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Thomas A. Look, M.D.
Selective activity of nuclear export inhibitors in MDS cases with inactivating mutations of TET2

Thomas A. Look, M.D.

Dana-Farber Cancer Institute

2018 Funding recipient

Selective activity of nuclear export inhibitors in MDS cases with inactivating mutations of TET2

EvansMDS Discovery Research Grant 2018

PROJECT SUMMARY

TET2 is one of the most frequently mutated tumor suppressor genes in patients with myelodysplastic syndrome (MDS), with inactivating mutations found in the bone marrow cells of 20-30% of MDS patients at the time of diagnosis. Recent findings have demonstrated that mutations in TET2 can be the “first–event” in hematopoietic stem and progenitors cells (HSPCs) in individuals who eventually develop MDS. When HSPCs lose the function of TET2 they become more competitive and expand at the expense of the normal HSPCs, and then accumulate mutations in other genes, leading to the onset of MDS. The goal of our study is to find small molecule drugs that will kill the blood stem cells that have TET2 mutations, but not the healthy normal stem cells. This will prevent the clones that lack the TET2 protein from expanding further and acquiring additional defects in other genes.

Our laboratory recently identified two drugs called selinexor and eltanexor that are active in killing TET2-mutant blood stem cells, but not the healthy normal stem cells. We found these drugs by testing hundreds of drugs in young zebrafish that have tet2 mutations similar to those in human MDS. The aim of our project is to evaluate these drugs in mouse models with Tet2-mutant blood stem and progenitor cells, so that we can prove that the drugs also have selective activity in mammals and establish mechanisms of selectivity. We will study the mechanisms of activity of these drugs against TET2-mutant HSPCs, and the molecular pathways that form the basis for sparing normal HSPCs from toxicity by these drugs. Our project will generate sufficient preclinical laboratory evidence using mouse models of MDS to justify a clinical trial of one or both of these drugs in human patients with TET2-mutant MDS.

Nicole Prutsch, Ph.D., presents data from this study at AACR 2019 in Atlanta.