Corporate Banner
Satellite Banner
Biomolecular Screening
Scientific Community
Become a Member | Sign in
Home>News>This Article

Blinding a CYCLOPS

Published: Monday, August 20, 2012
Last Updated: Monday, August 20, 2012
Bookmark and Share
Targeted therapies are changing cancer treatment.

Designed to wield laser-like precision, they focus on overactive proteins produced by mutated genes, destroying cancer cells but sparing normal cells. Most of the cancer drugs created in the last decade follow that model, exploiting knowledge of genetic mutations to stop cancer’s progression rather than aiming a fusillade of chemotherapy agents against all fast-growing cells, normal or cancerous.

But many mutations do not make good targets. Tumor suppressor genes – which normally act like the brakes on runaway cell growth –– are the most commonly mutated genes in cancer, but they are notoriously difficult to target with current techniques. New targets are needed, driving cancer researchers to seek out new therapeutic approaches.

Looking back to a hypothesis first proposed soon after tumor suppressor genes were discovered, a team of scientists from the Broad Institute and Dana-Farber Cancer Institute present a new paradigm for attacking vulnerabilities in cancer cells by targeting genes that don’t necessarily contribute to cancer formation but are altered along the way to becoming cancer.

Nearly 20 years ago Dana-Farber researcher Emil Frei proposed that when tumor suppressor genes were mutated, they weren’t the only parts of the genome being damaged. When mutations disarmed tumor suppressors, they also cut a wider swath of genomic instability. Nearby genes might also be injured, although to a lesser extent. A tumor cell might lose one of its two copies of a nearby gene, for example. That lone copy might be sufficient for cell survival, but additional stress could be more than the cell could tolerate.

In 1993, there was no large-scale way to test this hypothesis. Now scientists led by Broad associate members Rameen Beroukhim and William C. Hahn have harnessed computational strength and biological expertise to answer the question. Writing in the August 15 online edition of Cell, they report proof of principle for a novel strategy that attacks cancer cells by targeting genes partially lost on the path to cancer.

“Cancers delete parts of their genomes when they get rid of tumor suppressor genes, but that process of deletion also makes them susceptible to stresses that otherwise normal cells could tolerate,” said co-senior author Hahn, who is also a medical oncologist at Dana-Farber and an associate professor of medicine at Harvard Medical School. “This discovery opens up a whole new universe of potential targets that seem to distinguish a large fraction of cancer cells from normal cells,” said Beroukhim, co-senior author, a medical oncologist at Dana-Farber, and an assistant professor of medicine at Harvard Medical School.

To systematically identify these genes, the researchers, including co-first authors Deepak Nijhawan and Travis I. Zack, integrated data sets from Project Achilles, which is a comprehensive catalog of genes essential for cancer cell survival, and the Cancer Cell Line Encyclopedia, which includes copy number data. Their analysis yielded 56 genes that had lost one of their two copies. They call them CYCLOPS genes, short for Copy-number alterations Yielding Cancer Liabilities Owing to Partial loSs. Like the mythical one-eyed giant, they depend on that one copy to survive.

The CYCLOPS genes were not randomly assorted throughout the genome. Instead, they largely fell into three complexes important for cell proliferation and survival: the proteosome, the spliceosome, and the ribosome. The scientists narrowed their focus to PSMC2, a gene in the proteasome that has lost one of its gene copies in 10 percent of all cancers. In all, four proteasome CYCLOPS genes were found in a combined 40 percent of cancers.

In normal cells, the proteasome works like a sophisticated garbage disposal to chew up and dispose of proteins that are misfolded or no longer needed. The protein encoded by PSMC2 helps form the cylindrical proteasome’s two caps on its top and bottom. When PSMC2 protein levels are suppressed in a normal cell, the cell calls on a reservoir of PSMC2 protein in the cell. The CYCLOPS version of PSMC2 is unable to supply enough to fill that reservoir in the cell, so when it runs dry, the proteasome stops working and the cell dies.

Using nanoparticle technology to deliver gene-silencing RNA interference, the scientists specifically targeted tumors in mice. When they knocked out PSMC2, tumors were reduced by more than 75 percent and overall survival doubled.

Beyond its cellular importance, the proteasome is also an appealing target because the cancer drug bortezomib, sold as Velcade, is a proteasome inhibitor with tolerable side effects. Its mechanism is not well understood, Hahn said.

“Our paper doesn’t tell us why bortezomib does or doesn’t work in certain cancers, but it does tell us there might be more sophisticated ways to attack the proteasome,” he said. “That might help us understand which patients might benefit.”

Showing that cancer cells are dependent on one CYCLOPS gene in the proteasome opens up new avenues for future work, starting with the proteasome, spliceosome (a splicer of messenger RNA), or ribosome (site of protein synthesis) and possibly beyond, Beroukhim said.

“This opens up a potentially large variety of vulnerabilities to attack in cancer cells,” he said. “There is still work to be done, but if this phenomenon can be taken advantage of therapeutically, it would have a potentially widespread application.”

Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 4,000+ scientific posters on ePosters
  • More than 5,300+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

DARPA Awards $32 Million Contract to MIT, Broad Institute Foundry
A facility at the Broad Institute of MIT and Harvard and MIT that aims to achieve the full potential of engineering biology has received a five-year, $32 million contract from the Defense Advanced Research Projects Agency (DARPA).
Monday, September 28, 2015
Diagnostics Breakthrough Brings Viral Sequencing to Doctors’ Toolkit
New screening tool produces up to 10,000-fold improvement in viral matches compared with traditional high-throughput methods.
Monday, September 28, 2015
Two Studies Identify A Detectable, Pre-Cancerous State In The Blood
Findings pave way for new lines of cancer research focused on detection and prevention.
Thursday, November 27, 2014
Targeting Cancer’s “Queen Bees” with Better Tissue Modeling
In many types of cancer, standard chemotherapy cures only a fraction of patients.
Wednesday, October 30, 2013
Understanding Triglycerides’ Role in Coronary Disease
The study leverages new genetic data from a related genome-wide association study, suggests that lowering triglyceride levels through treatment may help reduce the risk of coronary heart disease.
Wednesday, October 09, 2013
Better Living through Proteomics
As a patient facing illness, knowing what’s ailing you can bring peace of mind and, more importantly, can inform treatment decisions.
Monday, September 09, 2013
Target Set on Cancer Gene MCL1
Broad Institute and Dana-Farber colleagues identify several chemical compounds that tamp down the expression of the MCL1 gene.
Friday, June 15, 2012
Broad Institute, Dana-Farber and Novartis Collaborate to Develop Cancer Cell Line Encyclopedia
Scientists have written the 'Book of Cancer Knowledge' to aid future research into drug discovery and personalized medicine.
Friday, March 30, 2012
Scientific News
Stem Cells in Drug Discovery
Potential Source of Unlimited Human Test Cells, but Roadblocks Remain.
Automated Low Volume Dispensing Trends
Gain a better understanding of the current and future market requirements for fully automated LVD systems.
Protein-Based “Cancer Signature” Uncovered
Researchers investigated the expression of ribosomal proteins in human tissues and discovered a cancer type specific signature which could be used to predict the progression of the disease.
Ribosome Recycling as a Drug Target
Researchers explain mechanism that recycles bacterial ribosomes stalled on messenger RNAs that lack termination codons.
Predicting Leukaemia Development in Cancer Patients
Biomarker may predict which formerly treated cancer patients will develop highly fatal form of leukemia.
Survey of New York City Soil Uncovers Medicine-Making Microbes
Microbes have long been an invaluable source of new drugs. And to find more, we may have to look no further than the ground beneath our feet.
'Lab on the Skin' for Sweat Analysis
Northwestern University researchers develop a low-cost wearable electronic device that collects and analyzes sweat for health monitoring.
Toxoplasma’s Balancing Act Explained
Parasite’s method of rewiring our immune response leads to novel tool for drug tests.
Cancer Signaling Pathway Illuminating Way To Therapy
Researchers refine a pro-growth signalling pathway, common to cancers, that can kill cancer cells while leaving healthy cells unharmed.
Breast Cancer Cells Starve for Cystine
Depriving triple negative breast cancer, a treatment-resistant form of breast cancer, of cystine results in cancer cell death.

SELECTBIO Market Reports
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
4,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,300+ scientific videos