Experimental drug combined with radiation kills brain tumors in pre-clinical studies

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A new study led by scientists at VCU Massey Cancer Center has shown that an experimental drug known as AZ32 selectively sensitizes brain tumors to radiation and significantly extends the survival of mouse models with human glioblastoma multiforme (GBM), the most common and deadly form of brain cancer. Published in the journal Molecular Cancer Therapeutics, the study builds on the research of principal investigator Kristoffer Valerie, Ph.D., and has paved the way for a phase 1 clinical trial testing a similar but more effective experimental drug, AZ1390, in combination with radiation therapy for the treatment of brain cancer. An accompanying study on AZ1390 that Valerie co-authored was recently published in Science Advances.

AZ32 is a member of a family of compounds referred to as ATM kinase inhibitors. ATM, or ataxia telangiectasia mutated, is an enzyme that facilitates repair of DNA damage in cells. Radiation therapy is first-line treatment for GBM; however, glioma stem cells are often able to resist DNA damage caused by radiation. By inhibiting ATM, AZ32 was shown to disrupt the process by which brain cancer cells resist radiation while sparing and potentially protecting healthy brain tissue.

"In 2009 and 2013, we were the first to show that an ATM kinase inhibitor could make brain cancer cells and tumors sensitive to radiation," says Valerie, a member of the Developmental Therapeutics research program at Massey, in reference to his prior research published in Molecular Cancer Therapeutics and Clinical Cancer Research. "This time with AZ32, we used an ATM kinase inhibitor that penetrates the blood-brain barrier. The combination of AZ32 and radiation was highly effective against GBM cells with mutant versions of the p53 tumor suppressor gene, which normally acts to promote radiation resistance."

As many as 80 percent of GBM patients have cancers with mutant or dysfunctional p53 signaling. The combination therapy forced GBM cells to undergo mitotic catastrophe, which occurs when external stressors cause a cell to inappropriately enter into mitosis, a phase of the cell cycle where cell division occurs, and ultimately led to cell death.

"Our study is the first to show that an ATM kinase inhibitor that can be taken orally and able to penetrate the blood- brain barrier radiosensitizes GBM in mouse models. It is also the first to explain the p53-based mechanism by which ATM kinase inhibitors selectively sensitize brain cancers to radiation," says Valerie. "We are excited to translate these findings into a clinical trial and hopefully bring more effective therapies to patients who typically do not have good outcomes."

This study laid the groundwork for a phase 1 clinical trial (NCT03423628) led by AstraZeneca that will test AZ1390 in combination with radiation therapy for the treatment of brain tumors. It will assess the safety and tolerability of increasing doses of AZ1390 in combination with different regimens of radiation therapy for recurrent GBM, brain metastases and newly diagnosed GBM. The trial is estimated to enroll 132 patients at seven medical centers in the US and the UK, including VCU Massey Cancer Center.

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Valerie collaborated on this study with Jeremy Karlin, M.D., Jasmine Allen, Syed F. Ahmad, Amrita Sule, Ph.D., Laura Biddlestone-Thorpe, Ph.D., Jenna Kahn, M.D., Jason M. Beckta, M.D., Ph.D., Nitai Mukhopadhyay, Ph.D., and Nicholas C.K. Valerie, all from the Department of Radiation Oncology at VCU Massey Cancer Center; as well as Gareth Hughes, Victoria Sheridan, Rajesh Odedra, Paul Farrington, Elaine B. Cadogan, Lucy C. Riches, Antionio Garcia-Trinidad, Andrew G. Thomason, Bhavika Patel, Jennifer Vincent, Alan Lau, Kurt G. Pike, Thomas A. Hunt, Bernard Barlaam, Sebastien L. Degorce, Jason Kettle, Nicola Colclough, Joanne Wilson, Aaron Smith, Ian P. Barrett, Li Zheng, Tianwei Zhang, Yingchun Wang, Kan Chen, Martin Pass and Stephen T. Durant, all from AstraZeneca.

This study was supported by grants R01NS064593, R21CA194789 and R21CA156995 by the National Institutes of Health (NIH) and National Cancer Institute (NCI); AstraZeneca; and, in part, by VCU Massey Cancer Center's NIH-NCI Cancer Center Support Grant P30 CA016059.

The full version of this manuscript is available at: http://mct.aacrjournals.org/content/molcanther/early/2018/05/16/1535-7163.MCT-17-0975.full.pdf

Valerie collaborated on the AZD1390 study with Jasmine Allen, Jenna Kahn, M.D., Amrita Sule, Ph.D., and Jeremy Karlin, M.D., all from the Department of Radiation Oncology at VCU Massey Cancer Center; as well as Durant S., L. Zheng, Y. Wang, K. Chen, L. Zhang, T. Zhang, L. Riches, A. Garcia-Trinidad, T. Hunt, K.G. Pike, J. Wilson, A. Smith, N. Colclough, V.P. Reddy, A. Sykes, A. Janefeldt, P. Johnström, K. Varnäs, A. Takano, S. Ling, J. Stott, I. Barrett, G. Jones, A. Pierce, A. Cronin, M. Chapman, Z. Yang, R. Illingworth, M. Pass., from AstraZeneca and the Karolinska Institutet.

The manuscript on the AZD1390 study is available at: http://advances.sciencemag.org/content/4/6/eaat1719.

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