Annotating MYC Status in Treatment-Resistant Metastatic Castration-Resistant Prostate Cancer with Gallium-68 Citrate PET
Abstract
The standard of care in advanced prostate cancer includes the use of several medications that inhibit testosterone signaling including abiraterone. Though effective initially in controlling tumor growth in most patients, resistance to abiraterone inevitably develops, and treatment options are limited once this occurs. A potential crucial mechanism of resistance to abiraterone may be related to a transformation of the cancer to a more aggressive subcategory of the disease termed "neuroendocrine prostate cancer." The average survival upon the development of neuroendocrine prostate cancer is less than 1 year with conventional therapy, underscoring the urgent need to develop new treatment strategies to both prevent and treat this oft-lethal disease. In our ongoing research program in which we perform tumor biopsies of metastases in men with resistance to abiraterone, we have identified overactivation of the MYC gene as a major promoter of abiraterone resistance and transformation to neuroendocrine cancer. Of equal importance, there are now drugs available for clinical testing that directly decrease MYC signaling and have shown promising activity against prostate cancer in animal testing. In order to boost our chances of successfully studying these treatment approaches in men with prostate cancer, we need to develop a marker that will allow us to identify and quantify whether the MYC protein is actually being inhibited in real time, using a non-invasive approach that does not require a tumor biopsy. Too many cancer drugs fail in early-stage prostate cancer clinical trials because the right dose is not chosen and/or there is no convenient means to gauge whether there has been target-specific response to treatment. To this end, we have developed a new imaging radiotracer called gallium-68 citrate, which when paired with positron emission tomography (PET) scanning, appears to be able to non-invasively identify MYC hyperactivity in prostate cancer cells. This has significant implications for the development of MYC-targeted treatment in prostate cancer and may ultimately allow us to select the right dose of the new medications and provide an early marker of response that can help greatly accelerate the timelines towards new drug approval for this high-risk group of patients. The objective of the current proposal is to perform the first-ever proof-of-concept patient studies of gallium citrate PET imaging in men with advanced prostate cancer, in which we aim to accomplish two crucial goals: (1) demonstrate that scan findings on gallium citrate PET are associated with level of MYC activity detected from paired tumor biopsy, thereby establishing the validity of the imaging test and (2) demonstrate that level of gallium citrate uptake on PET imaging diminishes upon treatment with one of the new drugs directed against MYC called GS-5829 (Gilead Sciences). This would serve as vital proof-of-concept evidence of gallium citrate PET as a target-specific marker of MYC activity, Applicability of the Research: The proposed project is designed to ultimately improve outcomes for patients with advanced prostate cancer whose tumors have become resistant to testosterone blocking medications including abiraterone. This represents a growing population of prostate cancer patients, who currently have limited treatment options and an average survival of approximately 1 year or less with conventional treatment. New treatment options are urgently needed, and we believe that targeting MYC may significantly improve outcomes in this setting of advanced prostate cancer. Preliminary data from our proposed study supporting the utility of gallium-68 citrate PET scans as a marker of MYC transcriptional activity would ultimately have broad applicability across many MYC-directed therapies currently under investigation in prostate cancer and would be expected to significantly accelerate the timelines towards making these therapies available for pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610469
Entities
People
- Rahul Aggarwal
Organizations
- United States Army
- University of California, San Francisco