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Old 10-10-2014, 02:37 PM
raja raja is offline
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Join Date: Jan 2007
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Default New study reveals potentially novel therapeutic targets for hepatocellular carcinomas

One of the options to treat late stage hepatocellular carcinomas (HCC)[1] is a drug called Sorafenib[2], developed and sold by Bayer and Onyx pharma. However, later in the course of treatment, several patients develop tumors that are resistant to the drug. In a study published[3] in the journal Nature Medicine[4], a research group from Tuebingen, Germany has used an shRNA[5] screen to look at mechanisms of how liver cancer cells develop resistance to sorafenib.

Approach used: In brief, they used a shRNA library to to “knock-down”[6] certain genes in cancer cells and test the effect of this reduction on whether sorafenib was able to kill the cancer cells better. They focused only on genes that were amplified[7] in human HCC since these are likely to be contributing to drug resistance.

Key findings: The gene Mapk14 (a.k.a p38alpha), was one of those genes amplified in HCC, which was found to play a role in resistance to sorafenib. It is a component of the MAP Kinase signaling pathway[8] used by all cells to control rate of cell division. When tested in mice, it was found that inhibiting Mapk14 in the cancer drastically improved the performance of sorafenib. Mapk14 can be inhibited either using a gene silencing shRNA or using pharmacological inhibitors specific to Mapk14. They tested a number of different human liver cancer cells lines and validated their findings. Additionally, the protein Atf2 (a transcription factor) which influences the expression of other genes was also found to play a role. Silencing this gene also had a beneficial effect in the action of sorafenib.

What does this mean? This means that adding additional drugs to the chemotherapy regimen can extend the effectiveness of sorafenib. In specific, the authors think inhibitors of Mapk14 in combination with sorafenib could be much more effective in late stage HCC. This also fits with the observation that 50% of all HCCs have an overactive MAP kinase pathway.

References:
1. Hepatocellular carcinoma. Wikipedia, the free encyclopedia (2014). at <http://en.wikipedia.org/w/index.php?title=Hepatocellular_carcinoma&oldid=621 949621>
2. Sorafenib. Wikipedia, the free encyclopedia (2014). at <http://en.wikipedia.org/w/index.php?title=Sorafenib&oldid=623890460>
3. Rudalska, R. et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20, 1138–1146 (2014).
4. Journal home : Nature Medicine. at <http://www.nature.com/nm/index.html>
5. Small hairpin RNA. Wikipedia, the free encyclopedia (2014). at <http://en.wikipedia.org/w/index.php?title=Small_hairpin_RNA&oldid=609796389>
6. Gene knockdown. Wikipedia, the free encyclopedia (2014). at <http://en.wikipedia.org/w/index.php?title=Gene_knockdown&oldid=624781781>
7. CancerQuest | Gene Amplification. CancerQuest | A Cancer Education Resource at <http://www.cancerquest.org/gene-amplification.html>
8. MAPK/ERK pathway. Wikipedia, the free encyclopedia (2014). at <http://en.wikipedia.org/w/index.php?title=MAPK/ERK_pathway&oldid=627249374>

Last edited by raja : 10-10-2014 at 02:57 PM. Reason: Formatting update
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