Targeting the Dopamine Receptor Pathway To Treat AML

Technology Networks recently interviewed Prof. Mick Bhatia, from McMaster University, to learn more about his research focused on the role of abnormal dopamine receptor pathway activation in adult patients with acute myeloid leukemia (AML).

Following the discovery of abnormal dopamine receptor pathway activation in these patients, Bhatia and colleagues conducted a Phase 1 clinical investigation of the dopamine receptor-inhibiting drug, thioridazine, for use as an anti-leukemic agent in 13 adults with AML. The study was published in Cell Reports Medicine.

Kate Robinson (KR): How did you discover the role of the dopamine receptor pathway in AML patients?

Mick Bhatia (MB): This was pure serendipity to some extent, as we were not looking for this at all. We tested a variety of off-patent US Food and Drug Administration (FDA) approved drugs for their ability to kill a special set of human cancer cells we had developed. Drugs related to neural disorders also showed the ability to kill human cancer cells. The group of molecules seemed odd, and unrelated, but we looked closer and realized they had something in common – they were all able to bind a dopamine receptor (DR). This led us to investigate further, in AML and breast cancer, and it turned out that a subset of patients in fact expressed these receptors. 

KR: How does thioridazine affect this abnormal activation of the dopamine pathway?

MB: From what we understand now, thioridazine effects are no different in terms of its mechanism via the DR, it is simply that cancer cells express the DR as a way to survive (patients with AML actually have a high level of serum dopamine compared to healthy individuals), whereas normal remaining healthy blood cells don’t express the DR, thus thioridazine has no effect on those cells.

KR: Are there any other drugs aside from thioridazine that could also target this pathway?

MB: Yes, but thioridazine was the best studied in patients with neural disorders, so in the approach of repurposing, we used thioridazine.

KR: Phase 1 of the study involved 13 participants, what will Phase 2 entail?

MB: We envision Phase 2 to be conducted using a new molecule, a version of an enantiomer that we just tested in our recent study. This version of thioridazine has less toxicity and is more efficacious in preclinical studies. Our goal is to use this version as a starting point for new leads. This might take us back to Phase 1 of course, but we need to get this right, as we see it expand beyond AML given the number of other cancers shown to have DR expression as part of the transformation process from a healthy cell state. 

KR: Your study focuses on adult AML, are there plans to do any future testing to include childhood AML?

MB: Childhood AML is fortunate, and has good remission rates, with low relapse. We haven’t looked yet, but we could envision this as part of our next set of studies when we have better targeting of drugs to the DR.

Mick Bhatia was speaking with Kate Robinson, Editorial Assistant for Technology Networks.