Genetic Screening May Be Tool For Selecting Cancer Treatment, Research Suggests

June 30, 1998

Tumors caused by a specific mutation in the cancer gene BRCA2 appear to be especially vulnerable to radiation and certain chemotherapy drugs, researchers at the Vanderbilt Cancer Center have found.

The finding suggests genetic screening might become an effective tool not only for assessing risk of developing cancer but also for tailoring treatment, the scientists report in the July 1 issue of the Journal of the National Cancer Institute.

"This is an exciting strategy because it takes what we know about a genetic defect that causes cancer and uses that knowledge to beat the cancer at its own game," said Dr. Jeffrey T. Holt, professor of Cell Biology and Pathology at Vanderbilt University School of Medicine.

Inherited abnormalities in the BRCA2 gene are responsible for a number of familial cancers, including breast, prostate and ovarian cancer. Mutations in the gene have also been found in about 10 percent of pancreatic cancers.

One of BRCA2's jobs is to help repair breaks in the double strand of DNA inside cells, earlier animal studies demonstrated. Several cancer treatments, including some chemotherapy agents and radiation, work by initiating double-strand breaks in DNA.

Other researchers had suggested that the effect of BRCA2 on double-strand break repair might be exploited for treatment, so Holt and his colleagues -- Derek W. Abbott, Ph.D., and Michael L. Freeman, Ph.D., associate professor of Radiation Oncology -- set out to test that hypothesis.

"Our bodies undergo DNA damage all the time, but most cells can repair breaks in DNA," Holt said. "Usually, when a cell is unable to repair breaks in the DNA, it's a bad thing because it can lead to cancer. In this case, maybe we can use this problem as a strategy for treatment."

The researchers started with a known cancer-causing abnormality in BRCA2 that is common among Ashkenazi Jews. They then found a pancreatic cancer cell line that contained this mutation, and they compared these cells with pancreatic cancer cells that had normal BRCA2 genes.

Using DNA repair tests, the scientists established that cells containing the BRCA2 mutation were strikingly deficient in their ability to repair double-strand DNA breaks.

In-vitro tests then showed that the BRCA2-defective cancer cells were three-to-10-times more sensitive than pancreatic cancer cells with normal BRCA2 genes to three drugs that cause double-strand breaks: mitoxantrone, amsacrine, and etoposide. The two cell lines were equally sensitive to other drugs, paclitaxel and hydroxyurea, which do not cause double-strand DNA breaks, the researchers found.

An increased sensitivity to radiation was also found in animal studies. The researchers induced tumors by injecting pancreatic cancer cells into the thigh muscles of nude mice (specially engineered mice whose bodies do not reject human cells). When the tumors reached a certain size, they were irradiated. The size of the BRCA2-defective tumors decreased 93 percent, while the control tumors did not shrink.

Other tumor-bearing mice were treated with mitoxantrone or etoposide. The tumors grown from BRCA2-defective cells were extremely sensitive to mitoxantrone, with a 96 percent overall reduction in tumor size. Etoposide produced a 45 percent shrinkage in the BRCA2-defective tumors. However, neither drug reduced the size of tumors grown from BRCA2-normal cells.

Holt cautioned against drawing broad conclusions from the studies because the results in mice may not be replicated in patients. Because these studies involved a specific mutation in inherited pancreatic cancer, similar results may not be seen in other cancers caused by other mutations in BRCA2. The work was funded by the National Cancer Institute and the Frances Williams Preston Laboratory of the T.J. Martell Foundation at the Vanderbilt Cancer Center.

Vanderbilt University Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to