CYCLOPS offers new vision for cancer therapies


It’s little wonder why scientists from the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard gave their latest discovery the ominous title, CYCLOPS. A monolithic villain who has taken on some of history’s most legendary champions, the Cyclops represents struggle at towering heights and impossible odds — and now, it also stands for Copy number alterations Yielding Cancer Liabilities Owing to Partial losS in the odyssey for a cancer cure.

In the Aug. 17 issue of the journal Cell, researchers detailed the new CYCLOPS class of genes, a group comprised of so-called passenger mutations that could double as targets for cancer therapies. Like other aims, CYCLOPS are essential to all cells, but unlike most targets, they do not turn normal cells cancerous.  Henceforth, these genes come to exist as lifelines for cancer cells and therein, if blocked by drug molecules, can end tumor-causing components without significantly harming normal cells in the process.

According to researchers, this discovery has been a long time coming.

“The existence of CYCLOPS genes was hypothesized 20 years ago but there were no ways to test whether such genes actually exist until now,” said the study's co-senior author William Hahn, MD, PhD, of Dana-Farber. “Combining cancer genome analysis with functional analysis of cancer genomes led us to find CYCLOPS genes. We were not surprised to find them but were excited about how strongly they scored."

Hahn referred to the 1993 work of Emil "Tom" Frei III, MD, Dana-Farber's director and physician-in-chief from 1972-1991, who hypothesized that blocking the remaining copies of neighboring genes (CYCLOPS) would cripple a cancer cell’s ability to grow and divide. Technology developed in the years since Frei proffered his theory has allowed for Hahn and his colleagues to make confirmation of existence as well associate passenger mutations with several forms of cancer, meaning many malignant menaces could be conquered in the near future.

“This provides proof of principle that one can target what are sometimes called passenger mutations in cancer. This is exciting because these targets are not only new but exist a large fraction of cancers,” Hahn said.

Researchers first looked at 3,100 samples of different cancers, discovering that most were lacking copies of genes across the genome. After analyzing project Achilles, a Dana-Farber research effort that has uncovered hundreds of genes critical to the reproduction of cancer cells, scientists combined the data from the samples and the project, finally arriving at 56 genetic instances where the loss of one copy of a gene rendered the remaining copy especially important to the cancer cell. These 56 genes were designated CYCLOPS, and almost all of them were neighboring missing tumor suppressor genes. 

"We found that they're heavily involved in the components of three critical cell structures: the spliceosome, the ribosome -- which use genetic information to construct proteins for the cell -- and the proteasome, which is a vital protein machine that disposes of unneeded protein material. This suggests that they're required for cell proliferation or survival," Hahn remarked in a press release.

A ranking of the 56 genes in regards to the degree to which cancer depended on them, little-known PSMC2 was promoted to the top of the list. A resulting test on mice, during which researchers administered PSMC2-blocking agents, only further confirmed their theory — the tumor cells shrank dramatically.

"It was a powerful demonstration of the potential of CYCLOPS genes to serve as targets for cancer therapies," Dana-Farber's Rameen Beroukhim, MD, PhD, who co-led the study, said in a press release.

When questioned about the future look of cancer therapies and how the CYCLOPS discovery would factor in, Hahn predicted a collaborative effort ensuing.

“My prediction is that therapies that target CYCLOPS genes will be used with other types of treatments [chemotherapy and other targeted therapy] to design effective combination treatments,” he told PhysBizTech.

He cited unification as a proponent of success in the research methods as well.

"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, we've been able to identify a distinct class of cancer-cell vulnerabilities associated with the copy number loss of essential genes."

Hahn mentioned these three take-home points physicians should remember about CYCLOPS:

  • Genomics is maturing and allowing us to define targets in specific tumors/patients.
  • CYCLOPS genes open the door to new classes of targets.
  • These drugs may be very specific with little side effects.

 

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