Development of Radioligand Therapy Targeting CD46 for Treatment of Metastatic Prostate Cancer
Abstract
Rationale, Objective, and Aims of the Application: Men with advanced, castration-resistant prostate cancer have poor clinical outcomes and often go on to die of their disease. There is a great need for improved therapies for men with advanced prostate cancer, and one of the Overarching Challenges of the Prostate Cancer Research Program is to develop treatments to improve outcomes for men with lethal prostate cancer. Recently, our research team discovered a new antigen for targeted therapies in prostate cancer named CD46. This antigen is highly expressed on prostate cancer, with low background expression, suggesting that drugs made against CD46 would be effective and non-toxic for treatment of prostate cancer. Therefore, we have developed a drug named [225Ac]DOTA-YS5 that is effective for treatment in mouse models. It works by binding specifically to the CD46 antigen and delivering a high dose of targeted radiation, while sparing normal background tissues. The therapy we have developed, [225Ac]DOTA-YS5, has several potential advantages over existing drugs. First, CD46, which is the target of [225Ac]DOTA-YS5, is very highly expressed, much greater than other cancer antigens, including prostate specific membrane antigen (PSMA). This high degree of expression suggests that this would be an ideal therapeutic target. Second, we can pair the [225Ac]DOTA-YS5 treatment agent with an imaging agent in a method called “theranostics” – a combination of the words “therapy” and “diagnosis.” In this theranostic method, an imaging test is used to select patients for the therapy. We have already developed this [89Zr]DFO-YS5 agent in a separately funded line of research. Finally, [225Ac]DOTA-YS5 uses highly lethal alpha particles for treatment. Unlike other types of drugs, it is extremely difficult to develop resistance to alpha particles. Overall, our design is highly promising for treatment of metastatic prostate cancer, and our preliminary data suggest that this proposal is very straightforward and feasible. In this proposal, we will further develop [225Ac]DOTA-YS5 in mouse models of prostate cancer and will perform the necessary experiments to pave the way for future first-in-man testing. We will determine the appropriate dosing levels and prove that the treatment is effective in mouse models that mimic human prostate cancer, including advanced variants. Next, we will test possible combination therapy regiments with antiandrogen therapies (the standard of care in prostate cancer), as well as with PARP inhibitors (recently Food and Drug Administration-approved for some patients with prostate cancer). Finally, we will study patient specimens to see their level of CD46 expression and then try the therapy against mouse models with similar levels of CD46 expression as in those patients. Overall, these experiments will prove that [225Ac]DOTA-YS5 is a safe and effective treatment for prostate cancer and will pave the way for future first-in-man studies of this therapy. What Are the Likely Contributions of This Study to the FY20 PCRP Overarching Challenges? The goal of this proposal is to develop [225Ac]DOTA-YS5 as a new therapy for treating men with advanced prostate cancer. Therefore, this proposal directly develops treatments that improve outcomes for men with lethal prostate cancer. While this proposal is mainly focused on preclinical studies, it sets the stage for a future clinical trial. What Type of Patients Will It Help, and How Will It Help Them? The [225Ac]DOTA-YS5 radioligand therapy that we are developing is a drug that will be used for treatment for men with advanced, metastatic prostate cancer. It will work by directly treating the cancer and will help slow or stop the progression of advanced, potentially lethal cancers. What Is the Projected Time It May Take to Achieve a Patient-Related Outcome? During this proposal, we will use patient samples to directly study the effectiveness of the therapy,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110792
Entities
People
- Robert R Flavell
Organizations
- United States Army
- University of California, San Francisco