Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients

Lili Aslostovar; Allison L Boyd; Yannick D Benoit; Justin Di Lu; Juan Luis Garcia Rodriguez; Mio Nakanishi; Deanna P Porras; Jennifer C Reid; Ryan R Mitchell; Brian Leber; Anargyros Xenocostas; Ronan Foley; Mickie Bhatia

doi:10.1016/j.xcrm.2021.100202

Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients

Cell Rep Med. 2021 Feb 16;2(2):100202. doi: 10.1016/j.xcrm.2021.100202.

Authors

Affiliations

¹ Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada.
² Department of Cellular and Molecular Medicine, Ottawa University, Ottawa, ON, Canada.
³ Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
⁴ Department of Medicine, McMaster University, Juravinski Hospital, Hamilton, ON, Canada.
⁵ Division of Hematology, Department of Medicine, University of Western Ontario, London Health Sciences Centre, London, ON, Canada.
⁶ Department of Pathology and Molecular Medicine, McMaster University, Juravinski Hospital, Hamilton, ON, Canada.

Abstract

The aberrant expression of dopamine receptors (DRDs) in acute myeloid leukemia (AML) cells has encouraged the repurposing of DRD antagonists such as thioridazine (TDZ) as anti-leukemic agents. Here, we access patient cells from a Phase I dose escalation trial to resolve the cellular and molecular bases of response to TDZ, and we extend these findings to an additional independent cohort of AML patient samples tested preclinically. We reveal that in DRD2⁺ AML patients, DRD signaling in leukemic progenitors provides leukemia-exclusive networks of sensitivity that spare healthy hematopoiesis. AML progenitor cell suppression can be increased by the isolation of the positive enantiomer from the racemic TDZ mixture (TDZ⁺), and this is accompanied by reduced cardiac liability. Our study indicates that the development of DRD-directed therapies provides a targeting strategy for a subset of AML patients and potentially other cancers that acquire DRD expression upon transformation from healthy tissue.

Keywords: Phase I trial; QTc interval; acute myeloid leukemia; cyclic AMP; dopamine receptor; leukemic progenitor; targeted therapy; thioridazine; xenograft.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Hematopoiesis / physiology*
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Neoplastic Stem Cells / metabolism*
Receptors, Dopamine / metabolism*
Signal Transduction / physiology
Thioridazine / metabolism*

Substances

Receptors, Dopamine
Thioridazine