Overcoming Platinum Resistance in Ovarian Cancer Through BET Inhibition
Abstract
Rationale and Objectives: Epithelial ovarian cancer (EOC) claims the lives of over 14,000 women in the United States annually; fewer than 40% of women diagnosed with EOC are ever cured. Chemotherapy, and platinum-based chemotherapy in particular, is generally effective in achieving some measure of disease control early on in a patient s course. However, ultimately, cancer growth occurs despite treatment; this is known as "resistance to chemotherapy." The most common subtype of ovarian cancer is known as high-grade serous ovarian carcinoma (HGSOC); although HGSOC initially responds well to platinum chemotherapy, the majority of patients will ultimately experience relapse. Most ovarian cancer is less sensitive to chemotherapy at the time of relapse than it was at the time of initial presentation. This decreased responsiveness to chemotherapy, and platinum chemotherapy in particular, leaves patients with limited treatment options, and the vast majority of affected patients will, unfortunately, die of their disease. Laboratory data suggest that a particular type of cell with distinct characteristics, called cancer stem-like cells (CSCs), contribute to the development of chemotherapy resistance. These CSCs are characterized by high expression of a gene called ALDH1A1, which results in high levels of a protein called aldehyde dehydrogenase (ALDH). Published findings from our lab demonstrate that the ALDH protein is important in a tumor’s ability to develop resistance to chemotherapy, and eradicating CSCs, which have high levels of ALDH, results in the re-sensitization of cancer cells to chemotherapy. Drugs that inhibit a protein called BET are able to eradicate CSCs and reduce ALDH. In short, a drug that inhibits BET may help to re-sensitize cancer cells to chemotherapy. One such drug of interest is called INCB57643. INCB57643 was selected by Incyte, Inc. over other BET inhibitors because it showed a favorable side-effect profile with minimal toxicity. We aim to conduct a Phase I clinical trial with the primary objective of determining the maximum tolerated dose (MTD) of INCB57643 in combination with carboplatin chemotherapy in patients with platinum-resistant ovarian cancer. Secondly, we will assess the safety of this combination by monitoring patients for side effects, and we will evaluate the effectiveness of this combination by monitoring patients’ CT scans on treatment. Finally, we will examine patients’ tumor samples to identify biomarkers that may help predict which patients are likely to respond to therapy, and which are not. The Central Problem Addressed in the Proposed Studies and How It Would Advance the Field of Ovarian Cancer Patient Care: Through this work, we aim to develop a new treatment strategy that will help overcome a central problem and a major cause of death in patients with relapsed, platinum-resistant ovarian cancer: resistance to chemotherapy. Patients with platinum-resistant ovarian cancer have limited treatment options, and re-sensitizing their disease to known, effective therapy could be tremendously impactful. The proposed studies are a critical first step to evaluate this combination, since we will define a safe dose and preliminarily assess side effects and antitumor activity. Short-term risks with any clinical trial include exposing patients to unanticipated side effects, but the individual and larger-scale potential benefits of prolonging effective cancer treatment are substantial. The results from this proposal will be a foundation to launch later phase evaluation of the combination of a BET inhibitor with carboplatin, which would be necessary to establish this combination as a new treatment paradigm in treating patients with platinum-resistant ovarian cancer. In addition, the laboratory studies we propose alongside the clinical trial will help identify patients likely to respond, with the goal of personalizing patient care. Since the majority of patients with ovarian cancer develop relaps
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810256
Entities
People
- Rugang Zhang
Organizations
- United States Army
- Wistar Institute