Hedgehog Inhibition Disrupts the Immune Privileges of Breast Cancer
Abstract
Through studies proposed in this application, we will address the overarching challenge of eliminating the mortality associated with metastatic breast cancer. Cancer cells interact with other cells in their surroundings and adapt to their environment. This niche contains abundant immune cells and is commonly referred to as the tumor immune microenvironment. We expect that our immune system will eliminate the tumor. However, cancer cells take over the immune system and create a tumor-promoting environment. This is even more obvious in triple-negative breast cancer (TNBC), which has a very potent tumor-promoting immune cell composition. This further exacerbates the complications of TNBC that does not have any markers for targeted treatment. While a combination of immunotherapy and chemotherapy seems to benefit a subgroup of early-stage TNBC patients, there are still a majority of patients for whom we need to do better by broadening the arsenal of chemotherapeutics. Informed by these challenges and the need for more effective treatment options for TNBC, my lab has a long-standing research program focused on dysregulated Hedgehog (Hh) signaling in TNBC. What is the ultimate applicability of the research, what patient population would it benefit, and how will it impact the BCRP’s mission of ending breast cancer? What is the feasibility of translational potential? We discovered that the U.S. Food and Drug Administration (FDA)-credentialed, orally available pharmacological Hedgehog (Hh) inhibitor, Vismodegib, reduces tumor-promoting immune cells in the triple-negative tumor and increases the population of tumor-eradicating immune cells. In addition to discovering the molecular changes that orchestrate these immune alterations, we will test the possibility that this altered immune environment of the Vismodegib-treated mammary tumor will be more responsive to immune checkpoint therapy. We will test a neoadjuvant strategy with Vismodegib in combination with anti-PD1 treatment with the goal of impeding metastasis and improving outcomes to decrease the mortality associated with TNBC. Our investigations are carefully designed to simulate a newly diagnosed TNBC patient and as such, our studies are positioned to benefit the TNBC patient community. Our goals are attainable because anti-PD1 therapy and Vismodegib are FDA-approved, thereby allowing us an immediately translatable path to the breast cancer clinic. What are the benefits and risks? What is the projected time it may take to achieve a patient-related outcome? Vismodegib and anti-PD-1 are FDA-credentialed with manageable side effects. As such, there seem to be no foreseeable risks or delays in achieving a patient-centric outcome. Thus, the outcomes will be transformative, fundamentally evolved, and have the potential to make a tangible impact.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310779
Entities
People
- Lalita A. Shevde
Organizations
- United States Army
- University of Alabama at Birmingham