Project Grant R21CA289213

TARGETING A PHGDH METABOLIC VULNERABILITY IN MELANOMA - SUMMARY WHILE THE LAST 15 YEARS HAVE BROUGHT REMARKABLE CLINICAL ADVANCES IN MELANOMA THERAPY, THE CURRENT STANDARD- OF-CARE TARGETED AND IMMUNE THERAPIES HAVE HIT A 'CEILING' THAT MUST BE OVERCOME TO FURTHER IMPROVE PATIENT OUTCOMES. THE IDENTIFICATION OF NOVEL TARGETS HOLDS TREMENDOUS PROMISE TO DEVISE STRATEGIES TO ADD TO OUR CLINICAL ARMAMENTARIUM OF MELANOMA THERAPIES. CANCER CELLS ADAPT THEIR METABOLISM TO MEET THE METABOLIC REQUIREMENTS OF SUSTAINED PROLIFERATION, INTERACTION WITH THE TUMOR MICROENVIRONMENT, AND OUTGROWTH AT DISSEMINATED SECONDARY SITES. METABOLIC ENZYMES WITH KEY ROLES IN CANCER CELLS ARE ENVISIONED AS ACTIONABLE VULNERABILITIES. ONE SUCH ENZYME IS THE PHOSPHOGLYCERATE DEHYDROGENASE (PHGDH), WHICH MEDIATES THE FIRST AND RATE-LIMITING STEP IN THE SERINE SYNTHESIS PATHWAY. PHGDH PLAYS AN IMPORTANT ROLE IN MELANOMA FORMATION AND METASTASIS. INTERESTINGLY, COMBINING PHGDH INHIBITION WITH EXTRACELLULAR SERINE STARVATION IS DETRIMENTAL TO COLON CANCER CELLS, SUGGESTING THAT LIMITING SERINE AVAILABILITY MAY BE A STRATEGY TO TARGET CANCER CELLS. HOWEVER, CURRENT PHGDH INHIBITORS ARE NOT SUITABLE FOR CLINICAL USE AND MAY ALSO CAUSE SYSTEMIC TOXICITIES. THUS, ALTERNATIVE APPROACHES TO LIMIT SERINE AVAILABILITY TO TARGET MELANOMA CELLS NEED TO BE DEVISED. WE DISCOVERED THAT ONCOGENIC BRAFV600E SIGNALING STIMULATES PHGDH EXPRESSION AND MAPK PATHWAY INHIBITION DIMINISHES BASELINE AND SERINE STARVATION-INDUCED PHGDH LEVELS IN MELANOMA. PRELIMINARY IN VITRO ANALYSES SHOWED THAT COMBINING A BRAFV600E INHIBITOR WITH EXTRACELLULAR SERINE STARVATION INDUCED MELANOMA CELL DEATH. WE THEREFORE HYPOTHESIZE THAT REDUCING PHGDH EXPRESSION BY INHIBITING BRAFV600E SYNERGIZES WITH DIETARY SERINE RESTRICTION TO REDUCE MELANOMA GROWTH. IN THIS PROPOSAL, WE WILL FIRST USE GENETIC APPROACHES TO TEST IF PHGDH DEPLETION IN ESTABLISHED MELANOMAS WILL AFFECT TUMOR GROWTH IN VIVO IN THE ABSENCE OR PRESENCE OF DIETARY SERINE RESTRICTION. ADDITIONALLY, WE WILL EVALUATE THE THERAPEUTIC POTENTIAL OF COMBINING DIETARY SERINE RESTRICTION WITH DIFFERENT SMALL MOLECULE INHIBITORS TARGETING THE BRAF/MAPK/MTOR AXIS, SOME OF WHICH ARE FDA-APPROVED. OUR STUDY WILL PRECLINICALLY ASSESS THE THERAPEUTIC POTENTIAL OF A NEW TREATMENT STRATEGY OF MELANOMA THAT COULD BE RAPIDLY TRANSLATED INTO THE CLINIC.