Use of mitochondrial activity inhibitors for the treatment of poor prognosis acute myeloid leukemia

An acute myeloid and inhibitory technology, applied in the field of treatment of acute myeloid leukemia, can solve problems such as discontinuity and incomplete response

Active Publication Date: 2019-04-26
UNIV DE MONTREAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Targeting the FLT3 receptor tyrosine kinase with FLT3 tyrosine kinase inhibitors (TKIs) has shown encouraging results in the treatment of FLT3-mutated AML, often associated with poor clinical outcomes, but in most patients , the response is incomplete and does not last
Furthermore, the induction of acquired resistance to TKIs has become a clinical problem

Method used

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  • Use of mitochondrial activity inhibitors for the treatment of poor prognosis acute myeloid leukemia
  • Use of mitochondrial activity inhibitors for the treatment of poor prognosis acute myeloid leukemia
  • Use of mitochondrial activity inhibitors for the treatment of poor prognosis acute myeloid leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0223] Example 1: Materials and methods

[0224] Human Leukemia Samples

[0225] The study was approved by the Research Ethics Board (REB) of the University of Montreal, Maisonneuve-Rosemont Hospital and Charles Lemoyne Hospital (QC Longueuil, Canada). All AML samples were collected between 2001 and 2017 with informed consent according to the procedures of the Banque de Cellules Leucémiques du Québec (BCLQ). Cord blood (CB) units were collected from consenting mothers and Positive selection kit (StemCellTechnologies, Vancouver, Canada, catalog number 18056) to isolate human CD34 + CB cells (Fares et al. Science. 2014 Sep 19;345(6203):1509-12).

[0226] chemical screening

[0227] Primary cells: Frozen AML monocytes were thawed at 37°C in Iscove's Modified Dulbecco's Medium (IMDM) containing 20% ​​FBS and DNase I (100 μg / mL). Cells were then cultured in optimized AML growth medium as previously reported (Pabst, C. et al. Nature methods 11, 436-442, 2014): IMDM, 15% BI...

Embodiment 2

[0248] Example 2: HOX-high AML patients generally have poor disease prognosis.

[0249] AML cell samples belong to the HOX network ( Figure 1A Consistently high expression of genes in ) was shown to correlate with significantly reduced overall patient survival ( Figure 1B ). Figure 1C The correlation between HOXA9 and HOXA10 expression in leukemia cells is shown. Figure 1D It was shown that the survival of AML patients belonging to the HOXA9 / HOXA10 high group was similar to the patients belonging to the HOX-network high subgroup shown in FIG. 1 . Such as Figure 1B As shown, it is suggested that high expression of HOXA9 and HOXA10 can be used as a surrogate to detect HOX network high-patients. Taken together, these data show that patients with highly expressed AML cells exhibiting HOX-network genes have a poor prognosis and will benefit from appropriate AML treatment.

Embodiment 3

[0250] Example 3: Mulitinib effectively inhibits HOX-high AML cells.

[0251] Using high expression of HOXA9 and HOXA10 as a surrogate for detection of HOX-network-high patient samples, HOX- Survival of high and HOX-medium / low samples ( Figure 2A ,Table 4).

[0252] Table 4: Chemical Screening Results of HOX-High vs. HOX-Medium / Low Samples

[0253]

[0254]

[0255]

[0256]

[0257] HOX-high patient cells were significantly more sensitive to the RTK ERBB2 inhibitor mulitinib when compared to HOX-medium / low samples ( Figure 2B ). No statistically significant differences were observed for the other compounds tested.

[0258] A dose-response validation screen in a large number of AML samples confirmed that HOX-high patient cells were significantly more sensitive to mulitinib than HOX-intermediate / low AML cells ( Figure 2C -D). Median mulitinib EC in the tested AML population 50 About 375nM ( Figure 2E ). Patients belonging to the mulitinib sensitive grou...

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Abstract

A method for treating acute myeloid leukemia (AML), such as poor risk AML, by administering to a subject in need thereof an effective amount of a mitochondrial activity inhibitor, for example a classA electron transport chain (ETC) complex I inhibitor such as Mubritinib or a pharmaceutically acceptable salt thereof, is disclosed. The AML to be treated may be characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and / or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, normal karyotype (NK), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and / or abnormal chromosome (5 / 7), and / or a high leukemic stem cell (LSC) frequency.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of Canadian Patent Application Serial No. 2,937,896, filed August 2, 2016, which is hereby incorporated by reference in its entirety. technical field [0003] The present disclosure relates generally to the treatment of acute myeloid leukemia (AML), and more particularly to subtypes of AML that are often associated with poor prognosis. Background technique [0004] Acute myeloid leukemia (AML) is a particularly deadly form of cancer, with most patients dying within two years of diagnosis. It is one of the leading causes of death in young people. AML is a collection of tumors with heterogeneous pathophysiology, genetics and prognosis. Based primarily on cytogenetic and molecular analyses, AML patients are currently classified into groups or subgroups of AML with significantly contrasting prognoses. Approximately 45% of AML patients are currently classified into different groups wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/422A61P35/02C07D413/12G01N33/48
CPCA61K45/06A61P35/02G01N33/57426G01N2800/52A61K31/422A61K31/4192C12Q1/6886C12Q2600/156C12Q2600/118
Inventor G·萨瓦格I·巴切利
Owner UNIV DE MONTREAL
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