Patients with advanced prostate cancer (PCa) 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 (mCRPC) phenotype. Treatment options for mCRPC patients are limited and continue to pose a significant oncological challenge. There is growing recognition that alterations in cell metabolism and reprogramming of metabolic pathways are key drivers of PCa aggressiveness, progression and eventual resistance to therapy. We propose to develop metabolic imaging to target treatment strategies of different metabolic sub-types of PCa. Two dysregulated meta...
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Patients with advanced prostate cancer (PCa) 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 (mCRPC) phenotype. Treatment options for mCRPC patients are limited and continue to pose a significant oncological challenge. There is growing recognition that alterations in cell metabolism and reprogramming of metabolic pathways are key drivers of PCa aggressiveness, progression and eventual resistance to therapy. We propose to develop metabolic imaging to target treatment strategies of different metabolic sub-types of PCa. Two dysregulated metabolic pathways in PCa are glycolysis and carnitine metabolism. Recent studies have demonstrated that the tumor's metabolic profile that impacts anti-androgens response can be identified early by using hyperpolarized Magnetic Resonance Imaging (HP-MRI). We will employ HP-MRI, and add Positron Emission Tomography (PET), to interrogate both glycolysis and carnitine metabolism. We will evaluate the treatment response of Enzalutamide in six clinically relevant mouse models. We will correlate imaging data with metabolomics, immunohistochemistry and transcriptome profile analysis of the ex vivo tissue samples to elucidate the metabolic drivers of resistance. We have identified Monocarboxylate Transporters (MCT) and Enolase-2 enzyme (ENO2) as key players in deregulation of glycolysis, therefore they can be viable targets for therapeutic intervention. In two of the resistant models, we will attempt to restore drug sensitivity by targeting the MCT and ENO2 using selective inhibitors and interrogate this transition from resistance to sensitivity by HP-MRI and PET. If successful, this proposal will advance knowledge on mCRPC tumors and validate the efficacy of targeting MCT and ENO2 for therapeutic benefit.
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