Targeted Therapies for Myeloproliferative Neoplasms
Abstract
This research application addresses the Fiscal Year (FY18) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of "Blood Cancers" and the FY18 PRCRP Military Relevance Focus Area of "Cancer Treatment." Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are blood cancers predominantly seen in adults. There are more than 250,000 MPN patients in the USA. MF is the deadliest among MPNs. The median survival for patients with MF is about 5 years. A single mutation/alteration (V617F) in the JAK2 gene has been found in a majority of patients with MPN (PV, ET, and MF). Currently, there is no curative treatment for MPN. Ruxolitinib, a JAK2 inhibitor, has been approved for the treatment of MPN/MF. Although Ruxolitinib can reduce the spleen size and other associated symptoms, it failed to produce disease remission in patients with MPN/MF. Thus, there is a need to identify new therapeutic targets/therapies for MPN. In preliminary studies, we have identified PIM1 and SHP2 proteins as potential therapeutic targets in MPN. We have found that PIM1 expression is significantly increased and SHP2 is constitutively activated in mouse and human MPN cells. We have observed that depletion of PIM1 or SHP2 inhibits the growth of MPN cells and blocks the development of MPN/MF in mice. Treatment with a novel PIM kinase inhibitor TP-3654 or SHP2 inhibitor SHP099 significantly inhibits the growth of MPN cells. More importantly, treatment of TP-3654 or SHP099 significantly inhibits the MPN/MF diseases in JAK2V617F knock-in mouse models. So we hypothesize that inhibition of PIM1 or SHP2 in combination with the JAK2 inhibition may represent a better strategy in treating MPN/MF. The objectives of this proposal are to determine the efficacy of a novel second generation PIM kinase inhibitor TP-3654 and an allosteric SHP2 inhibitor SHP099 alone or in combination with JAK2 inhibitor Ruxolitinib in MPN cells and animal models of MPN/MF. We will also determine the mechanism of inhibition of MPN cells by these drug combinations. At the completion of this project, it is our expectation that we will have the first demonstration that inhibition of PIM1 by TP-3654 or SHP2 by SHP099 in combination with the JAK2 inhibitor Ruxolitinib is a useful strategy in treating MPN/MF. Results from these studies will lay the groundwork for clinical trials of TP-3564/ Ruxolitinib or SHP099/Ruxolitinib therapy for treatment of MPN/MF. As such, the potential impact of this study is very high. Military personnel are at increased risk of developing blood cancers, since herbicides, chemical weapons, ionizing radiation, infectious agents, and environmental carcinogens have been linked to various forms of blood cancers. MPN diseases can be seen in military Service members and Veterans. The herbicide Agent Orange has been linked to polycythemia vera and myelofibrosis in Vietnam Veterans. Successful completion of this project may lead to new therapeutic approach for treatment of MPN and improve the health of US military personnel, Veterans, their beneficiaries and the general population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910280
Entities
People
- Golam Mohi
Organizations
- United States Army
- University of Virginia