The proposed research and career development plan have been designed to complete Dr. Ow?s path toward independence as a surgeon-scientist in translational head and neck cancer research. Dr. Ow has devoted his early research career to the study of factors associated with locoregional treatment failure in head and neck squamous cell carcinoma (HNSCC). This research addresses a major unmet need for the current diagnosis and management of patients with HNSCC. The research builds on Dr. Ow?s previous work, and proposes to use both clinical and laboratory research to examine the relationship between key genetic and molecular characteristics (TP53 mutation, p16INK4A/p14ARF expression, and BCL-family pro-survival molecule expression) of HNSCC and tumor cell resistance to cisplatin and radiation. The career development plan, through mentorship and formal training activities, builds on Dr. Ow?s previous training in laboratory methods, biostatistics, bioinformatics, and translational research methods. Upon completion of the K23 funding period, it is anticipated that Dr. Ow will be well-positioned to submit a Research Project Grant (RO1). Dr. Ow?s mentorship and advisory teams are composed of individuals who have had great success in all aspects of translational research, and will help Dr. Ow develop core skills necessary to carry out independent T1 translational research. Dr. Chandan Guha, MBBS, PhD, a radiation oncologist and translational scientist, will serve as primary mentor, while Mimi Kim, ScD (Biostatistics), Evripidis Gavathiotis, PhD (Biochemistry), and Nicolas Schlecht (Epidemiology) form a strong mentorship committee, each providing expertise in disciplines that are fundamental to the proposed research plan and translational science. Dr. Ow receives protected time, laboratory space, salary for a full-time research technician, supplies, and administrative support from the Department of Otorhinolaryngology-Head and Neck Surgery (Primary Appointment) and from the Department of Pathology (Secondary Appointment). Albert Einstein College of Medicine and Montefiore Medical Center (MMC) have demonstrated a commitment to Dr. Ow?s career as a surgeon scientist, evidenced by his support and education as a Paul Calabresi (K12) Scholar and a trainee in the Clinical Research Training Program administered by the Institute for Clinical and Translational Research. The current project proposes to develop a prediction model for locoregional treatment failure in HNSCC using a nested-case control study in a retrospective cohort of patients treated at MMC (Specific Aim#1). The association of the biomarkers in the prediction model with cisplatin and radiation response will also be evaluated in an innovative primary cell culture model (Specific Aim#2). The goals of these studies are to improve the ability to identify patients with HNSCC at high risk of treatment failure, and to develop methods to better understand the mechanisms of treatment resistance.
There are approximately 60,000 new cases and 12,000 deaths annually due to head and neck squamous cell carcinoma (HNSCC) in the United States. Overall, approximately 70% of patients present with stage III or IV disease. For patients with laryngeal, hypopharyngeal, and oropharyngeal cancers ? which represent approximately 30,000 of the cases of HNSCC in the United States per year - non-surgical, organ-preservation protocols, using radiation in combination with concurrent cisplatin, are the standard of care. This approach was instituted over 15 years ago, and it has been established that 20-30% of these patients will require salvage treatment for persistent or recurrent disease after failing therapy. Despite this, a method for recognizing who is at greatest risk of failing concurrent chemoradiation at the time of diagnosis does not exist. This project aims to create a prediction model using TP53 mutation, p16/p14ARF expression, and expression of Bcl-family pro-survival molecules for locoregional response to chemoradiation (Specific Aim#1). The association of these markers with cisplatin and radiation treatment will also be evaluated in tumor cells grown in an innovative in vitro primary cell culture model (Specific Aim#2). These studies have direct clinical relevance and are aimed at addressing a major dilemma in head and neck cancer treatment that has not changed substantially for nearly two decades. The ability to identify patients who are at high risk of locoregional failure would provide an opportunity to target this population with alternative treatment approaches, and a laboratory model that could preserve tumor characteristics related to treatment response would provide a means to more efficiently test new and effective therapeutic strategies.