IGF-IR targeted therapy for the treatment of metastatic breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #71 The type I insulin-like growth factor receptor (IGF-IR) regulates multiple aspects of malignancy and is the target of drugs currently in clinical trials. While its role in proliferation and survival is well-studied, the regulation of metastasis by IGF-IR is not as clearly delineated. Previous work showed that disruption of IGF-IR signaling via a dominant negative IGF-IR inhibited metastasis of MDA-435A/LCC6, a metastatic variant of the MDA-MB-435 cancer cells which form lung metastases when injected into the mammary fat pad of mice. To establish a clinically applicable approach to IGF-IR-mediated inhibition of metastasis, the effect of an inhibitory antibody against IGF-IR, EM164 on metastasis of cancer cells was examined. EM164 and AVE1642 did not inhibit primary tumor growth of LCC6 cancer cells but inhibited metastasis of these cells. Disruption of IGF-IR also resulted in a decreased number of circulating tumor cells (CTC) in blood of tumor-bearing mice. Disruption of IGF-IR inhibited invasion across Matrigel in vitro. When tumor cells were directly injected into the circulation via the tail vein of mice, IGF-IR disruption also resulted in significant reduction of pulmonary nodules, suggesting that regulation of invasion is not the only function of IGF-IR signaling. Inhibition of IGF-IR rendered cells more susceptible to anoikis. AVE1642 also inhibited metastasis of MDA-MB-231BO cells but not their primary tumor growth. Thus, IGF-IR regulated metastasis independently of tumor growth. We next examined if inhibition of IGF-IR could also be effective once micrometastases were already established since clinically many patient have micrometastases at the time of diagnosis. CTC were detected in blood of mice bearing LCC6 tumors approximately 12 days after injection of cells in the fat pad. At this time point micrometastases were not yet detected in the lungs by H&E staining. Therefore, we used presence of these CTC as an early surrogate marker of micrometastases in our model. Mice injected with LCC6 cells in the mammary fat pad were randomized to receive EM164 treatment on day 4 or day 12 after injection of cells. Treatments were administered until day 28 after injection of cells in the fat pad. There was a greater inhibition in the number of CTC in mice that received treatments on day 4 at which point CTC were not detectable, compared to mice that received EM16 beginning on day 12 when CTC were detectable. Similarly, when metastases were monitored by bioluminescence imaging of luciferase expressing LCC6 cells injected into the tail vein, mice that received EM164 starting on day 3 had greater inhibition of metastases compared to mice that received treatment starting on day 12. Thus, the multiple phenotypes regulated by IGF-IR must be considered and clinical trials of this therapeutic strategy may need to adjust their endpoints for assessing benefit by taking into account that inhibition of IGF-IR signaling may inhibit metastasis without affecting primary tumor growth. These results also suggest that inhibition of IGF-IR will be most beneficial to prevent metastases, but may be less successful in treating established micrometastatic disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 71.