Date of Award

9-22-2010

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

David Rimm, MD PhD

Abstract

EXPLORING A THERAPEUTIC ROLE FOR IGF1R INHIBITORS IN TRIPLE-NEGATIVE BREAST CANCER Onyinye Offor, Catherine Sullivan, Sofya Rodov, Kimberly Lezon-Geyda, Lyndsay Harris. Section of Medical Oncology, Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT There is substantial preclinical and clinical data suggesting that triple-negative breast cancer (TNBC), a breast cancer subtype that lacks HER-2, estrogen- and progesterone-receptor expression is associated with obesity, insulin resistance and metabolic derangements involving the insulin-like growth factor (IGF) pathway. We hypothesized that IGF-1 receptor (IGF1R) targeted therapy will be active in TNBC and will enhance the activity of chemotherapeutic agents used for breast cancer. We aimed (1) to determine if AG1024, an experimental tyrosine kinase inhibitor of IGF-1R, or Figitumumab, a human anti-IGF1R antibody, has a cytotoxic effect on TNBC cell lines as a single agent and (2) to determine if combining AG1024 or Figitumumab with conventional chemotherapeutic agents, doxorubicin or paclitaxel, in TNBC cell lines would enhance their cytotoxic effects. To evaluate the effect of these agents, cytotoxicity assays were conducted using four TNBC cell lines (MDA-MB-231, MDA-MB-468, SUM149 and BT20) and a non-TNBC cell line, MCF7, for comparison. Our results showed that AG1024 caused a dose-dependent decrease in cell viability in TNBC cell lines and that TNBC cell lines were more sensitive to AG1024 than non-TNBC cell lines. Also, the cytotoxic effects of AG1024 were enhanced in all TNBC cell lines by the addition of paclitaxel and in three out of four TNBC cell lines upon adding doxorubicin. Figitumumab monotherapy failed to have cytotoxic effects on TNBC cell lines but the anti-IGF1R antibody cytotoxic effects were enhanced by addition of doxorubicin in two TNBC cell lines and by addition of paclitaxel in one TNBC cell line. This study suggests that therapies targeting the IGF1R may have clinical application in the treatment of TNBC and tyrosine kinase inhibitors, such as AG1024, may be better suited for treating TNBC than monoclonal antibodies.

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