Project 4: MPN Clinical Consortium

PROJECT 4 ABSTRACT PIs: John Mascarenhas, MD; Ruben Mesa, MD; Marina Kremyanskaya, MD Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with an aggressive clinical course and a high risk for early death. Current therapeutic approaches for patients with Philadelphia chromosome negative MPNs aim to normalize blood counts, reduce splenomegaly and eliminate symptoms, but are incapable of halting disease progression/evolution. MF originates at the level of the hematopoietic stem cell (HSC) and the dysfunctional MF bone marrow and splenic microenvironments promote the predominance of the malignant HSC. Based on these observations, we hypothesize that therapeutic approaches which selectively target and deplete the MF HSC pool and restore the dysregulated MF microenvironment will be required to improve the treatment outcomes of MF patients. Concepts developed by members of the MPN-RC (Projects 1-3) have led to novel therapeutic approaches capable of depleting MF disease-initiating HSC. These strategies will be tested and validated in investigator-initiated clinical trials with accompanying correlative biomarkers to document therapeutic responses. These correlates are designed to assess the degree of MF HSC depletion as well as mechanisms underlying treatment responses and resistance. The trials will be pursued using the established infrastructure of the MPN Clinical Consortium, an effective independent clinical trials group focused on improving the outcomes of MF patients. To achieve these goals, the following specific aims will be pursued: (1) Assess whether mechanism- based strategies such as combination of an HDM2 antagonist and a BET inhibitor, are tolerable and clinically active in early phase MF clinical trials (MPN-RC 124). (2) Evaluate the safety and clinical activity of a novel type II JAK2 inhibitor in MF patients in an early phase clinical trial (MPN-RC 126). (3) Utilize biomarker studies from patients enrolled in MPN-RC clinical trials to determine target pathway engagement and association with clinical responses or lack of responses and mechanisms of therapeutic resistance in order to better inform future therapeutic development. (4) Annually obtain peripheral blood and/or bone marrow cells from MF patients (MPN- RC 106) which will be stored in Core B in order to provide mutational characterized specimens that will be utilized for the investigations planned in Projects 1-3.