Breast Cancer Pathways
Development of technologies providing improved surrogate predictive biomarkers of Avastin
Triple negative breast cancers (TNBCs) comprise 12-25% of newly diagnosed breast cancer cases, but poses a great challenge in making treatment decisions and their prognosis is poor. Most targeted breast cancer therapies don’t work in TNBC, the only promising targeted agent against TNBC is bevacizumab, an angiogenesis inhibitor drug. In February 2008 the FDA granted approval for Avastin in certain breast cancer types including TNBC. Until late 2010 Avastin was used in combination with chemotherapy in thousands of TNBC patients, and in a fair proportion proved highly successful. But responders and nonresponders couldn’t have been identified early on, side effects and rare fatal adverse events were encountered, and the FDA revoked Avastin’s license in breast cancer on November 18, 2011, and a valuable treatment option was lost for the good responder TNBC patients. Currently renewed efforts are undertaken to identify biomarkers, by which good responders for Avastin can be identified before or during the early phase of treatment. Our twofold proposal serves this aim. 1./ We plan to study bevacizumab-induced signaling pathways in tumor tissue by infrared technology, to identify new, more effective Avastin-containing combinations in preclinical animal models. 2./ We plan to study bevacizumab-induced signaling pathways in the normal vasculature by Pulse Wave Velocity (PWV) measurements in experimental animals. PWV parameters reflect increased arterial wall stiffness during the early course of treatment as a surrogate biomarker of bevacizumab’s anti-tumor efficacy. PWV measurement is a more sensitive surrogate biomarker of Avastin’s effect on the systemic vasculature than hypertension, and strongly correlates with its anti-tumor efficacy. After properly developing the system in animal models, the development of a human version for clinical use is planned.
Nov 19, 2011