My research has been focused on pre-clinical and early phase clinical investigations in developing molecular therapeutics for breast cancer. Currently, the laboratory is focused on the testing of IGF-IR antibodies and Chk1 inhibitors.
IGF/IGF-IR signaling is a crucial component of normal growth and is essential for malignant transformation and the development of breast cancer. Upon binding to IGF ligands, IGF-1 and IGF-2, IGF-IR undergoes autophosphorylation and activation of the receptor's tyrosine kinase activity which triggers a cascade of downstream signaling especially the PI3K pathways mediated by the insulin receptor substrate (IRS-1) and the Ras-Raf-MAPK signaling. Inhibition of IGF-IR suppresses xenograft growth of breast cancer cells in athymic mice. Therefore, IGF-IR is an attractive therapeutic target in breast cancer. However, the activity of single agent IGF-IR antibody is likely to be limited due to a variety of reasons. For instance, an IGF-IR antibody may not be active against tumors with constitutive activation of the PI3 Kinase pathway which is frequently observed in breast cancer. Recent studies suggested that IGF-IR signaling plays an important role in attenuating the anti-tumor effect of mTOR inhibitors through up-regulating AKT activity. The increased AKT activity following mTOR inhibition through this negative feedback loop could work against the anti-cancer effect of mTOR inhibitors. Targeting of IGF-IR by an inhibitor or antibody IMC-A12 abrogated the induction of AKT activity and enhanced the antiproliferative effect of rapamycin. These data suggest that IGF/IGF-1R may play a role in attenuating the effect of mTOR inhibitors and that clinical evaluation of combined inhibition of both pathways is reasonable. We therefore initiated a multi-center phase I/II study of IMC-A12 (ImClone Inc.), an IGF-IR antibody, in combination with temsirolimus in patients with metastatic breast cancer. Correlative studies on patients' specimens will be investigated to correlate with therapeutic efficacy. In addition, preclinical studies in patient tumor-derived breast cancer xenografts (HAMLET: Human and Mouse Linked Evaluation of Tumors) are underway to evaluate the potential predictors of response for this combination.
Chk1 plays a critical role for cell cycle arrest in response to DNA damaging agents, especially in p53 defective tumors. Inhibition of Chk1 function in p53 defective tumor cells induces "mitotic catastrophe" and apoptosis in response to DNA damaging agents. In collaboration with Drs. Helen Piwnica-Worms and Paula Fracasso, we are conducting an exploratory study of UCN-01, a Chk1 inhibitor, in combination with irinotecan in patients with triple negative breast cancer (negative for estrogen receptor, progesterone receptor and HER2 overexpression) and in patient tumor derived-breast cancer xenografts.
