Transferrin-Based PET to Detect and Monitor Treatment Response in Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer
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 (NEPC). In our recently published metastatic biopsy series in the Journal of Clinical Oncology, 17% of all biopsies harbored NEPC, underscoring the commonality of this event in the transformation of prostate cancer to a hormone-resistant disease. The average survival upon the development of NEPC is less than 18 months with conventional therapy, underscoring the urgent need to develop new treatment strategies to both prevent and treat this often lethal disease. A major hindrance, however, in the ability to develop new treatments for NEPC is the requirement for metastatic tumor biopsies for detection, which are invasive, may not be safe to perform in up to 50% of all patients, and, even when performed, do not have sufficient tumor for analysis in 20-30% of cases. Too many cancer drugs fail in early-stage prostate cancer clinical trials because patient selection and identification are barriers to successful accrual. With the support of our DOD Idea Development Award, we have performed first-in-human PET imaging studies with a new tracer, termed gallium citrate. We have scanned 30 patients with abiraterone/enzalutamide-resistant prostate cancer and identified preliminary evidence of an intriguing association between uptake on gallium citrate PET, with evidence of NEPC on paired tumor biopsy. We have further demonstrated that early changes on gallium citrate PET, prior to development of any changes on conventional imaging, are associated with subsequent response to treatment in patients with NEPC. In order to boost our chances of developing new therapies in NEPC, we need to validate gallium citrate PET as an accurate test that detects the presence of NEPC, which would ultimately negate the need for an invasive tumor biopsy for identification of this high-risk disease subset. To this end, we propose to extend our preliminary findings from the Idea Development Award in the proposed Expansion award to definitely test gallium citrate PET as a marker of NEPC. If proven successful, this would have immediate and significant implications for the development of the multiple emerging therapies targeting NEPC, enabling efficient patient selection and treatment response monitoring that would directly impact the likelihood of success of the multiple new therapies being tested in NEPC, translating into faster timelines towards new drug approval for this high-risk group of patients. The objective of the current proposal is to perform definitive prospective 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 the pathologic, clinical, and genetic features of neuroendocrine prostate cancer and (2) demonstrate that early changes on gallium citrate PET among men with NEPC are associated with subsequent clinical response to novel therapies being applied in this setting. Applicability of the Research: The proposed project is designed to ultimately improve outcomes for patients with NEPC, which arises as a resistance pathway to hormone therapy. NEPC is likely increasing in prevalence with earlier application of potent hormone blockade, with currently limited treatment options and an average survival of less than 18 months with conventional treatment. New treatment options are urgently needed. Preliminary data from our proposed study supporting the utility of gallium c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910585
Entities
People
- Rahul Aggarwal
Organizations
- United States Army
- University of California, San Francisco