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Andrea Butler
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VCU Massey Cancer Center researcher receives $1.25M grant to examine a novel drug’s ability to improve radiation therapy in mice for brain cancer

Research supporting potential of new drug to radiosensitize glioblastoma multiforme cancer cells published in Molecular Cancer Therapeutics

Richmond, Va. (Oct. 6, 2009) – A leading researcher at Virginia Commonwealth University Massey Cancer Center received a five-year, $1.25 million grant from the National Cancer Institute to study a novel drug’s ability to improve radiation treatment of glioblastoma multiforme in mice as a prelude to human testing.

The grant was awarded to Kristoffer Valerie, Ph.D., a professor in the VCU School of Medicine’s Department of Radiation Oncology and co-leader of Massey Cancer Center’s Radiation Biology and Oncology Program.

Glioblastoma multiforme is the most serious form of brain cancer, and few therapeutic options are available to patients. It’s incurable, and life expectancy is just one year.

The study’s approach

The study will focus on developing a highly specific inhibitor of the ATM kinase (ATMi) as a radiosensitizer for brain cancer. Radiosensitizers are drugs that enhance the action of radiation therapy. Radiation therapy is a critical component of treatment for this type of cancer.

The ATM gene, mutated in patients with the genetic disease ataxia telangiectasia (A-T), was identified more than 10 years ago. ATM is a protein kinase and master regulator of the DNA damage response, including cell cycle checkpoints, DNA repair and apoptosis (cell death).

Research has shown that cells from A-T patients are highly sensitive to radiation, so it follows that inhibitors of ATM would be expected to radiosensitize cancer cells. Indeed, specific ATM inhibitors have been developed recently by several drug companies.

Valerie’s group has gained access to a novel ATMi, KU-60019, from KuDOS Pharmaceutical Ltd./AstraZeneca, and is collaborating closely with their investigators. Together they have demonstrated that KU-60019 is very specific in its action and much improved over its predecessor. Their focus now is to determine whether this ATMi is an effective and safe radiosensitizer in mice as a prelude to human testing.

In addition to studies aimed at fighting the brain tumor, Valerie will also examine the effects of the ATMi and radiation on normal mouse brain stem and progenitor cells. These cells are very important to salvage since they are critical for rebuilding the brain after radiation. The overall goal is to maximize the impact of the ATMi and radiation on the tumor and minimize toxicity to normal brain in order to achieve the greatest possible therapeutic gains.

“The ideal radiosensitizer would be harmless when given to patients prior to radiation and highly efficient in augmenting tumor killing when combined with radiation,” said Valerie. “Indicators thus far are promising, and this next phase of study will be valuable in determining KU-60019’s prospects for human use.”

There are no similar drugs in use nor are there any from the same class currently being tested for the treatment of brain cancer.

Research that led to this new study

The study builds on previous work in Valerie’s lab over the past several years in collaboration with investigators from KuDOS/Astra-Zeneca to develop this second-generation ATMi. The study in today’s online edition of Molecular Cancer Therapeutics is the first to describe the superior properties of this novel compound.

In addition to its inhibitory effects on the DNA damage response and ability to radiosensitize glioma cells, Valerie’s group also discovered that the drug inhibited migration and invasion of glioma cells, potentially limiting tumor growth even without radiation. Inhibiting migration and invasion of glioma cells is critical to stemming the deadly spread of the tumor in the brain.

VCU investigators on the study include Tomasz Kordula, Ph.D., associate professor, Department of Biochemistry and Molecular Biology; Timothy Van Meter, Ph.D., assistant professor, Department of Neurosurgery; Habeeb Saleh, Ph.D., assistant professor, Department of Radiation Oncology; Nitai Mukhopathaya, Ph.D., assistant professor, Department of Biostatistics; as well as Grigori Enikolopov, Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.

About the VCU Massey Cancer Center:
The VCU Massey Cancer Center is one of 65 National Cancer Institute-designated institutions that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers more clinical trials than any other institution in Virginia, serving patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and, ultimately, to cure cancer. Visit Massey online at www.massey.vcu.edu or call 1-877-4-MASSEY.