Project Grant R43CA275560

DEVELOPMENT OF GB13 FOR THE TREATMENT OF PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA - PROJECT SUMMARY/ABSTRACT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) IS A RARE, PEDIATRIC TUMOR TYPICALLY ARISING IN THE VENTRAL PONS OF THE BRAINSTEM WITH NO EFFECTIVE TREATMENT OPTIONS. EVERY YEAR APPROXIMATELY 400 CHILDREN IN THE US ARE DIAGNOSED WITH THIS DISEASE. PHYSICAL LOCATION, THE BLOOD-BRAIN BARRIER AND LIMITED MOLECULAR UNDERSTANDING OF DIPG HAVE PLAYED KEY ROLES IN THE INABILITY TO IMPROVE DISEASE PROGNOSIS. CURRENTLY, THE ONLY TREATMENT OPTION IS RADIATION THERAPY, HOWEVER, THERE IS VERY LITTLE TUMOR RESPONSE AND THIS INTERVENTION IS LIMITED PRIMARILY TO PALLIATION. NEW TREATMENT OPTIONS THAT IMPROVE THE RADIATION RESPONSE WILL SIGNIFICANTLY ADVANCE THIS THERAPEUTIC DURABILITY. ONE MECHANISM TO OVERCOME DRUG DELIVERY CHALLENGES CREATED BY THE BLOOD-BRAIN BARRIER IS THROUGH CONVECTION ENHANCED DELIVERY (CED), WHICH ADMINISTERS TREATMENTS DIRECTLY INTO TUMORS AND INCREASES TREATMENT EFFICACY. AS SUCH, THIS PROPOSAL COMBINES A NOVEL TARGETED THERAPY WITH CED TO DRAMATICALLY ADVANCE TREATMENT RESPONSE FOR DIPG PATIENTS. IL13R2 IS A CANCER-SPECIFIC RECEPTOR EXPRESSED ON SEVERAL CANCER TYPES, INCLUDING DIPG, GLIOBLASTOMA AND ADRENAL CORTICAL CARCINOMA, AND FUNCTIONS TO BYPASS THE APOPTOSIS-INDUCING PATHWAY MEDIATED BY UBIQUITOUSLY EXPRESSED IL13R1 AND IL13. THE TUMOR CELL RESTRICTION ALSO PROVIDES AN OPPORTUNITY TO SPECIFICALLY TARGET CANCER CELLS BY LEVERAGING IL13/RECEPTOR ASSOCIATION. AS SUCH, TARGEPEUTICS HAS DEVELOPED A MUTATED IL13- DERIVED TOXIN, CALLED GB13, THAT PREFERENTIALLY BINDS TO IL13R2 AND POSSESSES A PSEUDOMONAS EXOTOXIN MOIETY TO KILL TARGETED CELLS. THE THREE AIMS OF THIS PROJECT INDEPENDENTLY WORK TO DEVELOP THE CLINICAL ADVANCEMENT OF GB13 FOR THE TREATMENT OF DIPG BY; 1) DETERMINING THE IN VIVO EFFICACY OF GB13 FOR IL13R2-POSITIVE MOUSE MODELS OF DIPG WHEN ADMINISTERED VIA CED, 2) ANALYZING THE ABILITY OF GB13 TO INCREASE SENSITIVITY OF DIPG CELLS TO RADIATION, AND 3) CORRELATING RNA AND PROTEIN EXPRESSION OF IL13R2 FOR BIOMARKER-BASED PATIENT INCLUSION. THE EXPECTED RESULTS OF THIS PROPOSAL WILL PROVIDE NECESSARY PROOF-OF-CONCEPT DATA TO SUPPORT AN IND SUBMISSION FOR A PHASE I TRIAL.