Project Grant R21CA290334

ETHNICITY-DRIVEN PFERNA IN AFRICAN AMERICAN HEALTH DISPARITIES IN LUNG CANCER. - PROJECT SUMMARY: NON-SMALL CELL LUNG CANCER (NSCLC) INCIDENCE AND MORTALITY RATES ARE HIGHER AMONG AFRICAN AMERICANS (AA) THAN OTHER RACIAL OR ETHNIC GROUPS. A LOWER PREVALENCE OF LUNG-CANCER-RELATED GENETIC MUTATIONS IN AA INDICATES THAT STUDYING TRANSCRIPTION FACTORS IS A NEW PROMISING DIRECTION. WE HAVE IDENTIFIED DIFFERENTIALLY EXPRESSED PFERNAS BY PROFILING 120 CLINICAL SPECIMENS FROM 72 PATIENTS, INCLUDING 12 SPECIMENS FROM 12 AA AND 108 SPECIMENS FROM 60 CAUCASIANS AND ASIANS USING SMALL NON- CODING RNA DEEP SEQUENCING FOLLOWED BY BIOINFORMATIC AND BIOSTATISTICS ANALYSES, AND ALL THESE PATIENTS WITH EITHER BENIGN OR MALIGNANT PULMONARY NODULES. WE IDENTIFIED A PFERNA THAT WAS ONLY EXPRESSED IN AA BUT UNDETECTABLE IN EITHER CAUCASIANS OR ASIANS, SUGGESTING THAT THIS PFERNA IS AN AA-SPECIFIC PFERNA (AA- PFERNA). THE USE OF AA, CAUCASIANS, AND ASIANS GIVES US DIRECT EVIDENCE THAT AA-PFERNA IS A POTENTIAL FACTOR IN HEALTH DISPARITIES IN NSCLC. THE USE OF PATIENTS' BENIGN AND MALIGNANT PULMONARY NODULES PROVIDES A PERFECT MODEL FOR UNDERSTANDING LUNG PRENEOPLASIA MALIGNANT PROGRESSION, AND THE AA-PFERNA WE IDENTIFIED IS SPECIFICALLY INDUCED ENDOGENOUSLY ONCE LUNG PRENEOPLASIA PROGRESSES TO NSCLC IN AA, GIVING DIRECT EVIDENCE FOR AA-PFERNA AS A THERAPEUTIC TARGET TO INHIBIT THE EVOLUTION OF LUNG PRENEOPLASIA TO NSCLC. IMPORTANTLY, WE IDENTIFIED AA-PFERNA FOLLOWING THE REQUIREMENTS OF THE CLINICAL LABORATORY IMPROVEMENT AMENDMENTS (CLIA) COMPLIANT A LABORATORY DEVELOPED TEST (LDT) ASSAY, PROVIDING EVIDENCE FOR TRANSLATIONAL DEVELOPMENT. FURTHER, ITS HIGH EXPRESSION PREDICTED WORSE OVERALL SURVIVAL OF AA WITH NSCLC. TO PREVENT AA-PFERNA FUNCTION AND DISRUPT NSCLC DEVELOPMENT, WE HAVE DESIGNED OLIGOS COMPLEMENTARY TO AA-PFERNA (CAA-PFERNA) AND OPTIMIZED MODIFICATIONS AND CONJUGATES TO DELIVER PFERNA TO NSCLC AND LIMIT ACCUMULATION IN NORMAL TISSUES. THEREFORE, IN THIS PROJECT, WE WILL PROVIDE MECHANISTIC RATIONALE AND THERAPEUTIC INSIGHTS INTO THE DRUGGABLE AA-PFERNA: (1) IDENTIFY THE TARGET PROTEIN IN CANCEROUS TISSUES FROM AA WITH STAGE-I/II NSCLC, CONFIRM THEIR INTERACTION PATTERN AND CELLULAR DISTRIBUTION IN BOTH CANCEROUS TISSUES AND CELLS, AND OBSERVE ITS EFFECTS ON THE BASIC BIOLOGICAL ACTIVITIES OF CELLS WITH AND WITHOUT THE TARGET PROTEIN; AND (2) EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIPS OF LIGATED-CAA-PFERNA-2'-MOE-PTO BY SYSTEMIC DELIVERY IN PRECLINICAL ANIMAL MODELS. OUR OPTIMIZED SPECIFIC & NATURAL PFERNA-BASED TARGETING SYSTEM WILL PROVIDE A NEW TREATMENT OPPORTUNITY FOR AA WITH NSCLC TO REDUCE RACIAL AND ETHNIC HEALTH DISPARITIES. ALSO, THE SYSTEM WILL BE OF SIGNIFICANT INTEREST TO RESEARCHERS IN THE FIELD OF SNCRNA-BASED THERAPEUTICS FOR CANCER TREATMENT.