Project Grant F31CA317987

DISCOVERY OF CANCER-SPECIFIC SURFACE PROTEIN CONFORMATIONS IN ACUTE MYELOID LEUKEMIA AND DE NOVO DESIGN OF HIGHLY SELECTIVE BINDERS IN PURSUIT OF IMPROVED IMMUNOTHERAPIES - PROJECT SUMMARY/ABSTRACT ACUTE MYELOID LEUKEMIA (AML) IS A DEADLY BLOOD CANCER WITH OVER 20,000 NEW DIAGNOSES IN US ADULTS ANNUALLY AND A 5-YEAR SURVIVAL RATE OF ONLY ~30%, HIGHLIGHTING THE MAJOR UNMET NEED FOR NEW THERAPIES. WHILE SURFACE ANTIGEN-TARGETED IMMUNOTHERAPIES, SUCH AS ANTIBODY DRUG CONJUGATES (ADCS), BISPECIFIC T-CELL ENGAGING ANTI- BODIES (TCES), AND CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS, HAVE EMERGED AS EFFECTIVE TREATMENTS FOR OTHER HEMATOLOGIC MALIGNANCIES, THE SAME SUCCESS HAS NOT YET BEEN REACHED FOR AML. WHILE VARIOUS CHALLENGES HAVE HINDERED IMMUNOTHERAPY DEVELOPMENT FOR AML, ONE OF THE MOST WIDELY RECOGNIZED IS THE LACK OF HIGHLY SELECTIVE SURFACE ANTIGENS THAT DISTINGUISH AML CELLS FROM HEALTHY HEMATOPOIETIC PROGENITORS AND/OR MATURE MYELOID CELLS. THIS "ON TARGET, OFF TUMOR" IMPACT LEADS TO SUBSTANTIAL CONCERNS ABOUT CLINICALLY UNACCEPTABLE TOXICITIES. SUCH CONCERNS HAVE IN FACT MANIFESTED IN SIGNIFICANT SIDE EFFECTS, INCLUDING DEATH, IN CLINICAL TRIALS OF IMMUNOTHERAPIES AGAINST CURRENT AML TARGETS. TO ADDRESS THIS CHALLENGE, OUR GROUP RECENTLY DESCRIBED A TECHNOLOGY WE CALL "STRUC- TURAL SURFACEOMICS." THIS CROSSLINKING MASS SPECTROMETRY-BASED EXPERIMENTAL METHOD ALLOWS FOR THE DISCOVERY OF CONFORMATION-SELECTIVE IMMUNOTHERAPY TARGETS IN AML THAT COULD NOT BE DISCOVERED BY PRIOR TARGET DISCOVERY APPROACHES RELYING ON GENE OR PROTEIN EXPRESSION ALONE. THE INITIAL VERSION OF STRUCTURAL SURFACEOMICS WAS AP- PLIED TO A SINGLE AML CELL LINE MODEL AND WAS ABLE TO IDENTIFY A HIGHLY PROMISING TARGET, THE ACTIVE CONFORMATION OF INTEGRIN BETA-2 (AITGB2). WHILE OUR PRELIMINARY DATA IS HIGHLY PROMISING, SIGNIFICANT GAPS REMAIN TOWARD 1) FURTHER ADVANCING THE STRUCTURAL SURFACEOMICS APPROACH TO DISCOVER A BROADER LANDSCAPE OF CONFORMATION-SELEC- TIVE AML TARGETS; 2) DEVELOPING A WIDELY APPLICABLE STRATEGY FOR DEVELOPING NOVEL THERAPIES AGAINST CONFORMATION- SELECTIVE ANTIGENS IN AML AND OTHER CANCERS. MY PROPOSAL AIMS TO ADDRESS THESE CHALLENGES. IN AIM 1, I WILL EXTEND THE CURRENT STRUCTURAL SURFACEOMICS TECHNOLOGY THROUGH USE OF NEW CROSSLINKERS, PROTEIN MODELING AP- PROACHES, AND MULTIPLE AML MODELS TO IDENTIFY AN EVEN BROADER LANDSCAPE OF AML-SPECIFIC THERAPEUTIC TARGETS. IN AIM 2, I WILL DEMONSTRATE A GENERALIZED STRATEGY FOR DEVELOPMENT OF NOVEL BINDERS AGAINST CONFORMATION-SELEC- TIVE TARGETS TO SERVE AS THE BASIS FOR IMMUNOTHERAPY DEVELOPMENT. I SPECIFICALLY TAKE ADVANTAGE OF OUR VALIDATED AML TARGET, AITGB2, AS A MODEL ANTIGEN FOR EMERGING AI-BASED DE NOVO BINDER DISCOVERY TOOLS AGAINST CONFOR- MATION SELECTIVE ANTIGENS. SUCCESSFUL COMPLETION OF THESE AIMS WILL ESTABLISH A NOVEL, CONFORMATION-BASED STRAT- EGY FOR IMMUNOTHERAPEUTICALLY TARGETING AML. MOREOVER, EXECUTION OF THIS WORKFLOW WILL DETERMINE AN EFFECTIVE PIPELINE FOR DISCOVERING AND TARGETING STRUCTURE-BASED ANTIGENS WHICH CAN BE APPLIED TO OTHER CANCERS AND EVEN OTHER DISEASES. THIS PROJECT WILL BE LED BY MYSELF UNDER THE SPONSORSHIP OF DR. ARUN WIITA AND DR. TANJA KOR- TEMME, EXPERIENCED MENTORS AND EXPERTS IN HEMATOLOGICAL MALIGNANCIES, CANCER IMMUNOTHERAPY, AND PROTE- OMICS, AND COMPUTATIONAL PROTEIN DESIGN, RESPECTIVELY. COMPLETION OF THIS PROPOSAL TOGETHER WITH MY TRAINING PLAN WILL STRONGLY SUPPORT MY JOURNEY TO BECOMING AN INDEPENDENT RESEARCHER PURSUING INNOVATIVE CANCER THERAPEUTICS.