Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

Abstract

There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

Metabolic Heterogeneity, Plasticity and Adaptation to “Gluta-mine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase – ω-Amidase (Glutaminase II)] Pathway.

“…However, due mostly to reasons provided in Section 10.2. above, only perfunctory attention has been accorded the GTωA pathway (i.e., L-glutamine KGM → α-ketoglutarate). Several authors (e.g., [158][159][160][161]) have quoted our work that demonstrates GLS1 protein/activity is increased in aggressive prostate cancer cells (cf., [1]), but neglected to provide the rationale associated with the upregulation of the GTωA pathway in these cells. This omission resulted in providing only partial understanding of the integrative relationship between the GTωA and canonical pathways for conversion of L-glutamine to α-ketoglutarate, particularly in cancerous tissues.…”

Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase—ω-Amidase (Glutaminase II)] Pathway

“…above, only perfunctory attention has been accorded the GTωA pathway (i.e., l -glutamine ⇆ KGM → α-ketoglutarate). Several authors (e.g., [ 158 , 159 , 160 , 161 ]) have quoted our work that demonstrates GLS1 protein/activity is increased in aggressive prostate cancer cells (cf., [ 1 ]), but neglected to provide the rationale associated with the upregulation of the GTωA pathway in these cells. This omission resulted in providing only partial understanding of the integrative relationship between the GTωA and canonical pathways for conversion of l -glutamine to α-ketoglutarate, particularly in cancerous tissues.…”

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

“…Although these therapies have been demonstrated to improve overall survival, the improvement is incremental, and resistance develops in the majority of cases(2, 8). One avenue of therapy for castration-resistant prostate cancer (CRPC) that has yet to realize its full potential involves the development of agents designed to selectively inhibit tumor metabolism(9, 10). To date, targeting tumor metabolism, particularly glycolysis or mitochondrial metabolism, has been stymied due to excessive toxicity and/or lack of efficacy(11).…”

“…Challenging our ability to develop drugs against this pathway are multiple enzymatic isoforms in the glycolytic pathway that perform overlapping functions, complicating specific targeting(15). Accordingly, flexibility and redundancy among metabolic genes could shape the landscape of positive and negative impact on targeting tumor metabolism(9, 15). As far as glycolysis is concerned, isoform specific contribution to tumor progression is exemplified by pyruvate kinase M2 (PKM2) and hexokinase 2 (HK2), where activation and inhibition have been shown to reduce tumor progression, respectively, despite continued expression of corresponding isoforms such as PKM1 and HK1(22, 23).…”