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1,3-THIOUREAS AS FIRST IN CLASS MITOCHONDRIAL INHIBITORS TO TREAT ORAL CANCER - ABSTRACT KERACEUTICALS IS DEVELOPING A PATENT-PROTECTED NOVEL CLASS OF ANTICANCER DRUGS CALLED 1,3-THIOUREAS FOR THE TREATMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC). OSCC IS THE MOST COMMON ORAL MALIGNANCY, ACCOUNTING FOR 80–90% OF ALL ORAL CANCERS AND 60% OF ALL CASES OF HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC). AMONG ALL TYPES OF HNSCC, OSCC HAS THE HIGHEST RECURRENCE RATES AND LOWEST MEDIAN SURVIVAL. EVEN WITH ADDITIONAL TREATMENT, THE SURVIVAL RATE FOR RECURRENT OSCC IS A MERE 6-7 MONTHS. PATIENT OUTCOMES FOR OSCC HAVE NOT CHANGED IN 50 YEARS, DUE IN PART TO THE FACT THAT NO TARGETED THERAPIES HAVE BEEN DEVELOPED FOR ADVANCED AND RECURRENT OSCC. THUS, THERE IS A SIGNIFICANT UNMET NEED TO IDENTIFY AND DEVELOP NOVEL THERAPIES TO TREAT OSCC. IN RESPONSE TO THIS NEED, KERACEUTICALS DEVELOPED 1,3-THIOUREAS THAT DEMONSTRATE POTENT ANTIPROLIFERATIVE EFFECTS AGAINST A PANEL OF CANCER TYPES INCLUDING OSCC, NON-SMALL CELL LUNG CANCER, BREAST, PROSTATE, BRAIN, AND ENDOMETRIAL CANCER IN VITRO. 1,3-THIOUREAS INHIBIT OXIDATIVE PHOSPHORYLATION (OXPHOS) AND CALCIUM HOMEOSTASIS IN CANCERS PROVIDING A ONE-TWO PUNCH THAT RESULTS IN ENDOPLASMIC RETICULUM STRESS, MITOCHONDRIAL MEMBRANE DEPOLARIZATION, AND SUBSEQUENT REACTIVE OXYGEN SPECIES-DRIVEN APOPTOSIS SELECTIVELY IN TUMOR CELLS. KERACEUTICALS’ LEAD COMPOUND, CIDD99 HAS SHOWN PROMISING RESULTS IN OSCC CELL LINES, AND SIGNIFICANTLY REDUCED TUMOR VOLUMES (5-FOLD) IN OSCC MOUSE XENOGRAFT MODELS WHEN ADMINISTERED INTRAPERITONEALLY. HOWEVER, ADDITIONAL R&D IS REQUIRED TO DEVELOP FORMULATIONS FOR ORAL AND/OR INTRAVENOUS ADMINISTRATION OF CIDD99 AND TO DETERMINE THE BIOAVAILABILITY OF SUBSEQUENT PK AND TISSUE DISTRIBUTION PRIOR TO INITIATING MANUFACTURING, FULL-SCALE TOXICOLOGY STUDIES, AND CLINICAL TRIALS. THIS PHASE I PROJECT PROPOSES THE FOLLOWING AIMS: 1. FORMULATE CIDD99 FOR ORAL AND/OR IV ADMINISTRATION. RAPID ASSESSMENT OF THESE ORAL AND/OR IV FORMULATIONS WILL BE PERFORMED ON BLOOD FROM NON-TUMOR-BEARING MICE AND ENABLE FAST IDENTIFICATION OF APPROPRIATE FORMULATIONS FOR LARGER EFFICACY STUDIES, COMPREHENSIVE PK STUDIES, AND TISSUE DISTRIBUTION ANALYSES. FORMULATIONS WITH EQUAL OR IMPROVED BLOOD CONCENTRATIONS WILL BE UTILIZED IN AIM 2. 2. CONFIRM FORMULATED CIDD99 EFFICACY AND COMPARE AGAINST STANDARDS OF CARE IN MOUSE OSCC MODELS. THE MOST EFFICACIOUS FORMULATION WILL BE EVALUATED AS A LONE TREATMENT OR IN COMBINATION WITH CISPLATIN OR THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITORS CETUXIMAB AND GEFITINIB. LASTLY, TONGUE TUMOR MODELS WILL BE USED TO ASSESS METASTATIC DISEASE. EFFECTS ON TUMOR GROWTH, NODAL DISEASE, TOLERABILITY, TISSUE DISTRIBUTION, AND HISTOPATHOLOGY WILL BE ASSESSED, AND INITIAL TOXICITY ANALYSES WILL BE PERFORMED. THESE KEY STUDIES WILL VERIFY EFFICACY OF FORMULATIONS THAT ENABLE ORAL AND/OR IV ADMINISTRATION FOR FUTURE CLINICAL TRIALS. MECHANISTIC EFFECTS ON IN VIVO EGFR SIGNALING, APOPTOSIS, AND MARKERS OF EPITHELIAL MESENCHYMAL TRANSITION WILL ALSO BE EVALUATED. THE ABOVE STUDIES AND PROPOSED MILESTONES WILL SERVE AS GO/NO GO CRITERIA FOR A FUTURE PHASE II APPLICATION THAT WILL CONFIRM EFFICACY IN ADDITIONAL MOUSE MODELS AND INITIATE GMP MANUFACTURING AS WELL AS IND-ENABLING TOXICOLOGY STUDIES IN PREPARATION FOR IND SUBMISSION.

DEVELOPING VERSATILE AND FACILE CHEMICAL SYNTHESIS METHODOLOGIES FOR PREPARATION OF 18F-TRACERS FOR PET IMAGING

SBIR PHASE I: DEVELOPMENT OF 18F-RADIOTRACER KITS FOR DETECTION OF BIOMARKERS BY POSITRON EMISSION TOMOGRAPHY -THE BROADER IMPACT AND COMMERCIAL POTENTIAL OF THIS SMALL BUSINESS INNOVATION RESEARCH (SBIR) PHASE I PROJECT EXTEND TO SEVERAL KEY AREAS. FIRSTLY, IT AIMS TO ENHANCE THE QUALITY OF HEALTHCARE AND IMPROVE THE HEALTH OUTCOMES OF THE AMERICAN PUBLIC BY OFFERING CUTTING-EDGE DIAGNOSTIC TOOLS FOR THE DETECTION AND ASSESSMENT OF VARIOUS DISEASES. THESE ADVANCED DIAGNOSTICS WILL PROVIDE CLINICIANS WITH PRECISE AND RELIABLE INFORMATION, THEREBY IMPROVING DISEASE MANAGEMENT AND PATIENT CARE. SECONDLY, THE PROJECT WILL CREATE VALUABLE OPPORTUNITIES TO TRAIN A SKILLED STEM WORKFORCE IN THE UNITED STATES. BY HIRING INDIVIDUALS WITH EXPERTISE IN CHEMISTRY AND BIOLOGY, IT WILL CONTRIBUTE TO THE ADVANCEMENT OF SCIENTIFIC FRONTIERS AND SUPPORT PARTICIPATION IN THE TECHNOLOGY-DRIVEN ECONOMY. THIRDLY, THE PROJECT FOSTERS THE INTEGRATION OF RESEARCH THROUGH COLLABORATION BETWEEN INDUSTRY AND ACADEMIA. BY LEVERAGING THE EXPERTISE OF NON-PROFIT RESEARCH INSTITUTIONS, IT WILL EXPAND THE PRACTICAL APPLICATIONS OF SCIENTIFIC DISCOVERIES TO INDUSTRY SETTINGS. LASTLY, THE DEVELOPMENT OF A GLOBALLY DEMANDED PRODUCT IS EXPECTED TO ENHANCE THE ECONOMIC COMPETITIVENESS OF THE UNITED STATES ON THE INTERNATIONAL STAGE. THIS SMALL BUSINESS INNOVATION RESEARCH SBIR PHASE I PROJECT FOCUSES ON HARNESSING RECENT ADVANCEMENTS IN THE BASIC SCIENCES, PARTICULARLY IN CHEMISTRY AND BIOLOGY, TO DESIGN INNOVATIVE DIAGNOSTIC PRODUCTS. THESE PRODUCTS HAVE APPLICATIONS IN BOTH PRECLINICAL RESEARCH AND CLINICAL DIAGNOSTICS, PARTICULARLY IN THE FIELD OF DISEASE DETECTION AND TREATMENT. THE PROPOSED DIAGNOSTIC AGENTS, DESIGNED FOR USE WITH POSITRON EMISSION TOMOGRAPHY (PET), WILL ASSIST RESEARCHERS AND PHYSICIANS SPECIALIZING IN ONCOLOGY. THESE TOOLS WILL ENABLE MORE PRECISE SELECTION OF APPROPRIATE THERAPIES FOR CANCER PATIENTS, PROVIDING CRITICAL DATA ON THE EARLY ASSESSMENT OF IMMUNOTHERAPY, WHICH IS CONSIDERED A BREAKTHROUGH TREATMENT IN ONCOLOGY. THE PROJECT NOT ONLY ADVANCES SCIENTIFIC KNOWLEDGE AND TECHNIQUES BUT ALSO ADDRESSES TECHNICAL CHALLENGES IN DEVELOPING NOVEL PET DIAGNOSTIC AGENTS. A MULTIDISCIPLINARY TEAM, RENOWNED FOR THEIR EXPERTISE IN NUCLEAR CHEMISTRY, MEDICAL IMAGING, AND IMMUNOLOGY, IS COLLABORATING TO ENSURE THE SUCCESSFUL COMPLETION OF THE PROJECT?S OBJECTIVES. THEIR COMBINED EFFORTS WILL PROPEL THE DEVELOPMENT OF THESE INNOVATIVE PRODUCTS AND TECHNOLOGIES, ULTIMATELY FACILITATING THEIR USE IN HUMAN HEALTHCARE. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

SBIR PHASE I: DEVELOPING BIOCONJUGATION AND PREPARATION OF 18F-BIOMOLECULES FOR PET IMAGING

OXYGEN-GENERATING DRESSING

MICROFLUIDIC DEVICE FOR EFFICIENT GENE-TRANSFECTION OF ADULT STEM CELLS

SEC. 9007 REAP-ENERGY EFFICIENCY IMPROVEMENTS GRANTS (MAN)