Targeting Cancer Stem Cells

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Cancer stem cells are slowly dividing tumourigenic cells that possess characteristics of normal stem cells. It has been proposed that these cells persist in treated tumours and are responsible for tumour re-growth and metastasis. As a consequence, more effective chemotherapy may be achieved by targeting these cells in addition to the rapidly proliferating tumour cells. So far, the difficulty has been the lack of understanding of cancer stem cells and how they might be selectively targeted over normal stem cells.
cancer stem cells
In research carried out at The Jackson Laboratory in mice, Alox5 (5-Lipoxygenase) has been shown to be essential for development and maintenance of cancer stem cells in bcr-abl dependent chronic myeloid leukemia (CML). CML did not develop in mice without the Alox5 gene as a result of impaired function of the leukemia stem cells. Importantly, the lack of Alox5 did not affect normal stem cells, indicating distinct pathways in normal and leukemic stem cells for differentiation and self-renewal.

zileuton structureAlox5 is known to be essential for processing fatty acids to leukotrienes, key components of the inflammatory response, and inhibitors of Alox5 have been developed for the treatment of asthma. Using the approved (for asthma) Alox5 inhibitor, Zileuton, the scientists at The Jackson Laboratory were able to demonstrate a greater therapeutic effect in the CML model than the gold standard, Gleevec. Combining the two therapeutics provided an even better response.

The full study is published in the journal Nature Genetics.

Alox5 has also been shown to be over-expressed in certain cancers, for example in colon cancer. The availability of a clinically approved Alox5 inhibitor should enable a rapid progression to clinical studies in cancer.

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