Author ORCID Identifier

https://orcid.org/0000-0002-4870-4635

Date of Graduation

5-2020

Document Type

Thesis (MS)

Program Affiliation

Cancer Biology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Marina Konopleva, MD, PHD

Committee Member

Koichi Takahashi, MD

Committee Member

Shiaw-Yih (Phoebus) Lin, PHD

Committee Member

Sean Post, PHD

Committee Member

Florian Muller, PHD

Abstract

LY3410738, a novel covalent Isocitrate Dehydrogenase 1 (IDH1) inhibitor in Acute Myeloid Leukemia, it is more effective than Ivosidenib (AG120) and has a potent anti-leukemic effect against IDH1 mutant acute myeloid leukemia in combination with Venetoclax (ABT-199).

Acute myeloid Leukemia (AML) is an aggressive neoplastic blood disorder characterized by proliferation of poorly differentiated cells of myeloid lineage. IDH1 is a cytoplasmic enzyme that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the citric acid cycle. Somatic gain-of-function mutations in IDH1 occur in ~10% of the newly diagnosed AML patients. The neo-enzymatic activity of mutant IDH1 results in accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), leading to a hyper-methylation phenotype, a block in cell differentiation, and tumor growth. Inhibitors of IDH1 mutant enzyme reduce 2-HG levels and release the differentiation block allowing AML cells to achieve terminal maturation. Recently, Ivosidenib (AG120), an IDH1 inhibitor, has been FDA approved for relapsed and newly diagnosed older AML patients. However, a subset of the mutant IDH1 AML patients treated with Ivosidenib are primary refractory or relapse while on therapy. This raises the need for development of more potent inhibitors targeting IDH1. Using a structure-based drug design approach, Lilly research laboratories developed a highly potent covalent inhibitor of mutant IDH, LY3410738.

Here we studied the pre-clinical efficacy of LY3410738 in AML cell lines engineered to express wild-type IDH1 or mutant IDH1R132H and in primary patient-derived AML cells harboring IDH1 mutation. LY3410738 caused rapid and more profound decrease in 2-HG levels than AG-120 in AML cells in vitro, translating into reversal of the differentiation block associated with IDH1 mutant activity. In vivo, we observed rapid and sustained 2-HG inhibition leading to a more robust and durable efficacy of LY3410738 compared to AG-120 in AML xenograft model derived from patient refractory to Ivosidenib. Since IDH1 mutant AML cells have been shown to strongly depend on the anti-apoptotic Bcl-2 for the survival, we further combined LY3410738 with FDA approved Bcl-2 inhibitor Venetoclax (ABT-199). In vitro, combining Venetoclax with LY3410738 demonstrated more profound reduction in cell viability and induction of apoptosis compared with single agent, in Doxycycline-inducible MOLM14/R132 cell line. Notably, the combination of LY3410738 with Venetoclax was efficacious in AML PDX xenograft models. Collectively, LY3410738 represents the first potent covalent IDH1 inhibitor that profoundly suppresses mutant IDH activity in AML cells harboring IDH1 mutation, induces differentiation and exhibits enhanced efficacy in combination with Venetoclax.

Keywords

Acute Myeloid Leukemia, IDH1, Targeted therapy, Combination therapy

Available for download on Thursday, April 08, 2021

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