Identifying Different Metabolic Subtypes of Prostate Cancer for Early Therapeutic Assessment
Abstract
Prostate cancer (PCa) is the second most common cause of cancer mortality in men. Patients with advanced disease receive anti-androgens (Enzalutamide) as the first line of treatment. Unfortunately, many patients develop resistance, and the disease relapses with aggressive histology and metastatic castrate-resistant phenotype (mCRPC). Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) patients are limited and continue to pose a significant oncological challenge. Metabolic biomarkers are urgently needed to access the treatment response of the patients receiving antiandrogen therapy, as well as classify different metabolic sub-types of PCa. The overarching goals of this Idea Development grant proposal is to develop personalized metabolic imaging modality to target treatment strategies of different metabolic sub-types of PCa and to interrogate different metabolic factors that are associated with a particular sub-type. Prostate cancer exhibits distinct metabolic characteristics that set them apart from many other tumor types. We have demonstrated alterations in PCa metabolism that occur during initial tumorigenesis and throughout disease progression that can be exploited for imaging. Recent studies from our group and others demonstrate that the tumor s metabolic profile that impacts anti-androgens response can be identified early on by using hyperpolarized Magnetic Resonance Imaging (HP-MRI). We also discovered that Monocarboxylate Transporter (MCT) pathway is dysfunctional in mCRPC and may be a viable target for therapeutic intervention. In this PCRP Idea Development Grant proposal to the Department of Defense, we will employ HP-MRI and Positron Emission Tomography (PET) to interrogate both glycolysis and fatty acid oxidation in PCa and evaluate the treatment response of antiandrogen drug, Enzalutamide, in four clinically relevant, well-characterized, patient-derived mouse models of PCa. Of these four models, two are resistant to treatment, while the other two are sensitive. In the resistant models, we will attempt to restore Enzalutamide sensitivity by targeting the MCT pathway by inhibiting that pathway with the clinical drug, Syrosingopine. Hyperpolarized magnetic resonance imaging (HP-MRI) offers unprecedented insights into cellular metabolism in real time by enhancing signal of conventional MRI by over 10,000-fold. For PET imaging, we will use a novel compound, Fluoropivalate, to image the fatty acid oxidation pathway. We will correlate imaging data with comprehensive metabolomics, transcriptomics, and immunohistochemistry analysis of the ex vivo tissue samples to understand the mechanistic basis of the success and/or failure of the two metabolic imaging modalities and to elucidate the metabolic drivers of resistance, as well as an in-depth characterization of the tumor sub-types. Thus, this Idea Development grant presents an exciting opportunity to realize imaging-based personalized medicine in PCa by two different imaging modalities. This proposal will address the following FY20 PCRP Overarching Challenges: (1) to define the biology of lethal prostate cancer and (2) to develop effective treatments and address mechanisms of resistance for men with mCRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110763
Entities
People
- Pratip Bhattacharya
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army