Resistance to therapy presents a major clinical challenge in cancer medicine today, and novel approaches to identify and overcome the mechanisms that cause resistance are desperately needed for improving outcome in patients. Over the past years epigenetic dysreguation in cancer has gained more and more attention. Chromatin regulators are aberrantly expressed in a wide variety of tumors, and cancer genome sequencing studies have identified frequent somatic alterations in many chromatin-regulating enzymes. Furthermore, epigenetic changes have also been implicated in the development of drug resistance. Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy that frequently relapses or becomes refractory. T-ALL frequently harbors activating mutations in NOTCH1, which confer sensitivity to NOTCH inhibitors such as gamma secretase inhibitors (GSI). Yet, the rapid development of resistance has limited their clinical success. I have recently shown that resistance to NOTCH inhibition in T-ALL is mediated by epigenetic mechanisms that confer unique dependencies on BET family bromodomain proteins (Nature Genetics, 2014). However, detailed understanding of the molecular mechanisms underlying the epigenetic state transitions are currently lacking. By combining functional perturbation of chromatin regulators with modern next-generation sequencing tools for chromatin state analysis, I will identify, mechanistically characterize, and therapeutically validate the epigeneti and compensatory oncogenic signaling dependencies in drug resistant T-ALL. Results of the in vitro studies will be further investigated using murine models of primary human T-ALL, and this will lay the foundation for future preclinical studies and clinical trials of targeted therapies inT-ALL. I am a pediatric oncologist with a Ph.D. and substantial prior research experience in T cell immunology who is seeking K08 support for mentored research in Dr. Bradley Bernstein's laboratory at MGH / Broad Institute with Dr. Jon Aster, BWH / DFCI acting as a co-mentor. My long-term career objective is to obtain a tenure-track position as a physician-scientist in a pediatric hematology/oncology department at an academic cancer center. The K08 award will provide the protected time I need for advanced training in cancer and chromatin biology, in particular, analysis of large-scale epigenome datasets, experimental therapeutics and translational research. I will devote a minimum of 80% of my time to a focused research program on epigenetic resistance mechanisms in T-cell acute lymphoblastic leukemia and translational research, and will complement this with 20% of my effort dedicated to clinical care for children with hematologic malignancies. Dana-Farber Cancer Institute / Boston Children's Hospital, Massachusetts General Hospital and the Broad Institute of MIT and Harvard are internationally recognized research programs with a number of expert researchers in the areas of stem cell biology, hematopoiesis, and cancer cell biology. Furthermore, the division of Pediatric Hematology/Oncology at Dana-Farber Cancer Institute / Boston Children's Hospital has a distinguished record of training successful physician-scientists. I have assembled an excellent mentoring and advisory committee, consisting of Dr. Kimberly Stegmaier, Dr. Charles Roberts and Dr. Benjamin Ebert, who will guide my research and training experiences. The expertise of my advisory committee will be complemented by a set of additional collaborators who are experts in their respective fields (Dr. James Bradner, development of chemical compounds against chromatin regulators; Dr. Andrew Kung, mouse models of cancer and experimental therapeutics; Dr. Lewis Silverman, translational and clinical research in pediatric oncology). This research proposal is part of a structured plan with scientific, technical, clinical training and career development components. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on cancer epigenetics and clinical pediatric oncology.
Despite modern combination therapies, T-cell acute lymphoblastic leukemia (T-ALL) continues to have high rates of refractory disease and early relapse due to rapid development of resistance. Although many malignant tumors carry epigenetic alterations, their relevance for resistant disease is poorly understood. This research proposal will investigate the epigenetic mechanisms responsible for drug resistance in T-ALL, and develop strategies for their therapeutic targeting, thus providing significant impact for a wide variety of malignancies beyond T-ALL.
|Knoechel, Birgit; Aster, Jon C (2015) Metabolic Mechanisms of Drug Resistance in Leukemia. Cell Metab 22:759-60|
|Knoechel, Birgit; Bhatt, Ami; Pan, Li et al. (2015) Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the Î³-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case. Cold Spring Harb Mol Case Stud 1:a000539|