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Press release: New possible combination therapy against cancer published in PNAS

News: Jun 18, 2014

Researchers at Sahlgrenska Cancer Center have identified a new way to treat cancer driven by the well-known cancer gene MYC. The mechanism of action turned out to be different than expected.

Deoxyribonucleic Acid (DNA) is the genetic material which stores the hereditary information in our cells. If all the DNA molecules of a cell would have been stretched, their total length would be around 2-3 m, far to long to fit inside a small cell. Therefore the DNA is wrapped around histones, like beads on a string, and further twisted and wound up to form higher-order chromatin and chromosomes. To be able to read (or transcribe) the genes in a controlled manner, the histones are modified with small chemical groups. These work as a flag and signals if the gene is going to be transcribed or not. One family of proteins in the cell, called BET bromodomain proteins, can bind the histone flags and instruct the cell to transcribe the gene.

Since cancer cells divide in an uncontrolled manner and their genes are transcribed in an altered way, cancer researchers developed a molecule called JQ1, which could block BET proteins from binding to the histone flags. When cancer cells were treated with JQ1 they stopped dividing and many of them died. Interestingly, a very well known cancer-causing gene, MYC, was no longer transcribed when JQ1 was administered to the cancer cells. This constituted a break-through since targeting MYC with drugs had been a longstanding goal in cancer research.

The problem with JQ1 was that it did not have drug-like properties so the concept of BET inhibition as a cancer therapy could not be tested in patients. Jonas Nilsson’s research team at the Sahlgrenska Cancer Center, in collaboration with the Canadian company Zenith Epigenetics, tested RVX2135, a novel BET inhibitor with more drug-like properties, in mouse models of MYC-driven lymphoma. Reassuringly, RVX2135 killed lymphoma cells which resulted in prolonged survival of the mice.

"When we observed these powerful killing capabilities of the drug candidate we were convinced that the effect was mediated via suppression of the MYC gene, but we were wrong," says Jonas Nilsson.

"Neither RVX2135 nor JQ1 blocked the MYC gene from being transcribed in the mouse cancer cells. We therefore concluded that MYC suppression may not be a pre-requisite for killing the tumor cells by BET inhibitors," Nilsson continues.

By examining all genes regulated by BET inhibitors the researchers noticed that some genes were activated, instead of being turned off. Unexpectedly, about a quarter of those genes had previously been shown to be activated by a class of drugs that are already used in patients, HDAC inhibitors. The researchers then demonstrated that a combined treatment with HDAC and BET inhibitors resulted in a more potent effect than treatment with the single drugs.

"In the combination treatment we could reduce the dose of HDAC inhibitors and get a good effect but fewer side-effects. This is very promising for the future clinical trials using these types of drugs, " Nilsson explains.

Ongoing studies focus on developing BET inhibitors for use against malignant melanoma. To that end, Jonas Nilsson started Sahlgrenska Translational Melanoma Group (www.satmeg.se) together with surgeons and oncologists at the Sahlgrenska University Hospital.

"Melanoma cells are notorious for being resistant to most therapies. Our initial studies show that melanoma cells stop dividing when treated with BET inhibitors but they do not die. We will meet that challenge by employing various combination strategies, " Nilsson says.

The article "BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma" by Joydeep Bhadury, Lisa Nilsson, Somsundar Veppil Muralidharan, Lydia Green, Zhoulei Li, Emily Gesner, Henrik Hansen, Ulrich Keller, Kevin McLure and Jonas Nilsson will be published this week in the Early Edition section of the Proceedings of the National Academy of Sciences (www.pnas.org).




Page Manager: Ulrika Lantz Carlsson|Last update: 3/13/2014

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