This proposal describes a 5-year training program designed to enable the applicant to develop an independent research career in the field of lymphoma biology and experimental therapeutics. The applicant is a pediatric oncologist at Weill Cornell Medical College (WCMC) who is committed to an academic career studying disease mechanisms in lymphoma and exploiting these mechanisms to develop novel therapies. Her current research focuses on targeting the histone methyltransferase EZH2 in B-cell lymphoma. The candidate?s immediate career goals are to gain further training in experimental design and develop expertise in epigenomics. Her long-term career goals are to establish independent laboratory space, lead a team of researchers, and make scientific contributions that allow her develop into a national/international leader in the field. To enable these goals this proposal outlines the following career development objectives: 1) formal training in experimental design, drug development, and statistical genomics; 2) coursework in epigenetic dysregulation, 3) regular meetings with an advisory committee composed of distinguished clinicians, scientists, and institutional leaders; 4) formal and informal professional development in leadership, management skills, public speaking and grantsmanship. The applicant?s mentors, Dr. Ethel Cesarman and Dr. Ari Melnick, are both tenured professors at WCMC and are international leaders in the study of viral-related lymphomas and epigenetic mechanisms in lymphoma respectively. Dr. Cesarman and Dr. Melnick have an extensive track record of collaboration including multiple joint grant awards and joint mentorship of trainees. The research proposal focuses on the rational translation of EZH2 targeted therapy in germinal center (GC) B-cell lymphomas. GC B-cell lymphomas are aggressive tumors that occur in pediatrics and adults. Relapsed/refractory disease represents an unmet need with most treatments failing to induce durable remissions. GC B-cell lymphomas are dependent on EZH2 which is a lineage factor for germinal center B-cells. EZH2 may play a unique role in EBV+ lymphoma where it contributes to restricted EBV viral latency that allows immune evasion. Small molecule inhibitors of EZH2 are currently in clinical development, including GSK126, which is being studied in a phase I trial that the applicant is conducting in collaboration with GSK. The unique mechanism and time course of epigenetic therapy requires careful consideration for effective clinical deployment. The overarching goal of this proposal is to develop a rational approach for the clinical use of EZH2i in lymphoma.
The specific aims are 1) Define the epigenetic and transcriptional background of lymphomas that respond to EZH2 inhibition (EZH2i); 2) Determine the kinetics of response to EZH2i and the point of maximum vulnerability to combination therapy; 3) Determine the impact of EZH2i on the vulnerability of EBV + lymphomas to immune mediated therapy. Overall this proposal will accomplish the rational evolution and deployment of a new class of therapeutic agents in lymphoma. This work will be the basis of future clinical trials, which the applicant will be positioned to lead.
Germinal center B-cell lymphomas, which include diffuse large B-cell lymphoma and Burkitt lymphoma, are aggressive tumors that are dependent on the histone methyltransferase EZH2. Small molecule inhibitors of EZH2 are currently in clinical trials but the unique mechanism of action and time course of response to these agents requires particular consideration for effective clinical deployment. In this proposal we will study the kinetics of EZH2 inhibition and the biology of response to EZH2 inhibitors to understand how best to utilize EZH2 inhibition for the treatment of lymphoma.
| Gulati, Nitya; Béguelin, Wendy; Giulino-Roth, Lisa (2018) Enhancer of zeste homolog 2 (EZH2) inhibitors. Leuk Lymphoma 59:1574-1585 |
