New work by MIT cancer biologists shows that the interplay between two key genes that are often defective in tumors determines how cancer cells respond to chemotherapy.
The findings should have an immediate impact on cancer treatment, say Michael Hemann and Michael Yaffe, the two MIT biology professors who led the study. The work could help doctors predict what types of chemotherapy will be effective in a particular tumor, which would help tailor treatments to each patient.
"This isn't something that's going to take five years to do," says Yaffe, who, along with Hemann is a member of the David H. Koch Institute for Integrative Cancer Research at MIT. "You could begin doing this tomorrow."
The work could also guide the development of new chemotherapy drugs targeted to tumors with specific genetic mutations.
Hemann, Yaffe, and their colleagues report their results in the Aug. 15 issue of the journal Genes and Development. Koch Institute postdoctoral associates Hai Jiang and H. Christian Reinhardt are lead authors of the study, which the researchers say is one of the first examples of how genetic profiling of tumors can translate to improvements in patient treatment.
"There's a huge amount of genetic information available, but it hasn't made its way into clinical practice yet," says Hemann.
The research team focused on two proteins often involved in cancer, p53 and ATM. One of the first tumor suppressor genes discovered, p53 serves a watchdog function over a cell's genome, activating repair systems when DNA is damaged and initiating cell death if the damage is irreparable.
ATM is also involved in controlling the cell's response to DNA damage and is known to help regulate p53.
Mutations in p53, ATM or both are often seen in tumor cells. (ATM mutations occur in about 15 percent of cancers, and p53 is mutated in about 30 percent.)
Scientists have long tried to pin down a relationship between mutations in these genes and the effectiveness of DNA-damaging chemotherapy agents, but published studies have produced conflicting reports.
"It's been unclear whether the loss of p53 made tumors easier to treat or harder to treat. You could find examples of either case in the clinical literature," says Yaffe, adding that the same holds true for ATM.
The new study, conducted with human cancer cells, shows that tumors in which both p53 and ATM are defective are highly susceptible to chemotherapy agents that damage DNA. The double mutation prevents tumor cells from being able to repair DNA, and the cells commit suicide.
However, in cells where p53 is mutated but ATM is not, that type of chemotherapy is less effective. Remarkably, tumors where ATM is mutated but p53 is not turn out to be highly resistant to those types of chemotherapy.
With this new information, doctors could choose chemotherapy treatments based on the status of the p53 and ATM genes in a patient's tumor. Traditional DNA-damaging chemotherapy would be a good option for patients with both p53 and ATM mutations, but not for those with normal p53 and mutated ATM.
For patients who have normal ATM and mutated p53, other options might be better: New drugs that inhibit ATM, now in clinical trials, could improve tumors' susceptibility to chemotherapy in those patients.
The study shows the importance of studying cancer genes as a network, rather than trying to predict outcomes based on the status of single genes such as p53, says Robert Abraham, director of the cancer drug discovery program at Wyeth Pharmaceuticals.
Once ATM inhibitors are approved, "understanding the combined status of ATM and p53 should allow physicians to identify patients who should be treated with ATM inhibitors and chemotherapy and those for whom such a therapy could potentially be harmful," Abraham says.
In patients with normal p53 and mutated ATM, doctors could use drugs that target alternative DNA repair pathways. In their Genes and Development paper, the MIT researchers showed that treating such tumors with a drug that targets DNA-PK, another protein involved in DNA repair, renders them vulnerable to chemotherapy.
The MIT researchers collaborated with scientists from the Centre for Genotoxic Stress Research in Denmark, Helsinki University Central Hospital in Finland, and Uppsala University Hospital in Sweden.
The research was funded by the National Institutes of Health, the David H. Koch Fund, the Deutsche Forschungsgemeinschaft, the Deutsche Nierenstiftung, the Danish Cancer Society, the European Community, the Czech Ministry of Education and the Helsinki University Central Hospital Research Fund.
Jen Hirsch | EurekAlert!
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences