CYCLOPS: An entirely new class of genes
In cancers with missing copies of tumour suppressor genes, blocking nearby CYCLOPS genes offers a promising way to decrease cell proliferation
- Date : 23 Aug 2012
- Topic : Personalised medicine
The genomic tumult within tumour cells has provided scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard with clues to an entirely new class of genes that may serve as an Achilles' heel for many forms of cancer. As reported in the August 17 issue of the journal Cell, the researchers identified 56 such genes, only a few of which had previously been identified as potential targets for cancer therapy. Unlike most such targets, these genes don't cause normal cells to turn cancerous. Instead, they are essential to all cells but have been disrupted as cancer progresses.
A new research based on an old observation
One of the hallmarks of cancer is genomic instability, in which entire sections of chromosomes can be lost or duplicated many times over. The result is that genes residing in those areas are either deleted or significantly over-copied, according to Dr Rameen Beroukhim of the Dana-Farber Cancer Institute, who co-led the study.
When tumour suppressor genes are lost, it's common for several nearby genes, which play no role in cancer development, to be lost as well, according to the study's co-senior author Dr William Hahn of Dana-Farber. Nearly 20 years ago, a scientist published a theory that blocking the remaining copies of these neighbouring genes would cripple cancer cells' ability to grow and divide. The author of that paper, in 1993, was Dr Emil Frei III. At that time, the tools didn't exist to determine whether the theory was valid. Only now, with the development of cutting-edge genomic technology, researchers were able to put it to the test.
Investigators began by scanning more than 3100 samples of different types of cancers, and found that most were missing copies of genes across wide stretches of the genome. They then analysed data from Project Achilles, a Dana-Farber research effort that has uncovered hundreds of genes critical to the reproduction of cancer cells.
Researchers combined both sets of data to find instances where the loss of one copy of a gene rendered the remaining copy especially important to the cancer cell. From an initial pool of 5312 genes, researchers identified 56 that met the desired criteria. They dubbed them CYCLOPS genes (for Copy number alterations Yielding Cancer Liabilities Owing to Partial losS), evoking the mythical giant that was dependent on its one eye rather than the normal complement of two.
When researchers checked to see if any of the CYCLOPS genes were neighbours of missing tumour suppressor genes, as Frei had hypothesized two decades earlier, they found that, indeed, many were.
CYCLOPS genes are involved in the components of spliceosome, ribosome, and proteasome
Investigators next surveyed the CYCLOPS genes to see if they have similar or divergent functions within the cell. They found that they are heavily involved in the components of three critical cell structures: the spliceosome, the ribosome, and the proteasome. This suggests that they are required for cell proliferation or survival.
When the investigators ranked the 56 CYCLOPS genes by the degree to which the cancer cells were dependent on them, the gene that topped the list was PSMC2. When they administered a PSMC2-blocking agent to mice whose tumours lacked a copy of the PSMC2 gene, the tumours shrank dramatically. It was a demonstration of the potential of CYCLOPS genes to serve as targets for cancer therapies.
The fact that CYCLOPS genes are often neighbours of tumour suppressor genes makes them even more attractive as drug targets. Tumour suppressor genes themselves have proven exceedingly difficult to target. In cancers with missing copies of tumour suppressor genes, blocking nearby CYCLOPS genes offers a promising way to decrease cell proliferation.
This study represents a bringing-together of two approaches to understanding the basic mechanics of cancer. One involves research into the effect of gene copy number changes on cancer. The other is a systematic exploration of the function of individual genes. By combining these approaches, the researchers have been able to identify a distinct class of cancer-cell vulnerabilities associated with the copy number loss of essential genes.
The study was funded in part by the USA National Institutes of Health and the National Cancer Institute (RC2 CA148268, U54 CA143798, K08 CA122833, T32 GM008313, RO1 GM051923-17, and U54 CA112962), the H.L. Snyder Medical Foundation, the V Foundation, a Conquer Cancer Foundation Young Investigator Award, and Sass Foundation Fellowship. The lead authors of the study are Dr Deepak Nijhawan and Travis Zack of Dana-Farber and the Broad Institute.
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