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DEVELOPMENT OF A RADIATION-ACTIVATABLE NANOPARTICLE FOR LUNG CANCER THERAPY - ABSTRACT LUNG CANCER IS THE SECOND MOST COMMON CANCER AND THE LEADING CAUSE OF CANCER-RELATED DEATHS. IN THE U.S., IT IS ESTIMATED THAT 234,580 PEOPLE WILL BE DIAGNOSED WITH LUNG CANCER IN 2024. NON-SMALL CELL LUNG CANCER (NSCLC) IS THE MOST COMMON TYPE OF LUNG CANCER, ACCOUNTING FOR 80-85% OF ALL CASES. DESPITE ADVANCES IN RADIATION THERAPY (RT), THE PROGNOSIS FOR PATIENTS WITH UNRESECTABLE STAGE III NSCLC REMAINS POOR. TO IMPROVE EFFICACY, CHEMOTHERAPY, MOST COMMONLY PLATINUM-BASED DOUBLETS, IS OFTEN ADMINISTERED TO PATIENTS DURING RT, KNOWN AS CHEMORADIOTHERAPY (CRT). HOWEVER, TOXICITY OFTEN LEADS TO TREATMENT DELAYS OR DISCONTINUATION. THEREFORE, THERE IS AN URGENT NEED FOR NEW CRT STRATEGIES THAT PROVIDE COMPARABLE OR SUPERIOR EFFICACY TO CONVENTIONAL CRT BUT ARE BETTER TOLERATED BY PATIENTS. ATHNA BIOTECH, INC. IS DEVELOPING A NOVEL CRT APPROACH THAT UTILIZES RADIATION TO LOCALLY ACTIVATE SYSTEMICALLY DELIVERED THERAPEUTICS. THE COMPANY HAS SYNTHESIZED A RADIATION-RESPONSIVE PRODRUG, DM1-NO, WHICH IS NITROSYLATED DM1, A MAYTANSINOID. THIS PRODRUG CAN BE LOADED INTO PEG-PLGA POLYMERIC NANOPARTICLES AND DELIVERED TO TUMORS. TO ENHANCE DELIVERY EFFICIENCY, THE NANOPARTICLES ARE CONJUGATED WITH NTSMUT, A LIGAND WITH HIGH AFFINITY TOWARDS NTSR1, WHICH IS UPREGULATED IN 59.7% OF LUNG TUMORS. DURING RT, IRRADIATION INCREASES OXIDATIVE STRESS IN TUMORS, RESULTING IN THE DISSOCIATION OF DM1-NO AND THE RELEASE OF DM1 AND NITRIC OXIDE (NO). BOTH DM1 AND NO ARE POTENT RADIOSENSITIZERS, WORKING SYNERGISTICALLY TO ENHANCE RT. DURING THE STTR PHASE I PERIOD, WE HAVE DEMONSTRATED THE SELECTIVE ACCUMULATION AND SUSTAINED RETENTION OF AB-001 WITHIN TUMORS, ENHANCED TUMOR PENETRATION, AND SUPERIOR EFFICACY IN COMBINATION WITH RADIOTHERAPY COMPARED TO CONVENTIONAL TREATMENTS WHILE MINIMIZING TOXIC EXPOSURE TO VITAL ORGANS. SUCCESSFUL COMPLETION OF PHASE I STUDIES VALIDATED THE FEASIBILITY AND EFFICACY OF AB-001. IN THIS PHASE II APPLICATION, ATHNA BIOTECH WILL WORK WITH OUR ACADEMIC COLLABORATORS AND INDUSTRY PARTNERS TO FURTHER DEVELOP AB-001. SPECIFICALLY, WE WILL SCALE UP AND OPTIMIZE THE MANUFACTURING PROCESSES OF AB-001, PRODUCE A GLP BATCH FOR STABILITY STUDY AND ANALYTICAL METHOD VALIDATION, AND ASSESS THE EFFICACY AND TOXICITY OF AB-001 IN ADDITIONAL MURINE LUNG TUMOR MODELS. FOLLOWING OUR PRE-IND MEETING WITH THE FDA, WE WILL CONDUCT IND-ENABLING TOXICITY EVALUATIONS AND COMPREHENSIVE PHARMACOKINETIC STUDIES WITH AB-001. SUCCESSFUL COMPLETION OF PHASE II WILL PAVE THE WAY FOR IND FILING AND SUBSEQUENT HUMAN CLINICAL TRIALS. THIS WILL ULTIMATELY ADVANCE AB-001 TOWARDS REGULATORY APPROVAL AND COMMERCIALIZATION, ADDRESSING AN UNMET MEDICAL NEED IN THE TREATMENT OF NSCLC.

DEVELOPMENT OF A SALT-BASED NANOMEDICINE FOR NON-MUSCLE INVASIVE BLADDER CANCER - ABSTRACT BLADDER CANCER COMPRISES 7% OF NEW CANCER DIAGNOSES IN THE US. IT IS THE SIXTH MOST PREVALENT MALIGNANCY, AND HAS THE HIGHEST LIFETIME TREATMENT COSTS AMONG ALL CANCER TYPES DUE TO THE NEED FOR LIFELONG SURVEILLANCE. EARLY STAGE BLADDER CANCER, ALSO KNOWN AS NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC), REPRESENTS 75% OF NEW BLADDER CANCER CASES. THE STANDARD TREATMENT IS TRANSURETHRAL RESECTION OF BLADDER TUMOR (TURBT), FOLLOWED BY INTRAVESCICAL THERAPY WITH CHEMOTHERAPEUTICS SUCH AS MITOMYCIN C OR BACILLE CALMETTE-GUÉRIN (BCG). HOWEVER, ~30% PATIENTS ARE REFRACTORY TO BCG. CHEMOTHERAPIES ARE ASSOCAITED WITH RELATIVELY HIGH RECURRENCE RATES AND INEFFECTIVE AS A SECOND-LINE TREATMENT FOR PATIENTS UNRESPONSIVE TO BCG. MEANWHILE, NO NEW INTRAVESICAL DRUGS HAVE BEEN APPROVED SINCE 1998. THERE IS AN UNMET CLINICAL NEED FOR NEW NMIBC THERAPIES. ATHNA BIOTECH, INC. IS DEVELOPING A SODIUM CHLORIDE NANOPARTICLE (SCNP) BASED CANCER THERAPEUTIC. SCNPS DELIVER LARGE AMOUNTS OF NA+ AND CL- INTO CANCER CELLS, BY DOING SO DISRUPTS THE OSMOTIC BALANCE ACROSS THE PLASMA MEMBRANE. UNIQUELY, SCNPS INDUCE IMMUNOGENIC CELL DEATH OR ICD. THIS MEANS THAT SCNPS ESSENTIALLY PRODUCE A VACCINE IN SITU OUT OF DYING CANCER CELLS, ELICITING AN ANTITUMOR IMMUNITY THAT PREVENTS TUMOR RECURRENCE AND PROGRESSION. SCNPS ARE INTRAVESICALLY INSTILLED INTO THE AFFECTED BLADDER TO KILL RESIDUAL CANCER CELLS AFTER TURBT. AFTER THE TREATMENT, SCNPS DEGRADE TO CONSTITUTE IONS THAT ARE EXCRETED IN THE URINE. THE PROCEDURE IS SAFE AND CAN BE APPLIED REPEATEDLY WITHOUT CAUSING LOCAL OR SYSTEMIC TOXICITY. IN PHASE I, WE WILL TEST THE EFFICACY OF SCNPS IN A MOUSE ORTHOTOPIC BLADDER CANCER MODEL. IN PHASE II, WE WILL EVALUATE THE EFFICACY OF SCNPS IN AN EXPANDED PRE-CLINICAL STUDY AND PERFORM IND-ENABLING PHARMACOKINETICS AND TOXICITY STUDIES.

DEVELOPMENT OF A RADIATION-ACTIVATABLE NANOPARTICLE FOR LUNG CANCER THERAPY - ABSTRACT LUNG CANCER IS THE SECOND MOST COMMON CANCER AND THE LEADING CAUSE OF CANCER-RELATED DEATHS. IN THE U.S., IT IS ESTIMATED THAT 234,580 PEOPLE WILL BE DIAGNOSED WITH LUNG CANCER IN 2024. NON-SMALL CELL LUNG CANCER (NSCLC) IS THE MOST COMMON TYPE OF LUNG CANCER, ACCOUNTING FOR 80-85% OF ALL CASES. DESPITE ADVANCES IN RADIATION THERAPY (RT), THE PROGNOSIS FOR PATIENTS WITH UNRESECTABLE STAGE III NSCLC REMAINS POOR. TO IMPROVE EFFICACY, CHEMOTHERAPY, MOST COMMONLY PLATINUM-BASED DOUBLETS, IS OFTEN ADMINISTERED TO PATIENTS DURING RT, KNOWN AS CHEMORADIOTHERAPY (CRT). HOWEVER, TOXICITY OFTEN LEADS TO TREATMENT DELAYS OR DISCONTINUATION. THEREFORE, THERE IS AN URGENT NEED FOR NEW CRT STRATEGIES THAT PROVIDE COMPARABLE OR SUPERIOR EFFICACY TO CONVENTIONAL CRT BUT ARE BETTER TOLERATED BY PATIENTS. ATHNA BIOTECH, INC. IS DEVELOPING A NOVEL CRT APPROACH THAT UTILIZES RADIATION TO LOCALLY ACTIVATE SYSTEMICALLY DELIVERED THERAPEUTICS. THE COMPANY HAS SYNTHESIZED A RADIATION-RESPONSIVE PRODRUG, DM1-NO, WHICH IS NITROSYLATED DM1, A MAYTANSINOID. THIS PRODRUG CAN BE LOADED INTO PEG-PLGA POLYMERIC NANOPARTICLES AND DELIVERED TO TUMORS. TO ENHANCE DELIVERY EFFICIENCY, THE NANOPARTICLES ARE CONJUGATED WITH NTSMUT, A LIGAND WITH HIGH AFFINITY TOWARDS NTSR1, WHICH IS UPREGULATED IN 59.7% OF LUNG TUMORS. DURING RT, IRRADIATION INCREASES OXIDATIVE STRESS IN TUMORS, RESULTING IN THE DISSOCIATION OF DM1-NO AND THE RELEASE OF DM1 AND NITRIC OXIDE (NO). BOTH DM1 AND NO ARE POTENT RADIOSENSITIZERS, WORKING SYNERGISTICALLY TO ENHANCE RT. DURING THE STTR PHASE I PERIOD, WE HAVE DEMONSTRATED THE SELECTIVE ACCUMULATION AND SUSTAINED RETENTION OF AB-001 WITHIN TUMORS, ENHANCED TUMOR PENETRATION, AND SUPERIOR EFFICACY IN COMBINATION WITH RADIOTHERAPY COMPARED TO CONVENTIONAL TREATMENTS WHILE MINIMIZING TOXIC EXPOSURE TO VITAL ORGANS. SUCCESSFUL COMPLETION OF PHASE I STUDIES VALIDATED THE FEASIBILITY AND EFFICACY OF AB-001. IN THIS PHASE II APPLICATION, ATHNA BIOTECH WILL WORK WITH OUR ACADEMIC COLLABORATORS AND INDUSTRY PARTNERS TO FURTHER DEVELOP AB-001. SPECIFICALLY, WE WILL SCALE UP AND OPTIMIZE THE MANUFACTURING PROCESSES OF AB-001, PRODUCE A GLP BATCH FOR STABILITY STUDY AND ANALYTICAL METHOD VALIDATION, AND ASSESS THE EFFICACY AND TOXICITY OF AB-001 IN ADDITIONAL MURINE LUNG TUMOR MODELS. FOLLOWING OUR PRE-IND MEETING WITH THE FDA, WE WILL CONDUCT IND-ENABLING TOXICITY EVALUATIONS AND COMPREHENSIVE PHARMACOKINETIC STUDIES WITH AB-001. SUCCESSFUL COMPLETION OF PHASE II WILL PAVE THE WAY FOR IND FILING AND SUBSEQUENT HUMAN CLINICAL TRIALS. THIS WILL ULTIMATELY ADVANCE AB-001 TOWARDS REGULATORY APPROVAL AND COMMERCIALIZATION, ADDRESSING AN UNMET MEDICAL NEED IN THE TREATMENT OF NSCLC.

DEVELOPMENT OF A SALT-BASED NANOMEDICINE FOR NON-MUSCLE INVASIVE BLADDER CANCER - ABSTRACT BLADDER CANCER COMPRISES 7% OF NEW CANCER DIAGNOSES IN THE US. IT IS THE SIXTH MOST PREVALENT MALIGNANCY, AND HAS THE HIGHEST LIFETIME TREATMENT COSTS AMONG ALL CANCER TYPES DUE TO THE NEED FOR LIFELONG SURVEILLANCE. EARLY STAGE BLADDER CANCER, ALSO KNOWN AS NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC), REPRESENTS 75% OF NEW BLADDER CANCER CASES. THE STANDARD TREATMENT IS TRANSURETHRAL RESECTION OF BLADDER TUMOR (TURBT), FOLLOWED BY INTRAVESCICAL THERAPY WITH CHEMOTHERAPEUTICS SUCH AS MITOMYCIN C OR BACILLE CALMETTE-GUÉRIN (BCG). HOWEVER, ~30% PATIENTS ARE REFRACTORY TO BCG. CHEMOTHERAPIES ARE ASSOCAITED WITH RELATIVELY HIGH RECURRENCE RATES AND INEFFECTIVE AS A SECOND-LINE TREATMENT FOR PATIENTS UNRESPONSIVE TO BCG. MEANWHILE, NO NEW INTRAVESICAL DRUGS HAVE BEEN APPROVED SINCE 1998. THERE IS AN UNMET CLINICAL NEED FOR NEW NMIBC THERAPIES. ATHNA BIOTECH, INC. IS DEVELOPING A SODIUM CHLORIDE NANOPARTICLE (SCNP) BASED CANCER THERAPEUTIC. SCNPS DELIVER LARGE AMOUNTS OF NA+ AND CL- INTO CANCER CELLS, BY DOING SO DISRUPTS THE OSMOTIC BALANCE ACROSS THE PLASMA MEMBRANE. UNIQUELY, SCNPS INDUCE IMMUNOGENIC CELL DEATH OR ICD. THIS MEANS THAT SCNPS ESSENTIALLY PRODUCE A VACCINE IN SITU OUT OF DYING CANCER CELLS, ELICITING AN ANTITUMOR IMMUNITY THAT PREVENTS TUMOR RECURRENCE AND PROGRESSION. SCNPS ARE INTRAVESICALLY INSTILLED INTO THE AFFECTED BLADDER TO KILL RESIDUAL CANCER CELLS AFTER TURBT. AFTER THE TREATMENT, SCNPS DEGRADE TO CONSTITUTE IONS THAT ARE EXCRETED IN THE URINE. THE PROCEDURE IS SAFE AND CAN BE APPLIED REPEATEDLY WITHOUT CAUSING LOCAL OR SYSTEMIC TOXICITY. IN PHASE I, WE WILL TEST THE EFFICACY OF SCNPS IN A MOUSE ORTHOTOPIC BLADDER CANCER MODEL. IN PHASE II, WE WILL EVALUATE THE EFFICACY OF SCNPS IN AN EXPANDED PRE-CLINICAL STUDY AND PERFORM IND-ENABLING PHARMACOKINETICS AND TOXICITY STUDIES.

DEVELOPMENT OF A RADIATION-ACTIVATABLE NANOPARTICLE FOR LUNG CANCER THERAPY - ABSTRACT NON–SMALL CELL LUNG CANCER (NSCLC) IS A LEADING CAUSE OF CANCER-RELATED MORTALITY. NSCLC ACCOUNTS FOR 85% OF ALL LUNG CANCERS, AND IS DIAGNOSED IN 234,030 PERSONS EACH YEAR IN THE US. FOR THE MAJORITY OF PATIENTS WITH LOCALLY ADVANCED OR LOCAL REGIONAL DISEASE, RADIATION THERAPY (RT) IS THE STANDARD CARE. HOWEVER, THE DOSE AND EFFICACY OF RT IS LIMITED BY NORMAL TISSUE TOXICITY. TO IMPROVE TUMOR CONTROL, RADIOSENSITIZERS SUCH AS CISPLATIN AND PACLITAXEL ARE USED IN CONCURRENT WITH RT, I.E. CHEMORADIOTHERAPY (CRT). HOWEVER, CRT IS ASSOCIATED WITH HIGH LEVELS OF ACUTE AND SYSTEMIC TOXICITY. MANY PATIENTS ARE UNFIT TO RECEIVE CRT OR COMPLETE THE PLANNED COURSES. THERE IS AN URGENT NEED OF METHODOLOGIES THAT CAN DELIVER RADIOSENSITIZERS SITE-SPECIFICALLY TO TUMORS TO ENHANCE RT. ATHNA BIOTECH, INC. IS DEVELOPING A NEW CRT APPROACH WHERE RADIATION IS UTILIZED TO LOCALLY ACTIVATE SYSTEMICALLY DELIVERED THERAPEUTICS. SPECIFICALLY, WE HAVE SYNTHESIZED A RADIATION-RESPONSIVE PRODRUG, DM1-NO, A NITROSYLATED MAYTANSINOID DM1. THE PRODRUG CAN BE LOADED INTO POLY(LACTIDE-CO-GLYCOLIC)-BLOCK-POLY(ETHYLENE GLYCOL) NANOPARTICLES AND DELIVERED TO TUMORS. TO IMPROVE DELIVERY EFFICIENCY, THE NANOPARTICLES ARE CONJUGATED WITH NTSMUT, A LIGAND THAT HAS HIGH AFFINITY TOWARDS NTSR1, WHICH IS UP-REGULATED IN 59.7% LUNG TUMORS. DURING RT, IRRADIATION ELEVATES OXIDATIVE STRESS IN TUMORS, RESULTING IN THE DISASSOCIATION OF DM1-NO AND THE RELEASE OF DM1 AND NITRIC OXIDE (NO). BOTH DM1 AND NO ARE EFFECTIVE RADIOSENSITIZERS, WORKING SYNERGISTICALLY TO ENHANCE RT. WITH NANOPARTICLE DELIVERY, NTSR1 TARGETING, CONFORMAL RADIATION, AND RADIATION-RESPONSIVE ACTIVATION, THIS APPROACH IS ASSOCIATED WITH HIGH TUMOR SELECTIVITY THUS PERMITTING ACCURATE RADIOSENSITIZATION. THE METHODOLOGY CAN BE EXTENDED TO TREATMENT OF OTHER CANCERS, SUCH AS PROSTATE, HEAD AND NECK, BREAST, AND COLON CANCER, WHERE NTSR1 IS ALSO UPREGULATED.

DEVELOPMENT OF A RADIATION-ACTIVATABLE NANOPARTICLE FOR LUNG CANCER THERAPY - ABSTRACT NON–SMALL CELL LUNG CANCER (NSCLC) IS A LEADING CAUSE OF CANCER-RELATED MORTALITY. NSCLC ACCOUNTS FOR 85% OF ALL LUNG CANCERS, AND IS DIAGNOSED IN 234,030 PERSONS EACH YEAR IN THE US. FOR THE MAJORITY OF PATIENTS WITH LOCALLY ADVANCED OR LOCAL REGIONAL DISEASE, RADIATION THERAPY (RT) IS THE STANDARD CARE. HOWEVER, THE DOSE AND EFFICACY OF RT IS LIMITED BY NORMAL TISSUE TOXICITY. TO IMPROVE TUMOR CONTROL, RADIOSENSITIZERS SUCH AS CISPLATIN AND PACLITAXEL ARE USED IN CONCURRENT WITH RT, I.E. CHEMORADIOTHERAPY (CRT). HOWEVER, CRT IS ASSOCIATED WITH HIGH LEVELS OF ACUTE AND SYSTEMIC TOXICITY. MANY PATIENTS ARE UNFIT TO RECEIVE CRT OR COMPLETE THE PLANNED COURSES. THERE IS AN URGENT NEED OF METHODOLOGIES THAT CAN DELIVER RADIOSENSITIZERS SITE-SPECIFICALLY TO TUMORS TO ENHANCE RT. ATHNA BIOTECH, INC. IS DEVELOPING A NEW CRT APPROACH WHERE RADIATION IS UTILIZED TO LOCALLY ACTIVATE SYSTEMICALLY DELIVERED THERAPEUTICS. SPECIFICALLY, WE HAVE SYNTHESIZED A RADIATION-RESPONSIVE PRODRUG, DM1-NO, A NITROSYLATED MAYTANSINOID DM1. THE PRODRUG CAN BE LOADED INTO POLY(LACTIDE-CO-GLYCOLIC)-BLOCK-POLY(ETHYLENE GLYCOL) NANOPARTICLES AND DELIVERED TO TUMORS. TO IMPROVE DELIVERY EFFICIENCY, THE NANOPARTICLES ARE CONJUGATED WITH NTSMUT, A LIGAND THAT HAS HIGH AFFINITY TOWARDS NTSR1, WHICH IS UP-REGULATED IN 59.7% LUNG TUMORS. DURING RT, IRRADIATION ELEVATES OXIDATIVE STRESS IN TUMORS, RESULTING IN THE DISASSOCIATION OF DM1-NO AND THE RELEASE OF DM1 AND NITRIC OXIDE (NO). BOTH DM1 AND NO ARE EFFECTIVE RADIOSENSITIZERS, WORKING SYNERGISTICALLY TO ENHANCE RT. WITH NANOPARTICLE DELIVERY, NTSR1 TARGETING, CONFORMAL RADIATION, AND RADIATION-RESPONSIVE ACTIVATION, THIS APPROACH IS ASSOCIATED WITH HIGH TUMOR SELECTIVITY THUS PERMITTING ACCURATE RADIOSENSITIZATION. THE METHODOLOGY CAN BE EXTENDED TO TREATMENT OF OTHER CANCERS, SUCH AS PROSTATE, HEAD AND NECK, BREAST, AND COLON CANCER, WHERE NTSR1 IS ALSO UPREGULATED.