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Targeted therapy for AML expressing mutant RUNX1

Courtney DiNardo

Courtney DiNardo


The University of Texas MD Anderson Cancer Center

Project Term: October 1, 2021 - September 30, 2024

Clinical outcome of high-risk Myelodysplastic Syndrome (MDS) and AML with mutant (mt) RUNX1 is relatively poor. Supported by our preclinical data, we propose a Phase Ib clinical trial of omacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies in patients with relapsed MDS or AML exhibiting mtRUNX1. Studies proposed will also determine pre-clinical activity of novel, OM-based combinations against mtRUNX1-expressing, patient-derived, pre-treatment AML cells.

Lay Abstract

Following treatment with current regimens, approximately 15-25% of adult patients with high-risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML) remain disease free over long periods. Mutations in RUNX1, a DNA-binding master regulator of gene expression, lead to a loss of function of RUNX1. Presence of mutant (mt) RUNX1 confers relative resistance to treatment and poorer survival in patients with MDS or AML. Germ-line mutations in RUNX1 cause Familial Platelet Disorder with propensity to evolve into MDS/AML. Lack of specific targeted therapy, coupled with resistance to standard therapy may account for the poorer outcome in MDS/AML expressing mtRUNX1. Therefore, there is an unmet need to develop novel therapies for MDS/AML expressing mtRUNX1. Our preliminary studies have shown that, knockdown of RUNX1 expression induces more death in AML blasts expressing mtRUNX1, compared to those expression normal, wild-type (wt) RUNX1. Utilizing the gene-expression signature of RUNX1 knockdown, we discovered that treatment with homoharringtonine (HHT), induced a similar gene expression signature as RUNX1 knockdown. Presence of mtRUNX1 is known to impair the formation of protein synthesis units, the ribosomes. Since treatment with HHT or its semisynthetic version omacetaxine mepesuccinate (OM), also inhibits protein synthesis in the ribosomes, OM treatment preferentially induced more cell death and anti-AML efficacy in mice harboring human AML expressing mtRUNX1. This was associated with repression of RUNX1 and its targets, as well as reduced levels of short-lived proteins including c-Myc and MCL-1 in AML cells. Notably, co-treatment with OM and venetoclax (Ven) was synergistically lethal and more effective in mice harboring human AML expressing mtRUNX1. Based on these findings, we hypothesize that combined therapy with OM and Ven will yield high remission rates and improved survival in patients with MDS or AML expression mtRUNX1. This will also be associated with specific gene-expression alterations in patients with high-risk MDS/AML expressing mtRUNX1. Specific aims of our studies proposed are: AIM 1: To conduct a Phase Ib/II clinical trial of combination of OM and Ven in patients with high risk MDS or AML expressing mtRUNX1. AIM 2: To assess whether genetic alterations, gene expression pattern, as well as whether impairment of ribosome synthesis determine efficacy/resistance to the combination treatment with OM and Ven, in patients enrolled on the Phase Ib/II trial. AIM 3: To assess efficacy of additional combinations of OM with BET protein or CDK9 inhibitor, as well as with novel drugs working against targets determined by CRISPR screening in AML cells.

Translational Research Program
Grant Subprogram
TRP Basic
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