Synthetic Lethal Targeted Therapy of TET2 Mutant Neoplasia with Eltrombopag
TET DNA dioxygenases hydroxylate 5-methylcytosine to 5-hydroxy-mC, leading to passive demethylation in hematopoietic stem cells (HSCs). TET2 mutations (TET2MT) are frequently found myelodysplastic syndrome (MDS), and clonal hematopoiesis of indeterminate potential (CHIP). We have shown that mutational exclusivity of TET2MT and IDH1/2MT results from production of a neomorphic natural TET2 inhibitor a-hydroxyglutarate (2HG) synthetically lethal to TET2-deficient TET2MT HSCs reliant on minimal residual dioxygenase activity supplied by TET1/TET3. This observation led to rational design and generation of TET-inhibitors, which turned out to be synthetically lethal to TET2MT cells. A high-throughput drug screen showed that eltrombopag (Epag), a thrombomimetic drug already in clinical practice, was a potent TET2-inhibitor. We have shown that this agent inhibits TET2MT cells in murine models independent of its thrombopoietic activity, and have determined its binding and mode of action on TET dioxygenases. Since Epag is an FDA approved drug, repurposing this agent as a TET inhibitor would shorten the development time needed for a new TET inhibitor and rapidly provide a well-tolerated drug for MDS patients with TET2MT. We have obtained granular molecular and response data from a historical trial of Epag trial in unselected MDS patients which indicated that indeed in some TET2MT MDS responded to Epag therapy, resulting in decreased TET2MT burden. We propose to further substantiate in human preclinical models the therapeutic potential of Epag using PDX models to provide rationale for design and conduct a biomarker-guided phase-II clinical trial of Epag in transfusion-dependent, erythropoietic agents-refractory IPSS low-risk TET2MT MDS.
We want to see the therapeutic potential that a drug called Epag has on cancer to help improve outcomes in patients. We will use mathmatical and scientific models to predict this rationale.