Friday Science Review: June 1, 2012
June 1, 2012
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The cancer stem cell (CSC) hypothesis – the concept that a small population of stem cell-like transformed cells is important for cancer initiation, progression and relapse – has gained quite a bit of attention in both academia and industry. It is proposed that these populations of cells have the unfortunate combination of being able to reinitiate tumour growth following treatment, as well as being more resistant to treatment, which explains the development of therapy resistance, minimal residual disease and tumour recurrence.
An attractive therapeutic rationale is therefore to develop drugs that either selectively target the cancer stem cells. However, any such treatment would need to have a therapeutic window between killing the cancer stem cells and killing an individual’s healthy stem cells, a population of cells that play important roles in tissue maintenance and repair. One approach is to discourage the proliferative self-renewal role that CSC’s favour and encourage their differentiation, thereby reducing their tumour growth potential. However, despite exactly this mechanism being used by Vesanoid, a treatment for acute promyelocytic leukemias developed over 20 years ago, no similar treatments for other cancers exist. However, the research by the Bhatia lab and collaborators at McMaster University is aimed at reinvigorating this approach.
They developed a discovery platform that can be used to screen molecules for their ability to induce the differentiation of a model of human CSC’s (a variant human pluripotent stem cell line) and but not normal pluripotent human stem cells. Applying their platform in a proof-of-concept screen, initially with well established, annotated compounds from the NIH Clinical and Canadian Compound collections they identified several candidates that induced morphological changes in the CSC model cells, but had no effect on normal stem cells. Unexpectedly a compelling hit arose from the antipsychotic drug thioridazine, with the apparent activity arising from the molecules action as a dopamine receptor antagonist.
With a paper that presents both a powerful screening tool, a potential repurposing of an approved molecule and a new potential target for the selective treatment of CSC’s, there is certainly no shortage of avenues to pursue and hopefully it will not be another 20 years before the we see the addition of another cancer therapy using the differentiation approach.
- Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development. PLoS One. British Columbia Cancer Research Centre
- Inhibition of Serine Palmitoyl Transferase I Reduces Cardiac Ceramide Levels and Increases Glycolysis Rates following Diet-Induced Insulin Resistance. PLoS One. University of Alberta
- Assessment and implication of prognostic imbalance in randomized controlled trials with a binary outcome – a simulation study. PLoS One. McMaster University