Project Grant R01CA293210

IDENTIFICATION OF NOVEL BIOMARKERS AND THERAPEUTIC STRATEGIES IN CHEMOBRAIN. - PROJECT SUMMARY WHILE CURRENT TREATMENT APPROACHES CAN CURE MOST CHILDREN DIAGNOSED WITH CANCER, CHEMOTHERAPY-INDUCED COGNITIVE IMPAIRMENT (CICI) HAS EMERGED AS A SIGNIFICANT MEDICAL PROBLEM WITH A NEGATIVE IMPACT ON QUALITY OF LIFE. GIVEN THAT MORE CHILDREN WITH CANCER NOW SURVIVE INTO ADULTHOOD, IDENTIFICATION OF BIOMARKERS THAT CAN PREDICT AND/OR MEDIATE SUSCEPTIBILITY TO COGNITIVE DECLINE, IN CONJUNCTION TO NOVEL THERAPEUTIC INTERVENTIONS TO TREAT CICI, ARE URGENTLY NEEDED. POLY (ADP-RIBOSE) POLYMERASE 1 (PARP1), THE MAIN NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+) CONSUMING ENZYME, IS ACTIVATED BY DNA DAMAGE AND CAUSES CELLULAR NAD+ DEGRADATION, CONTRIBUTING TO NEURODEGENERATION. SIMILARLY, OUR PRELIMINARY STUDIES DEMONSTRATE THAT VARIOUS CHEMOTHERAPEUTICS INCLUDING METHOTREXATE, CISPLATIN AND PACLITAXEL CAUSE NEURONAL DNA DAMAGE, RESULTING IN INCREASED CLEAVAGE OF PARP1 EXPRESSION IN THE ADULT MOUSE HIPPOCAMPUS AND HUMAN EXCITATORY NEURONS. REMARKABLY, WE FURTHER SHOW THAT PARP1 INHIBITION THROUGH ADMINISTRATION OF A POTENT PARP1/2 INHIBITOR, VELIPARIB EFFECTIVELY PREVENTS CISPLATIN-INDUCED ANXIETY-LIKE BEHAVIOR AND NEUROGENIC DEFECTS. TAKEN TOGETHER, THESE OBSERVATIONS STRONGLY SUGGEST THAT HYPERACTIVATION OF PARP1 BY CHEMOTHERAPY CAUSES NAD+ LOSS TO FURTHER IMPAIR NEURONAL AND COGNITIVE FUNCTION. BASED ON THESE TOGETHER WITH THE FACT THAT METHOTREXATE, WHICH IS ROUTINELY USED FOR CHILDHOOD CANCERS, ALSO INCREASES CLEAVED PARP1 EXPRESSION, POTENTIALLY MEDIATING NEUROTOXICITY, WE HYPOTHESIZE THAT METHOTREXATE-INDUCED PARP1 HYPERACTIVATION CAUSES CELLULAR NAD+ LOSS, AN EFFECT THAT CAN BE PREVENTED BY INHIBITION OF PARP1 ACTIVITY, AND THUS AMELIORATING CICI. IN ADDITION, GIVEN THAT NAD+ LOSS HAS PROVEN TO BE A PROMISING BIOMARKER FOR THE AGE-RELATED NEURODEGENERATIVE CONDITIONS, WE ALSO PROPOSE TO TEST THE HYPOTHESIS THAT NAD+ AND ITS ASSOCIATED METABOLITES CAN BE NOVEL BIOMARKERS TO PREDICT AND/OR MEDIATE CICI. TO ADDRESS THESE HYPOTHESES, AIM 1 WILL TEST IF VELIPARIB PREVENTS METHOTREXATE- INDUCED COGNITIVE IMPAIRMENT IN TUMOR-FREE AND PRIMARY T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL) JUVENILE MOUSE MODELS. IN ADDITION, GIVEN THE IMPORTANCE OF PARP1 SIGNALING IN CANCER DEVELOPMENT, WE WILL ALSO EVALUATE THE IMPACT OF VELIPARIB ON TUMOR GROWTH AND CHEMOTHERAPY'S ANTI-NEOPLASTIC ACTIVITY USING CLINICALLY RELEVANT T-ALL PATIENT-DERIVED XENOGRAFT (PDX) MICE. SUBSEQUENTLY, USING CELL-TYPE SPECIFIC CONDITIONAL PARP1 KO MICE, AIM 2 WILL TEST WHICH NEURAL CELL TYPE IS RESPONSIBLE FOR CICI. MOREOVER, WE WILL ALSO ELUCIDATE IF NF- KB-MEDIATED CYCLOOXYGENASE-2 (COX-2) INFLAMMATORY SIGNALING IS A KEY DOWNSTREAM PARP1 EFFECTOR DRIVING CICI. LASTLY, AIM 3 WILL TEST IF PARP1-DEPENDENT NAD+ METABOLIC PATHWAY CAN BE PROMISING BIOMARKERS THAT CAN PREDICT AND/OR MEDIATE SUSCEPTIBILITY TO COGNITIVE IMPAIRMENT IN A COHORT OF ALL PEDIATRIC PATIENTS AND PRIMARY T-ALL JUVENILE MICE. OUR PROPOSED TRANSLATIONAL WORK WILL PROVIDE CRITICAL MECHANISMS MEDIATING CICI AND PAVE THE WAY FOR TRANSFORMATIVE CLINICAL INTERVENTIONS TO AMELIORATE THE COGNITIVE DISABILITIES ASSOCIATED WITH CHEMOTHERAPY, ULTIMATELY IMPROVING THE QUALITY OF LIFE FOR PEDIATRIC ALL AND OTHER CANCER SURVIVORS.