HPD Research Day | February 16, 2018

21 Steele Auditorium Steele Auditorium 10:15 – 10:45 a.m. Targeting NEDDylation for Therapeutic Gain of Acute Lymphoblastic Leukemia Shuhua Zheng, Ph.D., OMS-I, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University Julio Barredo, M.D., Sylvester Comprehensive Cancer Center, University of Miami Objective. This comprehensive study aims to uncover the therapeutic potential of inhibiting the novel NEDDylation Activating Enzyme (NAE) using pevonedistat for the therapeutic gain of ALL treatment. Background. Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children. Previous data from our lab and others showed that ALL cells are sensitive towards endoplasmic reticulum (ER) stress/unfolded protein response (UPR) inducers. In search for novel strategies to target the ER stress/UPR pathways in ALL, we identified the novel NAE inhibitor pevonedistat can efficiently kill ALL cells in vitro and in vivo. Mechanistic studies indicated that hyper-activation of cytotoxic ER stress/UPR was mainly responsible for pevonedistat-induced ALL cell death. We also identified aberrant activation MEK/ERK signaling in pevonedistat-treated ALL cells as a compensatory pro-survival pathway, co-targeting of which will induce synergistic anti-ALL effects. Methods. Molecular biology techniques were used in this study. NSG bioluminescent mouse model was developed to evaluate the in vivo efficacy of pevonedistat. Results. We found that pevonedistat treatment induced concomitant activation of p-mTOR (Ser2448) pathway and de-phosphorylation/activation of p-eIF2alpha (Ser51) which will dysregulate the protein homeostasis in ALL cells, triggering proteotoxic ER stress. Combinational treatment of pevonedistat with clinical-in-use drugs showed potent synergistic drug-drug interactions. Further study identified Ca2+-dependent activation of MEK/ERK signaling activation in pevonedistat-treated ALL cells as a compensatory pro-survival mechanism. This study leads to the initiation of the Phase I clinical trial of pevonedistat for refractory/relapsed pediatric ALL treatment (ClinicalTrials.gov Identifier: NCT03349281). Steele Auditorium 10:45 – 11:15 a.m. HIV/AIDS and Populations at Risk in Broward County, Florida Alexandra C. Lenox, BS, OMS-II, Dr. Kiran C. Patel College of Osteopathic Medicine, Public Health, Nova Southeastern University Sharmila Aryal, MPH, Dr. Kiran C. Patel College of Osteopathic Medicine, Public Health, Nova Southeastern University Cyril Blavo, DO, Professor, Dr. Kiran C. Patel College of Osteopathic Medicine Objective. 1) Identify risk groups within Broward County with highest prevalence of HIV/AIDS; 2) Inform health professionals on local demographics of HIV/AIDS and inform policies and interventions. Background. Human Immunodeficiency Virus (HIV) attacks CD4 cells, leading to immune system destruction and can progress into Acquired Immunodeficiency Syndrome (AIDS). There is no effective cure for HIV/AIDS. The CDC reports that 1.1million people in the US have HIV and 1 in 7 people are unaware that they are infected. This study provides an analysis of Broward County populations at-risk for contracting HIV, and provides insight into health disparities and intervention strategies. Methods. Secondary data analysis with Microsoft Excel using de-identified data from AIDSVu and CDC National Surveillance Database from 2012-2015. Variables of interest included: age, gender, race, and zipcode. Results. In each of the years studied, black males, 45-59 years old, residing in the 33311 zip-code had the highest rates of HIV/AIDS in Broward County. Males consistently had higher rates of HIV/AIDS compared to females. The black population consistently had higher rates of HIV/AIDS over other races – followed by the white and hispanic populations, respectively. The 25-44 age group consistently had the second highest rate of HIV/AIDS. This zip-code observation parallels other disease statistics that indicate greatest prevalence in the 33311 zip-code including pediatric asthma and diabetes. Conclusion. There is a demand for HIV/AIDS health initiatives within Broward County, specifically in the 33311 region. Further studies aimed at gaining insight into disease management and access to clinical support for this at-risk population are necessary. Grants. None.