# Project 4: MPN Clinical Consortium

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $719,703

## Abstract

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.

## Key facts

- **NIH application ID:** 10866409
- **Project number:** 5P01CA108671-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** John Mascarenhas
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $719,703
- **Award type:** 5
- **Project period:** 2006-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866409

## Citation

> US National Institutes of Health, RePORTER application 10866409, Project 4: MPN Clinical Consortium (5P01CA108671-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10866409. Licensed CC0.

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