15 December 2011

The fight against oncogenes: a way around

A new strategy to fight the cancer gene
Nanonewsnet based on materials from Harvard College:
New Target Found for Aggressive Cancer GeneAmerican scientists have found a way to destroy cancer cells captured by a genetic "accelerator" – the oncogene Myc.

Myc-induced malignant tumors, for example, breast or prostate cancer, are particularly aggressive. This discovery not only reveals new molecular targets for drugs, but also points to a new possible strategy for influencing oncogenes.

In its non-malignant, healthy form, the Myc transcription factor "oversees" how genetic information is translated into proteins, usually those involved in the growth of new cells. But mutations can make Myc hyperactive, that is, oncogenic, and when this happens, the cells move to uncontrolled division, forming tumors.

Myc DNA and Protein Complex (AbsturZ)

Cells with oncogenic mutations in Myc are so dependent on this gene that they die if it "turns off". Scientists have long been trying to use this dependence to develop drugs. However, in its protein form, Myc is an extremely difficult target, mainly because it lacks binding sites with which chemical compounds with medicinal properties could effectively interact.

Therefore, Professor of the Department of Genetics at Harvard Medical School (Harvard Medical School) Stephen Elledge and his colleague Associate Professor at Baylor College of Medicine Thomas Westbrook decided to take a different approach. Their goal was to suppress the activity of Myc by disabling not the oncogene itself, but the helper genes necessary for it.

To find such genes, Elge and Westbrook used tiny molecules of short-hairpin RNAs (shRNAs) that block the activity of specific genes. Each experimental cell contained only one gene suppressed by shRNAs. If, when the oncogenic properties of Myc were activated, the cell died, then this "silent" gene could be one of those that Myc needed for tumor formation.

With the help of almost 75,000 shRNAs, scientists eventually found 403 potential candidates for the role of Myc helper genes. Some of them were close to the field of Myc biology, others were not.

"These genes are not oncogenes in themselves, but they encode proteins on which the Myc property of causing cancer is based," explains Professor Elge. "We consider them as potential targets for drug therapy, because if you can't target Myc, you can target these other genes and suppress their effects."

One of the most outstanding of the total number of candidates was the SAE2 gene. A Myc-activated cell with suppressed SAE2 is unable to build a normal division spindle, an intracellular structure that plays an important role in mitosis. The researchers found that SAE2 suppression blocks Myc's ability to activate genes involved in spindle formation. This suggests that the cells die because they cannot divide properly.

Adding weight to the results of this work, two research groups confirmed that SAE2 suppression slows down the growth rate of human Myc-dependent breast cancer cells both in vitro and after transplantation to immunodeficient mice. Finally, Elge and Westbrook stratified gene expression data from nearly 1,300 breast cancer patients based on Myc activity. Patients with high Myc activity had a better chance of survival in terms of metastasis formation at low levels of SAE2 activity, whereas for patients with low Myc activity, SAE2 levels did not matter. Thus, these data are also in good agreement with the results of the work.

"This study shows that cancers caused by the Myc oncogene are dependent on unique sets of proteins that are not in demand in ordinary, non–cancerous tissues," says Professor Westbrook. "And many of these cancer vulnerabilities are enzymes, which gives us new directions, following which we can quickly achieve results in the treatment of these particularly aggressive tumors."

Taken together, the results show that the suppression of SAE2 and similar enzymes is a new therapeutic strategy for the treatment of patients with Myc–dependent cancer. According to Professor Elge, in the near future they are going to study the effects of suppression of these genes on animals.

"We would like to know more specifically which proteins Myc depends on, because if we can hit these targets with drugs, we will be able to turn off Myc and selectively destroy cancer cells," he concludes.

The results of the study are published in the journal Science:
A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis.

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