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Researchers take an early step toward developing a new class of therapeutics for patients with a deadly blood cancer

Highlights

  • Leukemic progenitors are a critical cellular target of DRD2 antagonist TDZ
  • DRD2 protein expression is a reliable biomarker of TDZ response
  • DRD2 antagonism selectively triggers leukemic maturation programs via cyclic AMP
  • An enantiomer of TDZ displays a superior efficacy:risk ratio relative to racemic TDZ

A McMaster stem cell research team has made an important early step in developing a new class of therapeutics for patients with a deadly blood cancer.

The team has discovered that for acute myeloid leukemia (AML) patients, there is a dopamine receptor pathway that becomes abnormally activated in the cancer stem cells. This inspired the clinical investigation of a dopamine receptor-inhibiting drug thioridazine as a new therapy for patients, and their focus on adult AML has revealed encouraging results.

AML is a particularly deadly cancer that starts with a DNA mutation in the blood stem cells of the bone marrow that produce too many infection-fighting white blood cells. According to the Canadian Cancer Society about 21 per cent of people diagnosed with AML will survive at least five years.


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“We have successfully understood the mechanism by which the drug benefited patients, and we are using this information to develop a new, more tolerable formulation of the drug that is likely to work in some of the patients,” said senior author of the paper Mick Bhatia, a professor of biochemistry and biomedical sciences at McMaster. He also holds the Canada Research Chair in Human Stem Cell Biology.

The phase one study of 13 patients is being featured on the cover of the journal Cell Reports Medicine.

Bhatia said the team has continued to carefully analyze and further refine their therapeutic approach and results of the initial trial.

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“Together, these achievements highlight the importance of the new paradigm of that issues impacting patients can be taken to the lab bench and solutions back to patients. These “bed to bench, and back to bed” approaches and partnerships to advance novel therapeutics Canadians suffering from cancer,” he added.


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The study was supported, in part, by the Canadian Cancer Society.

Source

McMaster University

Journal Reference

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

Summary
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.


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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.

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