Detection and Characterization of Treatment Emergent Neuroendocrine Prostate Cancer Using Hyperpolarized 13C Magnetic Resonance
Abstract
The objective of this proposal is to test if the new technique of "hyperpolarized carbon-13 magnetic resonance imaging" can detect an aggressive subtype of castrate-resistant prostate cancer (CRPC), neuroendocrine (NEPC), that is induced by highly potent drugs (androgen pathway inhibitors or APIs). Currently in the clinic, NEPC disease is "suspected" when the patient shows advanced disease (spread of cancer to visceral organs such as the liver) and is only confirmed on biopsies, an invasive procedure that is subject to large sampling errors. The detection of this lethal form of prostate cancer is important since it coexists with and responds differently to therapy than other forms of CRPC. Currently, there is no proven imaging technique for reliable detection of this disease or monitoring its response to treatment. The aim of this study is to use a non-invasive, non-radioactive "hyperpolarized carbon-13 magnetic resonance imaging" to monitor the basic metabolic activities characteristic of NEPC and use that to distinguish itfrom other subtypes of prostate cancer. Application and Impact: The ultimate application of this project would be its clinical use to reliably detect the onset of the lethal NEPC variant. The findings of this research proposal will greatly benefit patients with advanced prostate cancer who are responding poorly to androgen deprivation therapy and are contemplating the use of APIs or chemotherapy. The improved biochemical characterization of the disease phenotypes present in individual patients with CRPC using a non-invasive metabolic imaging approach can aid in the improved selection and monitoring of current therapies or in the assessment of new therapeutic protocols. There are no risks associated with this imaging technique as it s non-invasive, non-radioactive, and employs innately occurring molecules like pyruvate, acetate, and glutamine that are quickly and naturally metabolized by the body as a fuel source. Magnetic resonance technique is considered the most innocuous yet powerful of the imaging modalities. Upon successful completion of this project in 3 years, the proposed biomarkers can be applied for clinical translational studies. One of the molecules, pyruvate, is already Food and Drug Administration (FDA)-approved for human use and has been successfully employed to detect prostate cancer at our institution. We anticipate the approval of glutamine, a common amino acid supplement that makes up 60% of muscles, to be swift, facilitated by the results from this preclinical study as proof of principle. Considering that acetate, which has been shown to be safe as high as 2mmol/kg body weight in people, is currently an FDA-approved PET (positron emission tomography) probe, its application for hyperpolarized magnetic resonance studies should be feasible. Some of the major contributions from this study that would advance the field of prostate cancer are: generation of direct proof of concept, indispensible for the quick translation of this technique; a comprehensive understanding of the metabolic machinery that drive this aggressive cancer that could provide insight into new therapeutic targets germane to this aggressive disease subtype; and establishment of a preclinical animal model that closely resembles therapeutically driven NEPC for further evaluation of new imaging probes and new drug testing. By detecting NEPC early and nonintrusively, "hyperpolarized carbon-13 magnetic resonance imaging," can significantly improve the management of patients by rationally guiding treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710471
Entities
People
- Renuka Sriram
Organizations
- United States Army
- University of California, San Francisco