Exploiting Metabolic Vulnerabilities to Target Multidrug-Resistant Ovarian Cancer
Abstract
Scientific Rationale and Objectives: Ovarian cancer is the deadliest gynecological cancer with over 21,000 new diagnoses and almost 14,000 deaths estimated in 2020 alone. Poly(ADP-ribose) polymerase (PARP) inhibitors are a new class of drugs that has transformed the clinical care of ovarian cancer over the past few years. However, emerging data from clinical trials shows that a subset of patients do not gain benefit from these drugs. New combinations have therefore been identified, such as inhibitors of another protein called Ataxia Telangiectasia Mutated (ATM), which are currently in Phase I clinical trials in combination with PARP inhibitors. Unfortunately, this combination is also not curative as a subset of multi-drug resistant cancer cells persist after treatment. Therefore, new therapies are needed to discover a long-term cure for these women. This proposal seeks to address this critical problem in ovarian cancer. Just like humans, ovarian cancer cells have to eat nutrients to survive. We discovered that ATM inhibitors increase the amount of nutrients ovarian cancer cells eat through a process called “macropinocytosis,” where ovarian cancer cells engulf nutrients in a non-specific manner. This leads to the ovarian cancer cells being able to grow and survive. At the same time, eating those nutrients from their surroundings limits how much immune cells can eat. The immune cells are like an army poised to battle against the tumor cells. Therefore, inhibition of ATM not only makes cancer cells more hearty, it may also limit the ability of the immune cell army to battle the ovarian cancer cells. In this scenario, the ovarian tumors comes out as the victor. In this proposal, we aim to determine how to kill the multi-drug resistant ovarian cancer cells using a two-pronged approach. First, we will limit the amount of nutrients ovarian cancer cells eat through inhibition of macropinocytosis, which we hypothesize will inhibit the multi-drug resistant phenotype observed in ATM and PARP inhibitor-treated cells. Second, we will exploit the fact that the immune cell army now has more fuel to eat, allowing it to conquer the tumor. Expansion of the Previous Award: The previous OCRP Pilot Award was based on the observation that ATM inhibitors made ovarian cancer cells more sensitive to the FDA-approved dyslipidemia drug fenofibrate. We hypothesized that ATM inhibitors made ovarian cancer cells eat more glucose through upregulation of proteins that specifically transport glucose from the outside of the cell into the cell. During the course of our studies, we found that this initial hypothesis was wrong. Although ATM inhibitors do increase the ability of cancer cells to eat glucose, we determined that other nutrients were also increased, and this was not due to the transporter proteins. Instead, we discovered that ATM inhibitors increase macropinocytosis. Using both cell lines and animal models, we found that macropinocytosis is critically important for ovarian cancer cells to grow and survive. This is a completely new discovery that will help us to better understand how ovarian cancer cells respond to ATM inhibitors, which are currently in Phase I clinical trials. The expansion of the OCRP Pilot Award is built on this basic science foundational discovery and the identification of a multi-drug resistant cell population after treatment with combined ATM and PARP inhibitors. We will use our new knowledge built on results funded by the OCRP Pilot Award to examine whether inhibition of macropinocytosis using FDA-approved drugs overcomes the multi-drug resistance phenotype. Relevance to the Vision and Mission of the OCRP: The proposed studies are highly relevant to the vision and mission of the OCRP. The proposed studies will use disease-relevant ovarian cancer models to study resistance of ovarian cancer. They will also further our understanding of immune cells and their activity in ovarian cancer, w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110840
Entities
People
- Katherine M Aird
Organizations
- United States Army
- University of Pittsburgh