A Novel Druggable Epigenetic Vulnerability Pathway in Breast Cancer
Abstract
Breast cancer is one of the most diagnosed cancers in women. According to the National Cancer Institute, over 226,000 women will be diagnosed with breast cancer and 41,000 will die due to breast cancer this year in the United States alone. The deaths due to breast cancer mainly occur due to the lack of effective therapies for treating advanced metastatic breast cancers. Specifically, for a breast cancer that expresses an oncoprotein MYC, the prognosis is particularly poor. These patients show aggressive tumor growth and metastatic spread. Additionally, breast cancer patients that have MYC protein expression in their tumor have high chance for their tumors to come back after treatment, a phenomenon also known as recurrence. Also, MYC-high breast cancers are typically resistant to treatment. It is estimated that about half of all breast cancers overexpress MYC protein. To make the matter worse, there is no effective treatment for these MYC-expressing breast cancers. Thus, treating MYC-expressing breast cancer remains an area of unmet medical need and requires immediate scientific attention. Therefore, we decided to identify new approaches for treating these MYC-expressing breast cancers. To do so, we developed an experimental approach based on the mouse model of human breast cancer tumor growth and metastasis. In this model of breast cancer tumor growth and metastasis, we inhibited the expression of 395 genes that encodes for epigenetic regulators. Epigenetic regulators are shown to be deregulated in breast cancer, and several of them are currently being tested for cancer therapy. Our experimental approach used a method called RNA interference. RNA interference works by specifically inhibiting the expression of specific target gene and thus can be used to study their biological function in cancer cells. Using this approach, we identified an enzyme named PRMT4 that when inhibited specifically kills the MYC-overexpressing breast cancer cells. Based on these results, in this research proposal, we will determine the role of PRMT4 in the growth and metastasis of breast cancer. For this purpose, we will use the breast cancer cell culture-based approaches and mouse models of breast cancer growth and metastases. Finally, and most importantly, we will test a small molecule drug named TP064 to specifically block the activity of PRMT4 to effectively treat MYC-overexpressing breast cancers using preclinical mouse models that recapitulate human breast cancer growth and metastasis. We will also include a humanized mouse model that carriers patient-derived tumors from real breast cancer patients, known as patient-derived xenograft or PDXs. Taken together, our proposed studies will establish the utility of PRMT4 as a drug target for treating breast cancer patients. Our research is highly translational because it will validate effective PRMT4 inhibitory drug TP064 for treating MYC-overexpressing breast cancers. Therefore, we anticipate that PRMT4 inhibitory drugs, such as TP064, can be rapidly brought to the clinic for clinical trials for treating breast cancer patients, including for treating patients that have difficult-to-treat metastatic and drug-resistant breast cancers with MYC overexpression. Furthermore, because PRMT4 inhibition will only kill MYC-overexpressing breast cancers, we predict that our therapeutic approach will be highly specific against MYC-overexpressing breast cancer cells and will produce minimal therapy-related side effects in breast cancer patients. Therefore, our proposal is in line with the Breast Cancer Research Program’s mission to end breast cancer and will address the overarching challenges to identify factors that drive breast cancer growth and determine how to stop it. Additionally, our research will also have significant impact on eliminating the mortality associated with metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910084
Entities
People
- Narendra Wajapeyee
Organizations
- United States Army
- University of Alabama at Birmingham