Estrogen receptor 1 (ER) is expressed in 70% of new breast cancers but de novo and acquired resistance to tamoxifen or aromatase inhibitors (AI) limit their efficacy. The cell cycle inhibitor, p27, is required for therapeutic effects of antiestrogens. p27 is reduced in 60% of human breast cancers and is a poor prognostic factor, particularly in ER+ cancers. Src phosphorylates p27 to promote its degradation. Her2 or Src activation in ER+ breast cancer cells alters p27 phosphorylation, impairs its Cdk2 inhibitory function and causes antiestrogen resistance. Expression profiling has revealed a Src activation gene signature in up to 40% of human breast cancers that powerfully predicts growth arrest by Src inhibitor drugs in vitro. We found Src activation in 39% of ER+ human breast cancers is associated with low p27. This may predict resistance to endocrine therapy. Antiestrogen resistance was reversed in ER+ breast cancers in vitro by combining the Src inhibitor drug, AZD0530, with tamoxifen or anastrozole. AZD0530 increased p27 and inhibited proliferation when added to anastrozole. AZD0530 also synergized with anastrozole to inhibit growth of orthotopic MCF-AROM5 xenograft tumors in vivo. Thus, AZD0530 may oppose resistance to the AI anastrozole in human breast cancers. We investigate the hypothesis that Src inhibition combined with anastrozole will lead to a greater reduction in tumor volume than anastrozole alone and increase in pCR rate following neoadjuvant treatment setting of locally advanced breast cancer. Moreover, we postulate that responsive breast cancers will show a greater increase in p27 with treatment and a Src activated protein or gene expression profile in the primary tumors that will change during treatment. We also postulate that changes in the tumor initiating cells (cancer stem cells) may be critically linked to both immediate responsiveness to neoadjuvant therapy and to long term outcome.
AIM 1 We propose a Phase II study to test if anastrozole combined with the Src inhibitor AZD0530 is better able to reduce tumor volume than anastrozole alone in postmenopausal women with locally advanced ER+/or PR+ (HR) breast cancer. This trial will be carried out after a Phase I trial to test tolerability and bioavailability of daily oral anastrozole and AZD0530 co-administration in post-menopausal women with HR+ metastatic breast cancer. A secondary trial endpoint will evaluate the ability of serial MRI changes in tumor diameter, volume and blood flow to complement clinical MD measurement of response. To define biologic endpoints or predictors of treatment response that may assist in patient selection for subsequent studies, AIM 2 will assay Src targets and upstream regulators using protein and gene expression profiles and quantitate tumor initiating cells in diagnostic samples, tumor biopsies at 8 weeks and in cancers resected after 4-6 months of neoadjuvant treatment with anastrozole alone or anastrozole and AZD0530. Evidence of short term efficacy of this new Src inhibitor and identification of predictive biomarkers would support subsequent phase II-III trials and further refinement of the potential predictive value of molecular Src activation profiles.
This grant will support a clinical trial that combines, for the first time, a novel molecular targeted drug, AZD0530, that inhibits the Src oncogene, with the antiestrogen anastrozole for women with breast cancer. In addition to testing the safety and early efficacy of this drug combination, this study will permit molecular tests to help predict which patients are likely to have a good response and which will have resistant disease. This trial may form the basis for subsequent, larger clinical trials to enhance the efficacy of endocrine therapy for breast cancer.
