Mechanisms of Adstiladrin Sensitivity and Resistance in Bladder Cancer
Abstract
Objective and Rationale: High-risk non-muscle invasive bladder cancer (NMIBC) is an aggressive and potentially life-threatening form of the disease. Patients with high-risk NMIBC are treated with surgery and a form of immunotherapy called Bacillus Calmette-Guerin (BCG), which is injected directly into the bladder through a catheter. Unfortunately, there have been chronic shortages in BCG supply, which have caused many patients to receive less BCG than is recommended by international guidelines. In addition, most patients experience recurrences and many develop BCG-resistant disease. While the recent Food and Drug Administration (FDA) approval of the immunotherapy, pembrolizumab (Keytruda), provides effective therapy for some of these patients, the drug only benefits about one-fifth of them, and the rest are treated with radical surgery (cystectomy) that involves removing their entire bladders. Therefore, developing therapies for high- (and intermediate-) risk NMIBC that work as well as BCG does but are not subject to chronic supply shortages is a very high clinical priority, as is developing therapies that work in BCG-resistant disease and can allow patients to keep their bladders. Our team developed a new drug called Adstiladrin which works in almost half of patients with BCG-resistant disease. We are planning future clinical trials with the drug to compare its effects in patients who would otherwise get BCG and that combine Adstiladrin with other drugs to enhance its clinical activity. However, we do not yet know enough about its mechanisms of action to know how it works and why resistance develops in some patients. Fortunately, we have access to all of the tissues that were collected in the recent clinical trial that is being reviewed by the FDA for drug approval, and we have unique laboratory tools that can also be used to understand its mechanisms. Here we propose to use these resources to better understand Adstiladrin’s mechanisms of action to develop biomarker sequencing tests that can be used for patient selection and to identify resistance mechanisms that can be targeted by other currently available and investigational therapies. Ultimate Applicability of the Proposed Research: Biomarkers can be used to give Adstiladrin to only those patients who will benefit from the drug; others can be offered other (potentially more effective) therapies. Understanding how resistance develops can help us design combination therapies that can benefit even more patients than benefit from Adstiladrin alone. Fiscal Year 2020 Peer Reviewed Cancer Research Program Military Focus Area: Mission readiness. Bladder cancer disproportionately affects military personnel; in fact one of the patient advocate leaders at Johns Hopkins is an Army Veteran of the Iraq war. Developing more effective therapies for aggressive forms of bladder cancer will enable more military and non-military citizens to stay productively engaged in their missions and avoid prolonged hospitalizations caused by bladder cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110698
Entities
People
- Colin Dinney
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army