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Gene Trio May Confer Radiation Resistance To Cancer Cells; Can a Molecular Dx Follow?

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A team of researchers from industry and academia said they have identified a group of proteins whose expression level will help determine which cancer patients are best suited to radiotherapy or chemotherapy, eliminating intensive, harmful radiation treatment for patients whose tumors are resistant to the treatment.

The group's research is published in this week's issue of the Journal of Biochemistry.

"This paper tries to find why these three proteins' crosstalk is important for long-term radiation-derived resistance," Jian-Jian Li, director of the division of molecular radiobiology at Purdue University School of Health Sciences, told Pharmacogenomics Reporter this week. "So the immediate meaning for clinical patients treated by radiotherapy [is that their tumors] might somehow develop this kind of resistance."

Li's team included researchers from Bio-Rad, the City of Hope National Medical Center, and the US National Institutes of Health. Their work may also prove to be useful in preparing tumors for treatment. "These [proteins] interact with each other to form a signal network to defend themselves from stress," said Li. "If we can block one of those signaling networks, we should be able to sensitize the tumor to chemotherapy or radiation therapy — that might increase the survival rate for cancer patients; that's the goal," he said.

His team's research involved "long-term … dosage. We give the tumor cells the same dose as a patient receives" on radiation-resistant breast cancer cell lines, he added. The group found that each of the three proteins — ERK, NF-kappa B, and GADD45 beta — become activated in a common pattern, he said. The proteins' over-expression, in turn, seemed to allow them to survive radiotherapy, he added.

Not only do the three genes his group has been studying protect tumor cells, they also seem to contribute to malignancy, Li said.

"If any cancer cells are really over-expressing those proteins, before any treatment — just diagnosis, we can define those patients as not really fit for radiotherapy," said Li. A treating oncologist might consider a different approach, such as chemotherapy or gene therapy, Li said. "Also, if the patient's tumor has very low expression of those proteins, they might be very fit for radiotherapy."

Results showing low expression of the three proteins may also allow lower doses of radiotherapy for effectiveness, Li said. In addition to breast cancer cells, his team found a similar result with skin and prostate cancer, he said. Other cell lines are currently being tested at Lawrence Livermore National Laboratory, he said.

Li and his colleagues have not discussed their results with diagnostics- or drug-development companies, he said. "So far, by my knowledge — through my colleagues and my work and my mentors — no hospitals have used this technology to design [a] therapy yet," he said. "So this might have some potential, especially [using] a protein array or a gene array for individual tumor [samples]. Hopefully this will open a new area for diagnosis."

The work to produce a useful assay would take about two or three years to complete, once sample-collection times are taken into account, Li said. "This cannot be done by a single hospital; it requires a collaboration," he said.

— CW

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