Project Grant R01CA279040

DEVELOPMENT OF NANOFUNCTIONALIZED CYBORG C-NOVYI NT FOR IMAGE GUIDED TRANS-ARTERIAL BACTERIOLYTIC EMBOLIZATION OF COLORECTAL LIVER METASTASIS - PROJECT SUMMARY THE LONG-TERM OBJECTIVE OF THIS PROPOSAL IS TO IMPROVE THE PROGNOSIS OF PATIENTS WITH COLORECTAL LIVER METASTASES (CRLM). ONLY 15% OF THESE PATIENTS ARE CANDIDATES FOR SURGICAL RESECTION DUE TO THE NUMBER, SIZE, AND LOCATION OF THEIR LIVER METASTASES. EVEN FOR RESECTION CANDIDATES, SURVIVAL RATES REMAIN DISMAL. IMPROVED APPROACHES ARE DESPERATELY NEEDED TO TREAT THIS DEVASTATING AND INCREASINGLY PREVALENT DISEASE. IT HAS BEEN RECOGNIZED THAT ANAEROBIC BACTERIA CAN PROLIFERATE ONLY IN THE HYPOXIC REGIONS OF SOLID TUMORS SUBSEQUENTLY LYSING TUMOR CELLS RESULTING IN MARKED DE-BULKING AND OFTEN COMPLETE REGRESSION. THE FAILURE OF CHEMOTHERAPIES FOR A BROAD RANGE OF TUMOR ETIOLOGIES, INCLUDING CRLM, HAS LED TO A REJUVENATED INTEREST IN THE DEVELOPMENT OF BACTERIOLYTIC APPROACHES FOR THE TREATMENT OF SOLID TUMORS. MOST RECENTLY, THE MODIFIED ANAEROBE CLOSTRIDIUM NOVYI-NT WAS IDENTIFIED AS AN IDEAL STRAIN FOR BACTERIOLYTIC THERAPY. PRE-CLINICAL ANIMAL MODEL STUDIES HAVE DEMONSTRATED THE STRIKING POTENTIAL OF C. NOVYI-NT TO ERADICATE SOLID TUMORS. RECENT CLINICAL TRIALS HAVE INVESTIGATED THESE BACTERIOLYTIC APPROACHES FOR THE TREATMENT OF PATIENTS WITH A BROAD RANGE OF TUMOR ETIOLOGIES. INITIAL RESULTS FROM THESE STUDIES HAVE BEEN HIGHLY PROMISING. HOWEVER, THESE STUDIES HAVE ALSO IDENTIFIED CRITICAL QUESTIONS THAT MUST BE ADDRESSED TO MAXIMIZE THE EFFICACY OF BACTERIOLYTIC APPROACHES, PARTICULARLY FOR THE TREATMENT OF CRLM: 1) SYSTEMIC INTRA-VENOUS (IV) DOSING OF C. NOVYI-NT SPORES CAN PRODUCE POSITIVE RESPONSES BUT THE RESIDUAL TUMOR TISSUES IN NORMOXIC AREA, ASSOCIATED TOXICITIES WITH LOW TARGETING EFFICACY AND REQUIREMENT FOR EXTENDED REGIMEN OF ANTIBIOTICS POST-THERAPY MAY BE PROBLEMATIC. FOR CRLM, SELECTIVE LIVER-DIRECTED TRANSCATHETER INTRA-ARTERIAL (IA) ADMINISTRATION SHOULD BE FEASIBLE. FURTHERMORE, GIVEN THE PREFERENTIAL ARTERIAL BLOOD SUPPLY OF CRLM, HYPOXIA AND SELECTIVE ANAEROBE GERMINATION COULD CONCEIVABLY BE ENHANCED VIA FOLLOW-UP INFUSION OF EMBOLIC MATERIALS TO BLOCK BLOOD FLOW TO THESE METASTASES. THE SALIENT COMBINATION OF THE LATTER APPROACHES WE HAVE NOW DUBBED `TRANSARTERIAL BACTERIOLYTIC EMBOLIZATION' (TBE). 2) OBLIGATE ANAEROBE C. NOVYI-NT SPORES GERMINATE IN ONLY HYPOXIC REGIONS AND DESTROY TUMOR CELLS VIA SECRETION OF LIPASES AND PROTEASES. ACCURATE DELIVERY OF C. NOVYI-NT SPORES TO THESE HYPOXIC REGIONS AND SUBSEQUENT TUMOR COLONIZATION WILL BE CRITICAL TO ACHIEVE POSITIVE OUTCOMES. IMAGING THE DYNAMIC DISTRIBUTION OF C. NOVYI-NT SPORES AND GERMINATED ANAEROBES (TRANSCATHETER IA DELIVERY TO THE TUMORS AND SUBSEQUENT COLONIZATION IN TUMOR) SHOULD CRITICALLY PERMIT A) INTRA-PROCEDURAL OPTIMIZATION DURING TARGETED ADMINISTRATION AND B) EARLY PREDICTION OF LONGITUDINAL OUTCOMES. THROUGH THIS COLLABORATIVE PROJECT BUILDING UPON OUR INTER-DISCIPLINARY STRENGTHS IN NANO/BIO INTERFACES, NANOMEDICINE, INTERVENTIONAL ONCOLOGY, AND RADIOLOGY, WE SEEK TO DEVELOP A NEW NANO-FUNCTIONALIZED CYBORG C. NOVYI-NT AND POWERFUL NEW APPROACH FOR IMAGE-GUIDED TRANS-ARTERIAL BACTERIOLYTIC THERAPY.