Targeting Serine and 1-Carbon Metabolism for the Treatment of RB-Deficient Aggressive-Variant Prostate Cancer
Abstract
Rationale: Prostate cancers marked by the loss of the tumor suppressor RB (encoded by the RB1 gene) represent a highly aggressive, genetically defined cancer subtype that is largely incurable. Hence, there is a pressing need to identify novel therapeutic approaches for the treatment of RB-deficient prostate cancers. While prior work has focused on RB’s role in cancer via its regulation of the cell cycle, emerging data from our group and others indicate that RB is also a major regulator of cancer cell metabolism. Using unbiased approaches to assess metabolism in preclinical models and patient cohorts, we identified the serine, glycine, and one-carbon pathway (SGOCP) to be upregulated following the loss of RB in prostate tumors. Biochemical and functional data from our laboratory demonstrate that the SGOCP is required for aggressive prostate cancer cell growth and survival. Further, RB loss sensitizes prostate cancers to the pharmacological inhibition of an enzyme called phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting step of serine biosynthesis. These findings indicate that the SGOCP may represent a mechanistically alternative therapeutic target. To drive the development of new SGOCP-directed therapies, several issues still need to be addressed: (1) it is not clear why RB-deficient prostate tumors require increased SGOCP metabolism; (2) we do not know the best way to target the SGOCP (ex. there might be better ways than PHGDH inhibition); and (3) it is unknown whether targeting the SGOCP will sensitize aggressive prostate cancers to existing standard of care treatments. These issues (defining an optimal targeting strategy and understanding the fundamental biology) need to be addressed to evaluate any mechanistically new therapy to determine whether it can be safely and effectively administered to the correct patient population. Objectives: The primary objective of this proposal is to characterize how increased serine and one-carbon metabolism caused by the loss of RB promotes prostate cancer progression. Further, we will rigorously test whether different parts of the SGOCP are bona fide therapeutic targets in preclinical models of RB-deficient prostate cancer. In addition, we will characterize whether this approach enhances the efficacy of existing drugs and assess whether there are potential side effects (positive or negative). Aims: Aim 1 will evaluate the unrealized metabolic functions of RB loss in controlling the SGOCP in rigorous, preclinical models of advanced prostate cancer. Here, we will use new and established cell and mouse models that mimic different stages of the disease (RB-positive and RB-negative) and that will allow us to test whether genetic inhibition of PHGDH blocks disease progression. Aim 2 will test whether RB1 depletion drives epigenetic changes and lineage plasticity, drivers of therapy resistance, via the SGOCP. To do this, we will use integrated metabolomic, proteomic, and epigenomic approaches to link RB loss-mediated SGOCP activity to epigenetic modifications and changes in cellular identity. Finally, Aim 3 will evaluate the safety and efficacy of targeting the SGOCP at different points in the pathway. We will also test if a specialized diet can improve the efficacy of SGOCP inhibitors in validated models of aggressive prostate cancer. Contributions to the Field and Patients: The development of any mechanistically novel therapeutic approach faces more barriers compared to the development of drugs that regulate old, established targets such as the androgen receptor (AR). In this regard, established targets are viewed as safer options for drug development because there is validated biology with known side effects. As such, most new therapies focus on well-known drug targets. However, current targeted therapies, such as those targeting AR, are not curative in advanced prostate cancer and new AR-directed agents typically only improve patient prognosis by
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310424
Entities
People
- Daniel Frigo
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army