Researchers from University of Texas Southwestern collaborated with VCU Massey Cancer Center and VCU School of Medicine on the development of a novel drug that increases the sensitivity of deadly brain tumors to radiation. The drug showed remarkable results in extending survival in mouse models of human glioblastoma multiforme (GBM) when given as an adjuvant to radiation therapy.
The latest research conducted by Virginia Commonwealth University Massey Cancer Center researchers and University of Texas Southwestern will help in the development of a novel drug that can increase the efficacy and sensitivity of traditional cancer therapies like radiotherapy to promote cancer cell death. The tumors of Glial cell (also referred to as gliomas) are mainly managed by surgical excision of the tumor mass followed by radiotherapy and chemotherapy.
Background of the research:
The research report published in the journal Clinical Cancer Research provided the first preclinical evidence that certain adjuvant drugs like ATM kinase inhibitors can increase the sensitivity of gliomas to radiotherapy. Glial cells provide structural and functional support to nerve cells by maintenance of internal environment of brain. Any DNA damage in these cells is repaired by the enzyme ataxia telangiectasia mutated (or ATM). Scientists introduced drug agent KU-60019 to block the activity of ATM in order to enhance the lethal DNA damage as a result of radiation therapy. Researchers believe that this approach can help in the management of 30% of all the gliomas that are caused by p53 tumor suppressor gene mutation.
The lead researcher of the study and professor in the Department of Radiation Oncology at VCU Massey Cancer Center, Kristoffer Valerie commented:
“Sadly, the average life expectancy of patients diagnosed with glioblastoma is just 12 to 15 months. By limiting the tumor’s ability to combat DNA damage caused by treatments such as radiation, we are hopeful that we can enhance our ability to specifically target the glioma, prolong survival and reduce damage to surrounding brain tissue.”
Valerie is also co-leader of the Radiation Biology and Oncology research program. Valerie and his team of researchers suggested that using other agents like ATM kinase inhibitors can increase the efficacy of traditional cancer therapies and that’s why radiation therapy was chosen, since it is already a recognized therapy for tumor management and is considered superior because of its accuracy and minimally invasive potential. Valerie and his associates conducted a study several years ago that indicated the specifity, potency and effectiveness of KU-60019 over ATM kinase inhibitor.
“If these findings hold up in early phase clinical trials, we expect patients with p53 mutant gliomas to respond well to this treatment while showing few side effects. Also, we anticipate that this same treatment strategy could be effective for other cancers that are treated with DNA-damaging chemotherapies. We are encouraged by these early findings and will continue to move forward with our research. However, more studies are needed before we can proceed with testing this new therapy in humans.”
Valerie and his associates are currently studying the effectiveness of ATM kinase inhibitors and KU-60019 on the management and clinical functioning of gliomas. In addition various new combinations are also being studied like combining ATM kinase inhibitors with PARP inhibitor (that blocks the activity of DNA repair enzyme poly ADP ribose polymerase (PARP) to increase the “synthetic lethality” (when the action of two interacting genes is simultaneously blocked, the rate of tumor cell death increases several folds – leading to “synthetic lethality”).
Researchers who collaborated with Valerie include:
VCU School of Medicine:
Sumitra Deb, Ph.D, Nitai D. Mukhopadhyay, Donna Gilfor, Laura Biddlestone-Thorpe, Alison F Wagner, Ashraf Khalil, Sarah E. Golding, Mary Tokarz, Jason M. Beckta, David G. Temesi, Alan Lau, Mark J. O’Connor, Nicholas C.K. Valerie, Bret R. Adams, Muhammad Sajjad, Elizabeth Rosenberg
University of Texas Southwestern:
Kevin S Choe, Luis F. Parada and Sang Kyun Lim.