatic disease. Similar to estrogen, the insulin-like growth factors (IGF) and their receptors have an important role in maintenance of the malignant phenotype. The type I IGF receptor (IGF1R) is a heterotetrameric, trannsmembrane tyrosine kinase receptor with a high degree of homology to insulin receptor. Physiologic activation of this receptor requires ligand binding. There are two circulating ligands (IGF-I and IGF-II) which are highly homologous to insulin. There is some promiscuity in the ligand-receptor interactions. For example, IGF-II has high affinity for the heterotetrameric insulin receptor. Though the potential for complex interactions are evident, the IGF system can be disrupted by several potential strategies including ligand deprivation, inhibition of ligand binding to the receptor, and inhibition of receptor tyrosine kinase function. To date, several anti-IGF monoclonal antibodies and tyrosine kinase inhibitors have entered clinical trial. Anti-IGF1R antibodies have activity as single agents and in combination with cytotoxic chemotherapy in sarcoma and lung cancer. While the future of these anti–IGF receptor antibodies are not clear yet it, appears that clinical activity would warrant further study. In breast cancer there are abundant preclinical data suggesting that IGF disruption could be an effective strategy. There are several important challenges regarding targeting the IGF system in breast cancer. First, it is uncertain which specific subtypes of breast cancer are sensitive to IGF system inhibition. Preclinical data suggests that every subtype of breast cancer (ER-positive, HER2 amplified, and triple-negative) could be IGF-driven. Second, some phenotypes driven by IGF1R do not result in an easily observable clinical outcome. For example, we have shown that disruption of IGF1R may block metastasis but does not interfere with tumor growth. Third, combining anti-IGF1R therapy with cytotoxic agents is not necessarily straightforward. We have shown that sequencing of IGF1R inhibition with administration of doxrubicin has an important effect on growth of xenograft tumors. Fourth, the role for insulin receptor in regulating breast cancer biology needs clarification. While we believe that specific anti-IGF1R therapies would be desirable, it is possible that insulin receptor could regulate breast cancer biology. Finally, there are no clear predictive factors for anti-IGF therapy. While expression of IGF1R is clearly required, receptor expression alone is not sufficient to predict response. Thus, it is encouraging that new therapies directed against key targets in breast cancer will soon likely become available. We will be challenged to fully elucidate IGF signaling pathways and their biological effects in order to optimize the therapeutic benefit of these new drugs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-3.