Myeloproliferative Neoplasms-Research Consortium

Overall Abstract Myeloproliferative Neoplasm- Research Consortium P.I. Ronald Hoffman M.D. The Myeloproliferative Neoplasm Research Consortium (MPN-RC) is an interactive group of laboratory, translational and clinical scientists from 13 institutions who have worked for almost 14 years in a coordinated fashion to develop and evaluate therapeutic strategies aimed to improve the survival of patients with myelofibrosis (MF). The MPNs, including polycythemia vera, essential thrombocythemia and primary MF, are clonal hematological malignancies which originate at the level of the hematopoietic stem cell. We will continue to focus our efforts on MF since it is the MPN associated with the shortest survival and at present allogeneic stem cell transplantation is the only curative therapeutic modality. Unfortunately, over 90% of MF patients are not candidates for stem cell transplantation. The only currently approved therapy for MF is first generation JAK2 inhibitor therapies, which have not proven to be disease modifying. Approximately one half of patients discontinue JAK2 inhibitor therapy within 3 years and three-fourths by 5 years. The median survival after discontinuation of JAK2 inhibitor therapy is approximately 14 months. The limitations of first generation JAK2 inhibitor therapy can be attributed to its inability to selectively attenuate the fitness of MF clonal hematopoietic stem cells. The overall strategy of the MPN-RC is based on the hypothesis that although MF is uniformly associated with activation of the JAK/STAT signaling pathways, that increased clinical benefit for MF patients will require the implementation of novel therapeutic strategies, which utilize combinations of drugs that interrupt dysregulated interacting cellular pathways and deplete or eliminate MF stem cells by directly targeting vulnerabilities in MPN stem cells and/or their interplay with the MF microenvironment. Based on discovery science and preclinical therapeutic studies, rationally designed therapies will be evaluated in rigorous, independent, investigator-initiated clinical trials, which will address key scientific hypotheses and therapeutic questions, which ultimately will prolong the overall survival of MF patients. In order to implement this overall strategy the following Specific Aims will be pursued: Aim 1: To identify and credential therapeutic strategies which deplete or eliminate MF HSCs by directly targeting malignant MF HSCs and/or their interplay with their tumor microenvironment. Aim 2: To rationally design and rapidly execute preclinical studies and investigator- initiated scientifically based phase 1/2 clinical trials with embedded biomarker studies, which assess our ability to attenuate the fitness of MF HSCs through stem cell and tumor microenvironment-targeting therapies. Aim 3: Actively and dynamically maintain a collaborative translational research network that supports and synergizes the laboratory and clinical studies led by MPN-RC investigators.