Targeting Tumor-Initiating Cells for the Therapeutics of Breast Cancer
Abstract
Despite advances in diagnostics and treatment, advanced metastatic breast cancer remains incurable. One pathway implicated in metastatic breast cancer involves hyperactivated signaling through the HER2 receptor. This receptor is overexpressed on cells of 20%-30% of metastatic breast cancers, and elevated HER2 expression correlates with poor prognosis. The HER2 receptor is often targeted as a first-line therapy for HER2+ breast cancer. Drugs targeting HER2 include trastuzumab (Herceptin), pertuzumab, Ado-trastuzumab emtansine or lapatinib, which are used alone or in combination with chemotherapy (e.g., docetaxel or paclitaxel). At first for over 50% of patients, HER2-targeted therapy is effective, but cancers quickly develop resistance. The reasons why resistance develops are largely unknown, but resistant cells likely originate in a reservoir of stem-cell-like, tumor-initiating cells (TICs). Under the pressure of current therapies, TICs have a survival advantage and may escape therapy. Thus, TICs likely account for drug resistance, tumor recurrence, and metastasis. To stop recurrence of HER2-positive breast cancer, breast TICs must be ablated, but currently, effective approaches for eliminating TICs are lacking. Our preliminary data indicate that breast TICs may escape therapy in part because they find ways to transactivate the HER2 receptor via pathways mediated by G protein coupled receptors (GPCRs). GPCRs are the largest family of cell-surface receptors and highly desirable drug targets for diverse diseases, including cancer. A subset of GPCRs, termed Gi/o-GPCRs, signal through Gi/o proteins. Gi/o-GPCRs are particularly important in breast cancer; many are overexpressed in breast cancer cells and implicated in cancer metastasis. Approximately 15% of breast cancers overexpress Gi/o proteins and 2% express a gain-of-function G-alpha-o mutant, R243H. R243H expression can neoplastically transform normal mammary epithelial cells. These data imply that blocking Gi/o-GPCR signaling might halt progression of breast cancer and maintain its response to therapy. Our proposal aims to pinpoint how TICs drive development of HER2+ breast cancer. We posit that upregulated Gi/o-GPCR signaling in TICs transactivates HER2 in the absence of a HER2 ligand. We will test whether blocking Gi/o-GPCR signaling prevents TICs from being able to transactivate HER2, thereby keeping them sensitive to HER2-targeted therapies. Our studies will use preclinical mouse models that closely recapitulate the pathology and heterogeneity of human HER2+breast cancer, such as genetically engineered and patient-derived xenograft models. Within 3 years, we should have proof-of-principle concerning whether upregulated Gi/o-GPCR signaling may serve as a therapeutic target and/or novel prognostic marker for trastuzumab-resistant HER2+ breast cancer. Moreover, our studies should lay the foundation to support development and translation of novel drugs that selectively target the Gi/o-GPCRs or their downstream c-Src signaling pathway, paving the way for clinical trials. Therefore, our proposed studies could potentially uncover a novel and efficacious approach for developing a new Gi/o-GPCR-targeted therapy that would improve the outcome for HER2+ breast cancer patients, including the women in the military services. This could be a major breakthrough both in our understanding of the molecular mechanisms that drive HER2+ breast cancer progression and in our effort to eliminate suffering and death caused by HER2+ breast cancer, considering that ~30% of breast cancers overexpress HER2. As such, our studies effectively address several Fiscal Year 2015 Breast Cancer Research Program overarching challenges, including "eliminating the mortality associated with metastatic breast cancer, distinguishing aggressive breast cancer from indolent cancers," and "identifying what drives breast cancer growth and metastasis."
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610261
Entities
People
- Songhai Chen
Organizations
- United States Army
- University of Iowa