Tumors have a unique vulnerability that can be exploited to make them more sensitive to heat and radiation, researchers at Washington University School of Medicine in St. Louis report.

The Washington University radiation oncology researchers found that tumors have a built-in mechanism that protects them from heat (hyperthermia) damage and most likely decreases the benefit of hyperthermia and radiation as a combined therapy.

By interfering with that protection, the researchers have shown that tumor cells grown in culture can be made more sensitive to hyperthermia-enhanced radiation therapy.

Radiation therapy is a mainstay of cancer treatment but doesn’t always completely control tumors. For several years, raising tumor temperature has been investigated as a radiation therapy enhancer with few adverse side effects.

“Past research has shown that hyperthermia is one of the most potent ways to increase cell-killing by radiation,” says senior author Tej K. Pandita, Ph.D., associate professor of radiation oncology and of genetics and a researcher with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

“But now we’ve found that heat also enhances the activity of an enzyme called telomerase in cancer cells,” he says. “Telomerase helps protect the cells from stress-induced damage and allows some of them to survive. We used compounds that inhibit telomerase and showed that cancer cells then become easier to destroy with hyperthermia and radiation used in combination.”

Telomerase repairs the ends of chromosomes by maintaining stability of specialized cellular structures called telomeres after cells divide. Without telomerase the number of cell divisions is limited. Telomerase is not active in most normal human cells but is active in most cancer cells, which rely on telomerase to continue to proliferate.

In this study, Pandita’s research group found that moderately turning up the heat also turns up the activity of telomerase in tumor cells. The researchers found that if they inactivated telomerase and then increased the temperature of tumor cells, more cells were killed by ionizing radiation. Because nearly all cancers have telomerase, drugs that turn off its activity could be useful against many cancers.

The researchers tested three compounds, and one, GRN163L, more strongly inhibited telomerase than the others. Many groups are studying GRN163L as an anticancer therapeutic, and it recently received clearance by the U.S. Food and Drug Administration to enter human phase I/II clinical testing in chronic lymphocytic leukemia. In some preliminary studies, GRN163L has been shown to be additive when used in combination with existing cancer drugs or radiation.

Next, Pandita and colleagues will test the effect of GRN163L on tumors in mice to see if it will enhance the cell-killing effect of hyperthermia and radiation. They are also working to develop chemicals that have heat-like effects to bypass the need to supply a physical heat source to tissue.

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Not a day goes by without a new story about the environment. Although we often consider the environment on a global scale, cells in our body also have to contend with environmental factors. New studies from a team of researchers from the Research Institute of the MUHC and McGill University show that the environment surrounding breast cancer cells plays a crucial role in determining whether tumor cells grow and migrate or whether they fade away. Their study is the first to identify the genes behind this environmental control and correlate them with patient outcome. Their findings are published in this week’s issue of Nature Medicine.

“A tumour can not exist on its own. It has to be supported and nourished by the cell types around it, the microenvironment,” says senior author Dr Morag Park, Director of the molecular oncology group at the Research institute if the MUHC. “When we began this study there was little known about the importance of this microenvironment on cancer initiation and progression. We now know that this environment is pivotal; different patients have distinct tumour microenvironments at a gene level. Our findings show that the gene profile of these distinct microenvironments can be used to determine clinical outcome — who will fare well and who will not.”

Dr Park, a professor of oncology, biochemistry, and medicine at McGill University, and her team analyzed tissue from 53 breast cancer patients. They used a unique technique, laser capture microdissection (LCM), to separate tumour cells from microenvironment tissue. They compared the gene expression between the microenvironment tissue and controls using micro-array analysis. From thousands of genes they identified 163, which correlated with patient outcome. A good outcome was defined as having no tumour metastasis and tumour migration and non-responsiveness to therapy was considered poor outcome.

From the original 163 genes, the team further identified a panel of 26 specific genes that could be used to accurately predict clinical outcome. This 26 gene-profile, called the stromal derived prognostic predictor (SDPP), was used to predict outcome from a second set of beast cancer patients.

“We were able to show that the SDPP effectively predicts outcome in a second group of patients,” says Dr Park, “This panel accurately forecasted patient status, suggesting that this may be a promising diagnostic tool.

“Our next steps are to develop this 26-gene predictor into a functional test. We are currently working on this and we anticipate a product for clinical trials within a year,” adds Park.

“This work takes tremendous dedication and collaboration from a number of people including pathologists, surgeons, oncologists as well as researchers. I would like to thank the outstanding work done by G. Finak from the laboratory of Dr M. Hallett of McGill’s Computer Science Department, the breast surgeons of the MUHC, including Dr S. Meterissian, and by the Department of Pathology at McGill, where Dr A. Omeroglu works.”

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