Translation of a Novel PET Imaging Companion Biomarker Targeting CD46 For Treatment Planning in Adenocarcinoma and Neuroendocrine Prostate Cancer
Abstract
Rationale: Metastatic prostate cancer is first treated with antiandrogen, or hormonal therapy. Typically, this therapy is successful in controlling the disease, but ultimately resistance develops. In the long run, most patients develop worsening disease in a phenomenon called metastatic castration-resistant prostate cancer (mCRPC). In this setting, patients can develop different types of mCRPC, including either adenocarcinoma or small-cell neuroendocrine prostate cancer (SCNC). Both of these advanced disease states have poor prognosis, and many men with these conditions will ultimately succumb to their disease. Therefore, there is great interest in developing new therapies for men with mCRPC. We have identified a new therapeutic target, called CD46, which can be targeted for treatment of men with mCRPC. Our team has developed a new antibody-drug conjugate called FOR46, which targets CD46 and is now in clinical trials. However, while genetic evidence suggests that men with mCRPC have increased CD46 expression, there is little known about how CD46 is expressed in individual patients and therefore who would respond to this new drug. In this proposal, we develop a new method that allows us to image CD46 expression in men with mCRPC using positron emission tomography (PET). This will provide critical information to inform on (1) to what extent CD46 expression is present in men with mCRPC and (2) whether drug development targeting CD46 is likely to bear fruit. Objective: The hypothesis of this grant is that overexpression of CD46 is a characteristic feature of mCRPC, suggesting the feasibility of treatments directed against this target. Our objective is to develop an imaging method, called [89Zr]DFO-YS5 PET, that will directly allow us to test this hypothesis in individual patients by directly imaging CD46 expression. Specific Aims: In Aim 1, we will test [89Zr]DFO-YS5 in cell and animal models of both adenocarcinoma and SCNC. This will provide direct evidence that the method can successfully image CD46 prior to a human study. In Aim 2, co-investigator Dr. Aggarwal will recruit a cohort of 10 patients who are about to undergo therapy with the new FOR46 drug, for this companion imaging study. We will include both men with adenocarcinoma and SCNC, matching the animal models from Aim 1. These patients will undergo a [89Zr]DFOYS5 PET study during the screening period while they are awaiting therapy on the FOR46 clinical trial. These patients will be ideal subjects for our trial, since they will also undergo a biopsy as part of the screening process; include both a mixture of adenocarcinoma and SCNC; and will undergo CD46-directed therapy, the same target as the imaging method. Finally, in Aim 3, we will use the imaging data we have collected to provide fundamental information about CD46 expression in these patients. We will prove that we are imaging the right target by comparing directly against the gold standard biopsy results. Furthermore, we will analyze the data to test the overall rate of CD46 expression in sites of metastatic disease to provide information about the overall extent of CD46 expression and to see whether the scan results predict who responds to FOR46 on the clinical trial. Ultimate Applicability of the Approach: What is the likely impact of this study on the FY19 Prostate Cancer Research Program (PCRP) Overarching Challenges? This study has direct impact on the PCRP Overarching Challenges to “help define the biology of lethal prostate cancer to reduce death,” and “develop treatments that improve outcomes for men with lethal prostate cancer.” What type of patients will this help, and how will it help them? This method is designed to help patients with mCRPC. This study will directly provide information about the expression of CD46, a promising new therapeutic target, in men with mCRPC, the most lethal form of prostate cancer. This will help design new drugs and treatments and wil
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010292
Entities
People
- Robert R Flavell
Organizations
- United States Army
- University of California, San Francisco