Use of Synthetic Antibodies Targeted to the Jak/Stat Pathway in Breast Cancer
Annual rept. 15 Feb 2010-14 Feb 2011
NORTHWESTERN UNIV EVANSTON IL
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This proposal seeks to generate SABs synthetic antigen binders against the PRLr prolactin receptor signaling complex to systematically inhibit and modulate its important activities in breast cancer. This complex has clearly been demonstrated to play a significant role in the development and spread of this disease, and yet the generation of pharmacologic agents that can specifically block their function has been slow. We hypothesize that SABs can be rapidly generated to the PRLr, CypA, CypB, Jak2, Stat3, and Stat5 and delivered into the cell, where these reagents will block breast cancer cell growth, survival, and spread. We have successfully generated inhibitory SAB to Cyp A and B. We have also identified SAB that are potent inhibitors of PRL binding to the ECD, through a novel allosteric mechanism, as determined by x-ray crystallography. The anti- PRLr SAB have been found to block PRL-driven signaling and breast cancer cell proliferation. It is the intent of this proposal to validate the efficacy of these highly innovative reagents on a panel of breast cancer cells in vitro, with future translation into pre-clinical testing.
- Medicine and Medical Research