In July 2015, the WES Foundation distributed 3 grants to the highly recognized researchers below because of you!
Acute myeloid leukemia (AML) is a type of blood cancer that is in need of new therapies, as patients suffering from high risk disease have little chance of cure. Aggressive treatment with traditional chemotherapy drugs can lead to complications and severe toxicities. Targeted therapy may have fewer side effects, and immune therapies in particular are a new class of treatments that offers great promise. Infusion of a type of immune cell, the T cell, modified to specifically recognize a cancer cell has been successful against pediatric acute lymphoblastic leukemia (ALL) in early clinical studies. We have developed a new type of modified T cell, genetically engineered to secrete a targeting engager molecule that directs these cells, as well as unmodified T cells, to attack AML cells. Preliminary studies have shown strong activity against AML in a preclinical animal model that mimics human disease. Because this is an original, innovative therapy that we plan to translate to human clinical trials, we propose the incorporation of a ‘safety-switch’ that will allow rapid destruction of modified T cells if unexpected toxicity is seen. Following testing of T cells containing both our ‘safety-switch’ and the secretable engager, we plan additional trials in our mouse model. If continued excellent anti-AML activity is seen, and further clinical development is justified, we plan to develop a clinical trial with a goal of ultimately benefiting all patients with AML.
Overview - P. Peter Ghoroghchian, MD, PhD is an attending physician at the Dana-Farber Cancer Institute, an Instructor in Medicine at Harvard Medical School, and the Charles W. and Jennifer C. Johnson Clinical Investigator in the Koch Institute for Integrative Cancer Research at MIT. He earned his B.S. in chemical engineering from MIT in 1999, followed by Ph.D. (2006) and M.D. (2008) degrees from the University of Pennsylvania. After medical school, Dr. Ghoroghchian completed internship and residency training in Internal Medicine at the Brigham and Women’s Hospital, as well as fellowship training in hematology and medical oncology at the Dana-Farber Cancer Institute and the Massachusetts General Hospital. His investigations are further informed by his experiences in the biotechnology industry; a co-founder and chief scientist at Vindico NanoBioTechnology, Inc., Dr. Ghoroghchian has also overseen research efforts at PhenoTech, Inc., and other firms.
Every year, 13,000 Americans are diagnosed with AML and > 50% of these patients die despite highly aggressive treatments. Over the last 30 years, multiple targeted therapies have shown outstanding in vitro efficacy but have failed to improve clinical outcomes. These agents are unable to eradicate the small minority of AML cells that have the capacity for self-renewal, disease initiation, and propagation, known as leukemia stem cells (LSCs). The goal of this project is to develop novel therapies that are capable of effective in vivo targeting of LSCs. Unfortunately, this task is quite challenging due to their similarities to normal hematopoietic stem and progenitor cells (HSPCs); both LSC and HSPCs are also maintained by in vivo interactions within the bone marrow niche that further hinder efforts at selective LSC elimination. Here, we aim to generate a bone-targeted drug delivery system to circumvent first-pass metabolism and to augment bone marrow concentrations of novel LSC-specific small molecule therapies. We will subsequently test the preliminary in vivo efficacy of our constructs for eradicating LSCs in mouse and patient-derived xenograft (PDX) models of AML.
Overview - Kimberly Stegmaier is an Associate Professor of Pediatrics at Harvard Medical School and a Principal Investigator at the Dana-Farber Cancer Institute (DFCI). She is the Co-Director of the Pediatric Hematologic Malignancy Program and an attending physician providing clinical care in Pediatric Oncology at DFCI and Boston Children’s Hospital (BCH). She is also an Institute Member of the Broad Institute of MIT and Harvard.
The Stegmaier laboratory develops and integrates “omic” approaches to identify new protein targets and small-molecule modulators of malignancy with an eye toward clinical translation. Acute myeloid leukemia (AML) is one major focus of her research. The laboratory has applied an integrative chemical and functional genomic approach to two primary avenues of investigation in childhood malignancy, including AML: the discovery of modulators of biological state switches, such as differentiation, and the modulation of aberrant transcription factors.
At a national level she is a strong advocate for pediatric cancer research, serving as a Council Member with the Society for Pediatric Research (SPR) and a Steering Committee Member with the AACR Pediatric Cancer Working Group. She has won numerous awards, including the A. Clifford Barger Excellence in Mentoring Award from Harvard Medical School, the SPR Young Investigator Award, the Sir William Osler Young Investigator Award from the Interurban Clinical Club, the Joanne Levy, MD, Memorial Award for Outstanding Achievement from the American Society of Hematology and a SU2C Innovative Research Grant.
Dr. Stegmaier received her undergraduate degree from Duke University, medical degree from Harvard Medical School, and trained in Pediatrics and Pediatric Hematology/Oncology at BCH and DFCI.
A hallmark of cancer cells is uncontrolled growth. In order to accomplish this, cancer cells have altered the ways in which they use energy and have enhanced their ability to produce the building blocks needed for the synthesis of proteins, fats, and DNA. Specifically targeting these altered metabolic mechanisms may enable us to inhibit growth of cancer cells more specifically than normal cells. In studying leukemia cells, we have identified a metabolic enzyme called MTHFD2, which is more highly expressed in leukemia and other cancer cells compared to normal cells. It functions within the mitochondria, the powerhouse of the cell, and has a critical role in making the building blocks needed for rapid cell growth. When we decrease levels of MTHFD2 in acute myeloid leukemia (AML) cells, they decrease their rate of growth, become more like normal white blood cells and eventually die. In this proposal, we will define the role of this enzyme in AML and study the metabolic and growth inhibitory effects of its suppression in AML cells in vitro and in animal models of AML. We will also determine genetic determinants of response to suppression of MTHFD2 in AML. Results from this proposal will pave the way for the development of drugs inhibiting MTHFD2 and for a new therapeutic approach for patients with AML.