CYCLOPS genes an Achilles’ heel in tumors?

The genomic tumult within tumor cells has provided scientists at the Harvard-affiliated Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT with clues to an entirely new class of genes that may serve as an Achilles’ heel for many forms of cancer.

Although most cancer therapy targets genes that cause normal cells to turn cancerous, these new potential drug targets are genes that are essential to all cells, but that have been disrupted as cancer progresses.

“One of the hallmarks of cancer is genomic instability, in which entire sections of chromosomes can be lost or duplicated many times over,” said study co-leader Rameen Beroukhim, an assistant professor of medicine at Harvard Medical School (HMS) and researcher at Dana-Farber. “The result is that genes residing in those areas are either deleted or significantly over-copied.”

This roiling of the chromosomes often leads to partial loss of essential genes, leaving cancer cells with barely enough of them to survive. Such genes become lifelines for tumor cells. Blocking them with drug molecules is far more likely to harm cancer cells than normal cells.

As reported in the Aug. 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.

One way that cancer cells lose these essential genes is in the process of becoming cancerous themselves. When cancer cells lose tumor suppressor genes — which normally act as a brake against runaway cell growth — it’s common for nearby genes to be lost as well, said the study’s co-senior author William Hahn, associate professor of medicine at HMS and director of Dana-Farber’s Center for Cancer Genome Discovery.

The work builds on a theory published nearly 20 years ago by Dana-Farber’s then-physician-in-chief, Emil “Tom” Frei III, who suggested in 1993 that blocking the remaining copies of these neighboring genes would cripple cancer cells’ ability to grow and divide.

At the time, the tools didn’t exist to determine whether the theory was valid. Only now, with the development of genomic technology, were researchers able to put it to the test.

Investigators began by scanning more than 3,100 samples of different types of cancer and found that most were missing copies of genes across wide stretches of the genome. They then analyzed 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 5,312 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 who was dependent on his one eye rather than the normal complement of two.

When researchers checked to see if any of the CYCLOPS genes were neighbors of missing tumor suppressor genes, as Frei had hypothesized two decades earlier, they found that, indeed, many were. Investigators next surveyed the CYCLOPS genes to see if they have similar or divergent functions within the cell.

“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 said.

When the researchers 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 tumors lacked a copy of the PSMC2 gene, the tumors shrank dramatically.

“It was a powerful demonstration of the potential of CYCLOPS genes to serve as targets for cancer therapies,” Beroukhim said.

The fact that CYCLOPS genes are often neighbors of tumor suppressor genes makes them even more attractive as drug targets, the study authors said. Tumor suppressor genes themselves have proven exceedingly difficult to target. In cancers with missing copies of tumor suppressor genes, blocking nearby CYCLOPS genes offers a promising way to dampen cell proliferation.

“This study represents a bringing-together of two approaches to understanding the basic mechanics of cancer,” Hahn said. “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.”