Therapeutic Strategies to Disrupt Cx26-FAK-NANOG Complex to Attenuate Cancer Stem Cell Self-Renewal and Triple-Negative Breast Cancer Progression
Abstract
Rationale, Objective, and Aims: Triple-negative breast cancer is the most aggressive breast cancer subtype and is resistant to therapies. Our objective is to neutralize cancer stem cells, which are thought to underlie resistance to chemotherapeutics, as well as recurrence and metastasis. In parallel, we seek to minimize collateral damage to normal non-cancer cells. We identified that the protein connexin 26 (Cx26) is necessary and sufficient for the survival of cancer stem cells in triple-negative breast cancer models. While Cx26 was previously proposed to be a tumor suppressor, epidemiological studies suggest otherwise, as patients with high Cx26 had a poorer prognosis. Our studies indicate that Cx26 promotes cancer stem cell survival by forming a protein complex with the transcription factor NANOG, a master regulator of cancer stem cell function, and focal adhesion kinase in triple-negative breast cancer but not in other breast cancers. Our objective is to prevent this complex from forming and thereby inhibit cancer stem cell survival and growth. We will develop a therapeutic strategy to target complex formation that will be tested in preclinical models. Overarching Challenge: The current studies effectively address the following Overarching Challenges: “identify determinants of breast cancer initiation, risk, or susceptibility” and “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” These studies will impact triple-negative breast cancer patients, who experience the worst prognosis of breast cancer patients due to the lack of therapeutic targets for inhibiting the growth of the cancer stem cells that reside in these tumors. By understanding how these proteins form a complex and drive cancer stem cell function, we can identify ways to prevent this interaction and therefore compromise cancer stem cell-mediated tumor growth. Patient Population: Triple-negative breast cancer represents 15%-20% of breast cancer cases and occurs typically in younger African American women, and patients have an overall survival of 3-5 years post-diagnosis. The name “triple-negative” refers to the lack of estrogen and progesterone receptors as well as the absence of amplification of the human epidermal growth factor receptor 2 oncogene. By virtue of the lack of expression of these receptors, patients with triple-negative breast cancer cannot benefit from the available highly effective targeted clinical therapeutics so are treated with toxic chemotherapeutics including doxorubicin. Thus, there is a clear need for developing new therapies for triple-negative breast cancer. Clinical Application: Based on encouraging preliminary data, we expect these studies to lead to new clinical approaches for the treatment of triple-negative breast cancer. Specifically, our studies will demonstrate the importance of the protein interactions between Cx26, NANOG, and focal adhesion kinase and assess a strategy that targets the interaction between these proteins that can be used for therapeutic development. The successful completion of these studies should provide a framework for development of therapeutics for enhancing patient survival for a cancer with otherwise poor prognosis. Projected Time to Achieve Outcomes: To achieve a patient-related outcome, extensive preclinical testing is necessary followed by systematic testing in a clinical trial setting. The studies in this proposal will provide needed preclinical evidence to develop a cancer stem cell targeting strategy that disrupts the Cx26/NANOG/focal adhesion kinase protein complex that would provide the roadmap for initiation of a clinical trial. It is anticipated that this initial step will be completed by the end of the 3-year funding period. Impact on Ending Breast Cancer: By identifying determinants and signaling complexes necessary for the maintenance of cancer stem cells to develop a therapeutic target
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910503
Entities
People
- Ofer Reizes
Organizations
- Cleveland Clinic
- United States Army