The overall aim of Core D is to provide correlative biomarker analyses of primary specimens in the MPN-RC tissue bank as well as from samples arising from all MPN-RC clinical trials and prospective tissue banking efforts. Core D will carry out assessment of somatic genomic alterations on all MPN-RC samples derived from tissue banking efforts, and from therapeutic trials at baseline and the time of response assessment. The core will also carry out dynamic analyses of other mechanism-based biomarkers (such as serum cytokines, gene expression profiling, cytogenetics, and histopathology) which pertain to each of the biologic and clinical studies in Projects 1-4. The use of genomic profiling will provide Projects 1-3 with the ability to select genetically annotated samples for biologic studies aimed at investigating the relationship between somatic mutations, biological features of disease pathogenesis, and therapeutic dependencies. The goal of these assays is to provide comprehensive genetic and biologic correlative studies as well as to help determine the mechanistic impact of the hypothesis-driven therapeutic interventions of clinical trials in Project 4. The core will also perform and analyze assays for Project 1-3, which are common to these projects. The proposed analyses will result in integrated genomic, gene expression, and cytokine data of a large number of clinically annotated and homogenously treated patients. As well, the clinical trials proposed in Project 4 are mechanistically based, and stem from work in Projects 1-3. The correlative biomarker assays are directly related to the proposed mechanisms of action of the therapeutic agents delineated and which will be investigated in Project 4. These studies will allow for an assessment of the mechanistic impact of specific therapeutic interventions and allow us to credential novel therapeutic targets and pathways. As well, these studies will allow biological assessment of treatment responders and non-responders, thus giving insight into mechanisms of resistance. Importantly, we have developed rigorous organizational tools in order to maintain data integrity, traceability and reproducibility standards when dealing with the amount and the variety of data involved in the large-scale biomarker analyses for this core. The integration of state-of-the-art and novel biomarker assays offered by Core D, with robust preclinical and clinical studies will afford a unique opportunity to gain new genomic, epigenomic and biologic insights into MPN pathogenesis.

Public Health Relevance

Myeloproliferative Neoplasms, which include myelofibrosis, are clonal hematopoietic stem cell disorders with limited therapeutic options currently. There is thus a need to develop innovate therapeutic approaches. Such efforts require the use of rational, targeted therapies in order to maximize therapeutic efficacy. The MPN-RC seeks to develop novel therapeutic strategies and understand the disease biology of myelofibrosis. Core D will carry out dynamic analyses of mechanism-based biomarkers, including genomic studies, which pertain to each of the biologic and clinical studies proposed by the MPN-RC. These studies will allow for an assessment of the mechanistic impact of specific therapeutic interventions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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Icahn School of Medicine at Mount Sinai
New York
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