Targeting serine and one-carbon metabolism for the treatment of RB-deficient aggressive variant prostate cancer

Clinically defined aggressive variant prostate cancers (AVPC) represent a highly aggressive subtype of prostate cancer that shares molecular features with small cell prostate cancer (SCPC) and are characterized by a poor response to standard of care androgen receptor (AR)-targeting therapies as well as combined alterations in RB I , TP53, and/or PTE N. Of these , RB loss is found in 70-90% of SCPC PC and is arguably the signal greatest predictor of resistance to existing therapies and poor overall survival for men with prostate cancer . Thus, the treatment of RB-deficient tumor presents a significant clinical challenge. While RB s tumor suppressive effects on cell cycle control are well established, emerging data indicate an important role for RB in regulating cancer cell metabolism. Given AVPCs ' aggressive behavior, we speculated that AVPC might exhibit altered metabolism, and this would be largely driven by the loss of RB function. Preliminary data using metabolomics and transcriptomics generated from PDX and isogenically matched cell models in combination with clinical correlates from external clinical trials identified serine and one-carbon metabolism as significantly altered in RB-deficient AVPC compared to less aggressive, RB-intact prostate cancer sub types. Pharmacological inhibition of the serine biosynthesis pathway resulted in a dose-dependent reduction in prostate cancer cell proliferation that was dependent on the loss of RB. ew data indicate that RB lo ss may also promote epigenetic changes. However, what is unclear is why RB-deficient prostate cancers increase serine and one-carbon metabolism, whether this contributes to lineage plasticity, a hallmark of many AVPCs, and whether this altered state could be therapeutically exploited. In collaboration with Dr. Daniel Frigo Departments of Cancer Systems Imaging & Genitourinary Medical Oncology UT MD Anderson Cancer Center for the purpose of testing whether RB I depletion drives epigenetic changes and lineage plasticity via the SGOCP. To do this , our lab will use integrated multi-omics and isotopomer mass spectrometry as the major approaches to identify the correlation between one-carbon metabolism and histone methylation in order to understand the link RB loss-mediated SGOCP activity to epigenetic modifications and changes in cellular identity .