AZACITIDINE (AZA) ENHANCES ANTILEUKEMIC ACTIVITY OF THE MDM2 INHIBITOR MILADEMETAN IN TP53 WILD-TYPE ACUTE MYELOID LEUKEMIA (AML)
Author(s): ,
Shingo Noguchi
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
,
Takahiko Seki
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
,
Nobuaki Adachi
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
,
Hiroyuki Sumi
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
,
Rika Nakano
Affiliations:
Daiichi Sankyo RD Novare Co., Ltd.,Tokyo,Japan
,
Koichiro Inaki
Affiliations:
Daiichi Sankyo RD Novare Co., Ltd.,Tokyo,Japan
,
Chisa Wada
Affiliations:
Daiichi Sankyo RD Novare Co., Ltd.,Tokyo,Japan
,
Kenichi Wakita
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
,
Kenji Nakamaru
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
Masato Murakami
Affiliations:
Daiichi Sankyo Co, Ltd,Tokyo,Japan
EHA Library. Noguchi S. Jun 14, 2019; 266015; PF225
Shingo Noguchi
Shingo Noguchi
Contributions
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Abstract

Abstract: PF225

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background
Milademetan (DS-3032b) is a small-molecule MDM2 inhibitor that activates p53 and induces apoptosis by disrupting the MDM2-p53 interaction. Milademetan has demonstrated single-agent antileukemic activity in preclinical and clinical studies in AML. AZA, a hypomethylating agent, is used to treat AML and myelodysplastic syndromes by upregulating epigenetically silenced genes in AML cells. We conducted a preclinical study of milademetan in combination with AZA because both agents modulate gene expression related to cell growth or apoptosis.

Aims
To investigate the efficacy of milademetan in combination with AZA in TP53 wild-type AML and to identify the underlying molecular mechanisms of action.

Methods
The effects of milademetan and AZA as single agents and in combination were assessed in vitro and in vivo. The human TP53 wild-type AML cell lines MOLM-13, ML-2, and OCI-AML5 were investigated. Cell growth was evaluated in ATP assays, and apoptosis induction was assessed in annexin V assays. In vivo activity was evaluated in mice that were subcutaneously xenografted with MOLM-13 cells then treated with oral milademetan for 7 days and intravenous AZA for 5 days.

Results
The growth inhibitory effects of milademetan and AZA in various treatment schedules as single agents and in combination were investigated in AML cell lines and in vivo using the MOLM-13 xenograft model. In the xenograft study, a sequential combination of AZA followed by milademetan caused greater tumor growth inhibition than single-agent and other combination schedules of milademetan and AZA. This sequential combination increased annexin V–positive cells and upregulated p53 and p21 protein expression in cell lines. Interestingly, AZA treatment induced a protein that may be a faster-migrating form of MDM2. Characterization of this protein and further analyses, including RNA sequencing and genome-wide DNA methylation profiling, to provide additional mechanistic insights are ongoing.

Conclusion
Preclinical results demonstrated that a sequential combination treatment with AZA followed by milademetan enhanced antileukemic activity in cell lines and a mouse xenograft model. A phase 1 clinical trial of this combination has been initiated based on these results.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Acute myeloid leukemia, AML, P53

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