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Novel Targeted Therapy for AML

Kapil Bhalla

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National Institutes of Health (NIH)
There is a clear unmet need to develop novel, targeted and safer therapies for acute myeloid leukemia (AML). Approximately 30% of AML carry a heterozygous mutation in the nucleophosmin 1 (NPM1), which results in the cytoplasmic dislocation of the mutant NPM1 (mtNPM1). Wild-type NPM1 (wtNPM1) is a nucleolar phosphoprotein, which functions as a molecular chaperone for proteins and nucleic acids (4). The N-terminal conserved oligomerization domain of NPM1 is critical for its multiple functions. In AML, presence of the cytoplasmic, dislocated mtNPM1 attenuates the levels of the nucleolar wtNPM1. As a founder mutation in AML, mtNPM1 is a haploinsufficient tumor suppressor of myeloid malignancies and appears to also confer a gain of function for the AML phenotype. Although its presence is associated with a relatively better prognosis in AML, mtNPM1 is often co-expressed with mutant FLT-3-ITD (internal tandem duplication), which represents an aggressive and relatively treatment-refractory sub-type of AML. Recently, we reported that knockdown of the levels and/or function of NPM1 induces growth arrest, differentiation and apoptosis of AML cells with mtNPM1, as well as sensitizes the AML cells to differentiation induced by all-trans retinoic acid (ATRA). Therefore, there is a strong rationale and need for fully evaluating the anti-AML efficacy and its mechanism following the targeted knockdown of the level and/or function of NPM1 along with a differentiation inducing agent or a FLT3-TKI. Based on this, the objectives of this proposal are to fill the gap in our knowledge about the mechanism by which knockdown of NPM1 induces differentiation and apoptosis and increases sensitivity of AML cells with mtNPM1 to differentiation-inducing therapy and FLT3-TKI. Proposed in vitro and in vivo studies in mouse models will create the supportive pre-clinical data for further clinical development of the novel combinations of NPM1 antagonist-based therapy of AML. These studies will test the unifying hypothesis that knockdown of NPM1 levels/function overcomes differentiation arrest and sensitizes AML cells that express mtNPM1 to differentiation-inducing agents, as well as sensitizes AML cells that co-express FLT3-ITD and mtNPM1 to FLT3-TKI. The specific aims of the proposal are: AIM 1: To determine the in vitro and in vivo effects of the knockdown of NPM1 (mtNPM1 versus wtNPM1 plus mtNPM1) levels or function on cell growth, differentiation and survival of cultured and patient-derived primary AML cells expressing mtNPM1. AIM 2: To determine the sensitizing effect of knockdown of NPM1 levels or function on the in vitro and in vivo activity of differentiation- inducing agents, e.g., all-trans retinoic acid (ATRA) or a histone deacetylase (HDAC) inhibitor, against cultured and primary AML cells. AIM 3: To determine the in vitro and in vivo anti-AML activity of combined targeting of NPM1 and FLT3-ITD in cultured and primary AML cells that co-express mtNPM1 and FLT3-ITD. Overall, these aims will establish NPM1 as a 'druggable' target and pave the way for performing high throughput screening and development of novel compounds that target NPM1 for the therapy of AML expressing mtNPM1.

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