Targeting SOCE-Mediated Metabolism in Breast Cancer
Abstract
One in four persons will succumb to cancer over their lifetime, as cancer remains the second most important cause of premature deaths among Americans. Breast cancer is the most frequently diagnosed cancer in women and is the second leading cause of cancer-related deaths in women; however, men are also diagnosed with breast cancer. The American Cancer Society estimates that about 268,600 women and 2,670 men will be diagnosed of invasive breast cancer in year 2019. An estimated 41,760 breast cancer deaths in women, and 500 in men are expected in year 2019. These astonishing figures clearly indicate more research is needed to understand causes of breast cancers and to find newer treatment strategies. Although over past decade we have made significant advancement in diagnosis of breast cancer due to newer radiological techniques, the research to understand which tumor will become aggressive and which will not is still lacking. Additionally, we need more research to identify novel pathways that provide proliferative advantage and survival to cancer cells and can serve as targets for cancer therapy. Overarching Challenges: This proposal will address the following overarching challenges: (i) “Identify what drives breast cancer growth: determine how to stop it” and “eliminate the mortality associated with metastatic breast cancer” by identifying novel mechanisms of tumor cell proliferation and survival and testing a novel therapeutic strategy using a unique model of tumor progression. We have identified Ecdysoneless (ECD), a novel protein that regulates proliferation and survival of breast cancer cells. ECD is overexpressed in breast cancer, and its overexpression correlates with poor prognosis/shorter survival in breast cancer patients, particularly those that are ER-/ ErbB2+ and triple-negative breast cancer (TNBC), two breast cancers with known poor prognosis. In this proposal, we focus on TNBC. We have experimentally shown that overexpression of this protein in normal mammary cells in cell culture systems and in mouse model leads to mammary cancer and metastasis formation. To begin to understand how this protein regulates cell proliferation and cell survival, we have identified a paradigm-shifting mechanism of a calcium-regulated pathway called Store-operated calcium entry (SOCE) that elucidates how ECD upon overexpression promotes breast tumor cell abnormal proliferation and promotes tumorigenesis/metastasis. A large body of evidence supports the role of abnormal SOCE to promote breast cancer cell migration, invasion, and metastasis. Significantly, a novel SOCE inhibitor RP4010 (Rhizen Pharmaceuticals) has entered into Phase 1 clinical trials for lymphoma, and we have permission to use this inhibitor. Studies here are geared to gain in-depth insights into the workings of this molecular mechanism and use this to test a novel therapy approach for TNBC. Successful completion of our goals will establish the role of a novel mechanism of TNBC oncogenesis that can be targeted by a novel SOCE inhibitor, RP4010, already in clinical trials for other cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010546
Entities
People
- Vimla Band
Organizations
- United States Army
- University of Nebraska Medical Center