Targeting Chromatin Regulator WDR5 to Treat Breast Cancer Metastasis
Abstract
In the United States, breast cancer is the most common type of cancer and the second most common cause of cancer death in women. Advanced breast cancer is associated with significant mortality because it metastasizes or spreads to other vital organs. The available treatment options only have limited clinical benefits for a small subset of patients. Thus, it is critical to identify and validate new drug targets for the development of efficacious therapies. Similar to genetic aberrations, a different type of change that occurs without a change of DNA sequence, termed epigenetic alterations, are likely the major drivers of breast cancer metastasis. However, these changes are not well understood in the context of breast cancer metastasis. Our long-term goal is to elucidate how these alterations contribute to cancer development. Because epigenetic changes are reversible, enzymes that regulate these changes are very attractive targets for cancer therapy. To this end, we recently identified an epigenetic protein WDR5 as a new therapeutic target for breast cancer metastasis. This protein can be removed, using newly developed small molecules called degraders, from tumor cells to treat triple-negative breast cancer (TNBC). We showed that the WDR5 regulated pathway correlates with poor survival of breast cancer patients. We showed that WDR5 is required for tumor metastasis in multiple animal models of cancer. However, further dissection of the roles of WDR5 in breast cancer progression and metastasis, and evaluation of WDR5 targeting strategies, are needed to translate these findings to the clinic. Therefore, the objectives of this project are to determine whether and how WDR5 depletion can be used to treat metastatic breast cancer, and to develop WDR5 targeting strategies. In Aims 1 and 2, we will further study how WDR5 promotes tumor growth and metastasis in TNBC models. In Aim 3, we will evaluate the efficacy of WDR5 degrader monotherapy and combination therapy with everolimus (an approved drug to treat hormone receptor positive, HER2 negative breast cancer) on metastatic TNBC. Regarding the ultimate applicability of the proposed research, our proposed studies will address several overarching challenges related to metastatic breast cancer, including: eliminating the mortality; identifying drivers of cancer growth and metastasis; preventing lethal recurrence; and developing novel treatment regimens. Our study to understand and target breast cancer metastasis will benefit breast cancer patients with metastatic disease. Since our preclinical mouse models are based on TNBC, patients with TNBC, the most aggressive subtype of disease, will likely benefit the most from our research. In addition, we have shown that WDR5 is critical for the growth of ER+ and HER2+ breast cancer, and our findings could also benefit patients with these subtypes of breast cancer. Our proposed translational studies could lead to new treatment regimens to treat metastatic breast cancer and reveal new prognostic and/or predictive biomarkers of metastatic breast cancer. We will achieve a patient-related impact by validating WDR5 degrader as a new therapeutic strategy and revealing biomarkers of this drug for metastatic breast cancer in 2 to 3 years. Our collaborator Dr. Jian Jin is working closely with Cullgen, a biotech company, to further develop WDR5 degraders for clinical use. As the Principal Investigators (PIs) collaborate closely with clinicians, including Dr. Lajos Pusztai and Dr. Patricia LoRusso who run phase I breast cancer clinical trials at the Yale Cancer Center, this strategy could be translated rapidly to the clinic. Relevant to this, PI Dr. Qi Yan and Dr. Pusztai communicate frequently as scientific co-directors of the Center for Breast Cancer at Yale Cancer Center and Smilow Cancer Hospital. In summary, our studies are expected to reveal a paradigm-changing treatment strategy, which could be rapidly tested in the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310602
Entities
People
- Qin Yan
Organizations
- United States Army
- Yale University