Project Grant R44AI177220

MITIGATION OF RADIATION INDUCED GASTROINTESTINAL SYNDROME. - ABSTRACT: CURRENTLY RAS HAS BEEN CONSIDERED A HIGH VALUE TARGET IN CANCER DRUG DEVELOPMENT CONSIDERING THAT OVER 30 PERCENT OF ALL HUMAN CANCERS - INCLUDING 95% OF PANCREATIC CANCERS AND 45% OF COLORECTAL CANCERS - ARE DRIVEN BY MUTATIONS OF THE RAS FAMILY OF GENES. THE FIRST CLINICAL LAUNCH OF A G12C KRAS INHIBITOR IS LUMAKRAS (SOTORASIB) FROM AMGEN FOR NON-SMALL CELL LUNG CARCINOMA AND MIRATI ADAGRASIB IS ON THE WAY TO APPROVAL WITH ITS G12C INHIBITOR HOWEVER, THE DEVELOPMENT OF G12D AND V INHIBITORS OF KRAS ARE STALLED IN THE PRECLINICAL REALM WITH SIMILAR STRATEGIES USED FOR G12C INHIBITORS WHICH IS LIKELY MORE DIFFICULT OR IMPOSSIBLE TO APPLY TO OTHER MUTATIONS. IN ADDITION, THEN THERE IS ALSO THE CHALLENGE OF OVERACTIVE WILDTYPE RAS MUTATIONS WHERE TARGETING MUTATIONS IN THE PROTEIN BECOME DIFFICULT WITH AN OVERACTIVE RAS PATHWAY WHICH CAN RESULT FROM RAS UPREGULATION OR DYSREGULATION OF ITS PARTNERING PROTEINS. THIS IS NOT ADDRESSED BY THE CURRENT APPROACHES WHICH SEEKS TO INHIBIT THE MUTANT FORMS ONLY BUT IN FACT HAS LED TO A MECHANISM OF RESISTANCE WITHIN THE MUTANT FORMS OF RAS WITH A COMPLEX NETWORK OF PATHWAYS WHERE ISOTYPES OF RAS ARE INVOLVED. HERE WE PRESENT WHAT IS UNFOLDING AS ANOTHER POSSIBLE TARGET FOR ONCOGENIC RAS. A HALLMARK OF ALL ONCOGENIC RAS IS SUPPRESSION OF PHOSPHATASE AND TENSIN HOMOLOG IS A PHOSPHATASE (PTEN) EXPRESSION. PTEN IS A MULTI- FUNCTIONAL TUMOR SUPPRESSOR THAT IS VERY COMMONLY LOST IN HUMAN CANCER BUT IS A REQUIREMENT IN CANCEROUS RAS SIGNALING TO PREVENT THE CELLS FROM BEING ABLE TO DIE (CAUSING IMMORTALIZATION). THUS, THIS IS WIDELY REGARDED AS A DRIVER MUTATION. THE OTHER HALLMARK OF ONCOGENIC RAS SIGNALING IS A PROTEIN KNOWN AS GSK3 IS OVEREXPRESSED. WE HAVE RECENTLY REPORTED BCN057 RESTORES PTEN EXPRESSION TO ABROGATE THE IMMORTALIZED PHENOTYPE IN ONCOGENIC KRAS. WHY THIS IS IMPORTANT IS BECAUSE THE SIGNAL TRANSDUCTION "WIRING" APPEARS TO DIFFER IN KRAS MUTANT VS NORMAL TISSUE. THUS, NORMAL TISSUE RESPONDS BY INCREASING ITS RESISTANCE TO CHEMOTHERAPY AND RADIATION WHILE INDUCING CELL DEATH IN THE KRAS MUTANT TUMOR CELLS RESULTING IN AN INCREASE IN THE THERAPEUTIC INDEX. THIS IS A BREAKTHROUGH FOR ONCOGENIC KRAS EPITHELIAL CANCERS AND COLORECTAL CANCER TREATMENT AND MAY EVENTUALLY HAVE SIGNIFICANT IMPLICATIONS FOR A VARIETY OF CANCERS. IN THE US ALONE THERE ARE OVER 150,000 NEW CASES OF COLORECTAL CANCERS AND STUDIES LIKE FOUNDATION MEDICINE (FM) ESTIMATE A KRAS MUTATION FREQUENCY OF APPROXIMATELY 50%. IN SUMMARY, THE PROPOSED WORK WILL PROVIDE A CLEAR PATH TO SUBSEQUENT STUDIES RELATED TO PRODUCT DEVELOPMENT IN A PHASE II APPLICATION.