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. 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.
"One of the hallmarks of cancer is genomic instability, in which entire sections of chromosomes can be lost or duplicated many times over," says Dana-Farber's Rameen Beroukhim, MD, PhD, who co-led the study. "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 these genes 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.
One way that cancers lose these essential genes is by the loss of nearby tumor suppressor genes, which act as a brake against runaway cell growth. Whereas normal cells harbor two copies of each gene, cancers often lose at least one copy of important tumor suppressor genes, unleashing cell proliferation.
"When tumor suppressor genes are lost, it's common for several nearby genes -- which play no role in cancer development -- to be lost as well," explains the study's co-senior author William Hahn, MD, PhD, of Dana-Farber. Nearly 20 years ago, a scientist published a theory that blocking the remaining copies of these neighboring genes would cripple cancer cells' ability to grow and divide.
The author of that paper, in 1993, was Emil "Tom" Frei III, MD, who was Dana-Farber's director and physician-in-chief from 1972-1991. At the time, the tools didn't exist to determine whether the theory was valid. Only now, with the development of cutting-edge genomic technology, were researchers able to put it to the test.
Investigators began by scanning more than 3,100 samples of different types of cancers, 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 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 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 remarks.
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 explains.
The fact that CYCLOPS genes are often neighbors of tumor suppressor genes makes them even more attractive as drug targets, the study authors say. 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 states. "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."
The study was funded in part by the 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 Deepak Nijhawan, MD, PhD, and Travis Zack, of Dana-Farber and the Broad Institute. Co-authors are Matthew Strickland, Rebecca Lamothe, and Shyemaa Shehata of Dana-Farber; Steven Schumacher and Joseph Rosenbluh, PhD, of Dana-Farber and the Broad; Aviad Tsherniak, Glenn Cowley, PhD, Barbara Weir, PhD, Jill Mesirov, PhD, and David Root, PhD, of the Broad; Yin Ren PhD of the Harvard-MIT Division of Health Sciences and Technology; Henrike Besche, PhD, and Alfred Goldberg, PhD, of Harvard Medical School; and Sangeeta Bhatia, MD, PhD, of the Broad and the Harvard-MIT Division of Health Sciences and Technology.About Dana-Farber Cancer Institute
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org.
Further reports about: > Beroukhim > Broad Institute > Cyclops > Dana-Farber > Gates Foundation > Health Sciences > PSMC2 > Universität Harvard > cancer cells > cell proliferation > genes > health services > information technology > methanol fuel cells > normal cells > suppressor gene > tumor suppressor > tumor suppressor gene
Studying a catalyst for blood cancers
25.04.2017 | University of Miami Miller School of Medicine
Atomic-level motion may drive bacteria's ability to evade immune system defenses
24.04.2017 | Indiana University
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
24.04.2017 | Physics and Astronomy
24.04.2017 | Materials Sciences
24.04.2017 | Life Sciences