Unraveling the Functional Molecular Nodes Underlying Benign-to-Malignant Transitions in Breast Cancer
Abstract
Overarching challenges: This study will address two overarching challenges: (1) Identify what drives breast cancer growth; determine how to stop it, and (2) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. What types of patients will it help and how will it help them? In recent years, there has been a dramatic increase in the detection of Ductal Carcinoma In Situ (DCIS). In 2021, there will be an estimated 60,290 new DCIS cases. DCIS is a non-obligate precursor to invasive ductal carcinoma. A large number of cases (approximately 20%-53%) will progress to Invasive Ductal Carcinoma (IDC) if left untreated. It is known that DCIS increases (8-10 times) the risk for invasive breast cancer. With such a large number of new cases of DCIS each year, it will be greatly beneficial to develop prevention strategies to impede DCIS and prevent DCIS-to-IDC transition. We believe that DCIS-at-risk of developing invasive disease has a unique biology that results in the aggressive progression. Our study is designed to understand the unique biology of DCIS-at-risk and we plan to exploit this knowledge to develop effective strategies against DCIS-to-IDC progression. In our initial studies, we observed a significant loss of tumor suppressor Serine Threonine Kinase 11/Liver Kinase B1 (STK11/LKB1) in human DCIS/IDC tandem lesions (where DCIS showed a transition to IDC in the same breast). Also, STK11-null DCIS cells exhibit higher invasion and migration potential in comparison to control-DCIS cells showing inherently aggressive nature acquired upon STK11-loss. We used a pooled small hairpin (sh) RNA interference screen in STK11-null DCIS cells and uncovered genes that, when suppressed, specifically inhibit DCIS growth, and discovered that MED1, an oncogenic transcription factor, functions as a survival input for DCIS cells. Our novel preliminary findings also suggest that with inherent loss of STK11, DCIS cells gain an oncogenic input in the form of activated MED1 signaling. Encouraged with our novel preliminary findings, we propose to investigate how loss of STK11 in DCIS might lead to acquisition of higher MED1, and drive DCIS-to-IDC transition. We have planned to exploit our valuable cohort of clinical samples and analyze DCIS and IDC samples to establish STK11-loss and elevated MED1 as biomarkers of aggressive progression of DCIS. We will utilize these biological insights to test safe and effective therapeutic strategies to target DCIS-at-risk of progression to IDC. We have screened ~ 30 known bioactive compounds to discover a natural compound, Erucin, a bioactive agent from cruciferous vegetables, which is orally available, non-toxic, and most effective at inhibiting MED1. We have also developed novel analogs of Erucin with increased effectiveness. Based on these important developments, we propose to conduct mouse trials using mouse models of spontaneous DCIS development and intraductal DCIS-in-mouse models. In addition, based on our preliminary findings, we will also examine whether we can repurpose existing drugs verteporfin and dasatinib for inhibition of DCIS progression. Blocking the overexpressed MED1 as a strategy to inhibit DCIS-to-IDC progression is an approach that is based on the unique biology of DCIS-at-risk and will significantly impact DCIS patients at risk of developing IDC. Potential clinical applications and projected time to patient-related outcome: The proposed studies will provide new molecular understanding regarding DCIS-to-IDC progression and establish key molecular nodes that drive aggressive progression of DCIS. Another very important aspect of this project is to examine the efficacy of a bioactive compound, Erucin, for inhibiting DCIS-to-IDC progression. Successful completion of these preclinical studies using Erucin and its novel analogs for DCIS will provide support for their future clinical development. We are
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210110
Entities
People
- Dipali Sharma
Organizations
- Johns Hopkins University
- United States Army