Investigators Seeking Misregulated Mechanism In Human Cancers With The Help Of Fruit Flies

Nov 22, 2012 Full story: MediLexicon

Changes in how DNA interacts with histones - the proteins that package DNA - regulate many fundamental cell activities from stem cells maturing into a specific body cell type or blood cells becoming leukemic.

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Since: Dec 05

Reading, PA

#1 Nov 24, 2012
In an issue of PNAS (Proceedings of the National Academy of Sciences) features a lead article by investigators at NYU, Cornell and Rational Therapeutics, on the identification of three compounds that inhibit the important cell signaling pathway known as WNT (catenation of Wg and Int).

The WNT signaling pathway was originally described in fruit flies as a determinate of wing shape. It was subsequently shown to be an important factor in human stem cell differentiation. Thereafter, its role in cancer was described.

A green glow from a fruit fly is giving researchers the green light when they are on the right path in their quest to develop compounds that help prevent cancer.

The glow, the result of some tinkering in Drosophila, the workhorse of the genetics world, lets researchers know when powerful cancer-prevention signals similar to those spurred by protective chemicals in broccoli, cabbage (where sulforaphane is found), and other foods, have been turned on in the organism.

Certain colon cancers associated with a familial syndrome have a mutation in the WNT pathway. This results in an extremely high incidence of colon cancer. It is known that lung cancers, breast cancers, leukemias and lymphomas may share this pathway.

To date, there have been no clinical therapies available to treat WNT-driven tumors. Recognizing the importance of this pathway, the investigators at NYU and Cornell used a technology known as small interfering RNA (SIRNA) to shut down the WNT signal. They then screened 14,000 known chemicals for activity that mimicked the SIRNA effect. Three compounds were identified.

When the compounds showed activity in cell-lines that were WNT addicted, the investigators at NYU provided the compounds to Rational Therapeutics where they applied the EVA-PCD (functional profiling) technique to measure activity in human tumor samples.

The results confirmed activity and showed that several colon cancers, as well as other tumor types, had favorable profiles. The compounds were not uniformly effective, indicating that they were not simply toxins. Instead, they appeared to selectively injure cells that we assume are driven by WNT-related events.

The beauty of this study represents the introduction of a new paradigm of drug development. Following the elegant and highly sophisticated high throughput method employed by investigators at NYU and Cornell, these compounds were put to the very practical test of human relevance.

The identification of activity in human tissues at concentrations similar to those associated with other classes of drugs, suggest that these novel compounds may have promise with these heretofore-untreatable cancers. This highly productive collaboration could prove a new model for the development of effective new therapies. PNAS April 12, 2011 vol. 108 no. 15 5929-5930.

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