Blocking newfound protein in tumor cells boosts their radiosensitivity, without collateral damage

May 12, 2010
Lois Wingerson

A little-known enzyme found almost exclusively in tumor cells appears to help them resist radiation damage (until a way can be found to thwart their effects)

Current chemoradiation is a one-two punch, pairing the different toxic effects of drugs and radiation, and hoping for the best. There has been strategy, of course. Anti-cancer drugs may be used to decrease the tumor load before radiotherapy, or the risk of metastasis afterwards. They may render tissues or cells more receptive to radiation damage. Radiation oncologists have done their best to find the most effective combination, but it hasn't been clear how to avoid damaging normal tissues at the same time. That is, perhaps, until now.

Chemoradiation began in the mid-1980s at the NCI, combining a doxorubicin-based regimen with radiotherapy for lymphomas. The treatment succeeded, but sometimes the patients died from the treatment, or at least became very ill. Since then, various combinations have topped different flavors of chemotherapy with radiation. To judge from a review published last month in The Oncologist, the results are rarely gratifying for either patient or doctor.

The standard against which other chemoradiation regimens are compared are those involving cisplatin, which are more effective than either the drug or radiation alone against cervical, esophageal, head and neck, and non-small cell lung cancers. But responses are seldom complete, and around a third of patients experience severe diarrhea. A particular combination may be more effective than monotherapy against a certain tumor type, with acceptable toxicity, but except for cisplatin no chemoradiation regimen has had noteworthy results against a range of tumors.

What can be done to improve the situation? The authors of the review suggest finding ways to assure that the radiation actually strikes its target and exploring the potential of highly conformal radiotherapy to exclude normal tissue. A team of radiation oncologists and biologists at the University of Oxford have tried a different tactic: Look specifically for something unique to cancer cells that would protect them from radiation damage, and knock it out.

The lead author of the review in The Oncologist, radiation oncologist Michelle Mierzwa of the University of Cincinnati's Barrett Cancer Center, calls their work a "promising" new advance toward the "holy grail" of radiation oncology: treating tumors without causing damage to normal tissue and subsequent side effects.









The sad fact is that we don't know many of the reasons why some tumor cells are not radiosensitive while others are, as Geoff Higgins and others from Gillies McKenna's group at the University's Gray Institute for Radiation Oncology and Biology point out in their recent report in Cancer Research. "It is not that [radioresistant] cells are particularly virulent," Higgins explains. It's just that radioresistance can render tumor cells invulnerable, and thus the disease incurable.

One important fact is known, however: When radiation therapy succeeds, unsuccessful repair of DNA damage caused by radiation plays a crucial role in that success. By a process of logical elimination, the Oxford researchers winnowed the 200 genes known to be involved in DNA repair, in search of those whose inhibition would sensitize tumors to radiation.

They used a method called RNA silencing to target and physically block the action of specific genes. The study involved normal cells, both irradiated and unirradiated, and cell cultures of tumors from the larynx, bladder, pancreas, and cervix. An initial screen of the 200 DNA-repair genes identified those whose "knockdown" with RNA silencing specifically rendered tumor cells, but not normal cells, sensitive to radiation. They focused on the 30 genes for which the difference in this effect was largest.  

Several of these, including BRCA1 and BRCA2, were already known to increase radiosensitivity, but some were previously unknown to be involved in radiation damage. One among them, the team found, prevents DNA repair exclusively in irradiated tumor cells, while having no such effect on normal cells. It's called DNA polymerase theta, or POLQ for short, a member of a class of enzymes that build DNA sequences or repair damage to them. Other than that, little is known about POLQ, except that it's relatively sloppy at its task.

The team confirmed the radiosensitizing effects of disabling POLQ on 3 separate tumor cell lines, including two not used in the original screen, by doing time-consuming and labor-intensive clonogenic cell assays that involve counting the number of tumor cells that survive a treatment. For all 3 cell lines, "knockdown" of POLQ increased radiosensitivity to a degree that correlated with the radiation dose-implying that the effect is specific to radiation damage, not to some other property of the enzyme, and that it may pertain for a variety of tumors.

Another intriguing fact about POLQ is that its presence is almost exclusive to tumor cells. The Oxford studies showed that normal fibroblasts don't manufacture POLQ. Previous research shows that among normal cells it exists primarily in fetal lymphoid tissues, and appears to be absent from the tissues in which radiation damage most often limits the intensity of radiation therapy: lung, heart, brain, and the gastrointestinal system. Thus any intervention that involves POLQ is unlikely to affect these tissues.

Higgins says that no drug or other chemical is yet known to inhibit the effects of POLQ. Very likely it's worth the effort to look for one.