Development of a Radioligand to Detect Glucocorticoid Receptor Expression in Enzalutamide-Resistant Prostate Cancer with Positron Emission Tomography
Abstract
Objective and Rationale: The purpose of this grant application is to develop a PET (positron emission tomography) scan to image and thereby detect the subset of metastatic prostate cancer that has acquired certain molecular features that make it resistant to standard of care therapy. The imaging test will identify those tumors that have spontaneously expressed a single protein (termed the "glucocorticoid receptor") that acts biologically like the target of standard of care therapy, but cannot be inhibited by the therapy. There is a need for an imaging test to identify tumors with this protein for several reasons. Foremost, the glucocorticoid receptor can be inhibited with drugs, several of which originally developed for non-malignant conditions (e.g., depression), that target this protein have already been evaluated in patients and show acceptable safety profiles to justify a clinical trial in treatment-resistant prostate cancer. Indeed, although the glucocorticoid receptor resistance mechanism was only reported in early 2014 by an academic group at Memorial Sloan Kettering Cancer Center, one trial combining a drug targeting the glucocorticoid receptor and standard of care prostate cancer therapy has already commenced at the University of Chicago, and several other academic and pharmaceutical groups are actively pursuing new drugs to target the glucocorticoid receptor. That said, the community understands that about half of the patients that acquire resistance to standard-of-care therapy will have tumors expressing the glucocorticoid receptor. Consequently, a clinical trial that recruits "all-comers" will almost certainly accrue patients whose tumors will not respond to anti-glucocorticoid receptor therapy, subjecting them to needless treatment, and convoluting the interpretation of response data. A convenient companion diagnostic assay to pre-screen patients tumor biology as a condition for trial enrollment is justifiable, and the proposed imaging test would be a substantial improvement over the current gold standard, invasive biopsy. Beyond the pain and inconvenience to the patient, biopsy of metastatic prostate cancer frequently fails to return tumor tissue (the lesions are typically small and located in areas of the body that are challenging to access), and biopsy of one lesion may not be representative of the overall properties of the patients disease (patients with metastatic prostate cancer typically have >20 lesions, which can be heterogeneous). An imaging test overcomes these issues, as it is non-invasive, applicable to any center with a clinical PET scanner, and presents a global view of the biology of all metastatic tumors in a given patient. Applicability: This new PET scan will be applied to patients with the most advanced and fatal form of prostate cancer, for whom there are no treatment options after acquiring resistance to standard-of-care therapy. This test will identify those patients that are most likely to respond to new therapies targeting the glucocorticoid receptor. After the PET scan is validated in preclinical systems, it will take 1-2 years to translate the technology to the clinic. Advancing the Field: This study will endow the community with a diagnostic exam to conveniently and clearly characterize the biology of a patient s tumor in a manner that will allow for more conscientious treatment planning. Prior drug development programs for other targets or indications have shown that companion diagnostic tests like the one proposed in this grant accelerate the clinical development of their respective drugs. For instance, the exam can be used to identify the subset of patients whose tumors harbor the drug target, and it can be applied after the initiation of drugs to confirm that the drug has engaged the target.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510552
Entities
People
- Michael J. Evans
Organizations
- United States Army
- University of California, San Francisco