In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1132-1132
Abstract:
DS-M1 is a novel, potent, orally bioavailable small molecule inhibitor of the binding of MLL1 fusion proteins and wild-type MLL1 to Menin in development for the treatment of patients with MLL1-rearranged (MLL1-r) or NPM1-mutated (NPM1-mu) acute leukemia. The interaction of MLL1 fusion proteins with menin plays an important role to enhance the proliferation and block the differentiation of hematopoietic cells, ultimately leading to acute leukemia. Furthermore, patients with MLL1-r acute leukemia respond poorly to currently available treatments, emphasizing the urgent need to develop more effective therapies directly disrupting the menin-MLL1 complex. Here we describe the characterization of DS-M1 and this study demonstrates the mechanism of action of DS-M1 as well as supports the oral dosing regimen planned for the initial clinical studies. DS-M1 selectively inhibited the cellular growth of MLL1-r or NPM1-mu human leukemic cell lines and primary cells from patients with GI50 of less than about 100 nM along with the cellular differentiation in vitro. RNA-seq and ChIP-seq analysis revealed that DS-M1 reduced the expression levels of MEIS1, PBX3 and HOXA9 genes in a concentration-dependent manner and dissociated the menin-MLL1 complex from the MEIS1 gene locus in MV-4-11, MOLM-13, and patient derived AML cells with MLL1-rearrangement. Interestingly, DS-M1 reduced the number of CD34+/CD38- leukemic stem cells (LSCs) in patient derived AML cells and induction of differentiation was also confirmed as measured by increased CD11b or CD14 expression. These results suggest that enhanced differentiation and loss of LSCs via the reduction of MEIS1, HOXA9, and PBX3 gene expression by DS-M1 is one of the main mechanisms of action for the antitumor activity of DS-M1. DS-M1 demonstrates significant survival benefit along with inhibition of MEIS1, HOXA9 and PBX3 expression in aggressive disseminated leukemia models intravenously inoculated with MV-4-11 and MOLM-13 cells as well as in patient-derived xenograft (PDX) models of MLL1-r or NPM1-mu acute leukemia. In disseminated MOLM-13 xenografts, treatment with 100 mg/kg qd of DS-M1 for 19 days produced durable response with event free survival & gt;100 days after last dose (5 out of 6 mice, increase in life span (ILS) & gt;515%). Furthermore, MLL1-r pediatric B-ALL-PDX mice treated with 50 mg/kg bid for 28 days and NPM1-mu AML-PDX mice treated with 100 mg/kg bid for 35 days were all survived (ILS & gt;254% and & gt;300%) without any detectable leukemic blast cells in bone marrow at 120 and 60 days after cessation of therapy, respectively. These data indicate that DS-M1 has a high potency as an antitumor drug with the potential to provide survival advantage in acute leukemia patients with MLL-r and NPM1-mu. Currently, a Phase 1/2 clinical study of DS-M1 is planned in AML and ALL patients with MLL-r or NPM1-mu. Citation Format: Masashi Numata, Machiko Shiroishi, Kenji Yoshikawa, Noriyasu Haginoya, Tsuyoshi Hirata, Yoshimi Takata, Reina Nagase, Kohei Takashima, Akiko Kurimoto, Fumie Tanzawa, Yumiko Tomoe, Tomoaki Hamada, Ryutaro Kanada, Jun Watanabe, Yoshiko Kagoshima, Eri Tokumaru, Kenji Murata, Takayuki Baba, Taeko Shinozaki, Kazuyuki Hashimoto, Motohiro Kato, Shinji Tsutsumi, Mayumi Kitagawa, Kosaku Fujiwara, Yuki Abe. Development and characterization of a novel orally bioavailable menin-MLL inhibitor for treatment of acute leukemia patients with MLL-rearrangement or NPM1 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1132.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2021-1132
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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