ATM Kinase Inhibition Preferentially Sensitizes p53-Mutant Glioma to Ionizing Radiation

Abstract

Purpose Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12–15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of GBM patients is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. ATM, ataxia telangiectasia (A-T) mutated, is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, growth, and potently radiosensitized human glioma cells in vitro. Experimental Design Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intra-cranially, and KU-60019 was administered intra-tumorally by convection-enhanced delivery or osmotic pump. Results Our results demonstrate that the combined effect of KU-60019 and radiation significantly increased survival of mice 2–3 fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.

Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019

“…2d 3 ). Taken together, these data indicate that the employed dosing (12.5 ll of a 250 lM solution in PBS), reported to be effective in radiosensitization of orthotopic GB, 4 is not toxic. Quantification of KU60019 via HPLC/MS allowed to determine that the drug is stable at body temperature (37 C) and diffuses rapidly in the brain during delivery.…”

“…However, analysis of proliferation over an 80-day period showed radiosensitization after either one, two or three KU60019 plus IR treatments (Figs. 5e [4][5][6] and f 4,5 ; Table 1). Previous studies have identified subgroups of GB based on genetic and epigenetic variations of a number of genes including H3F3A and IDH1.…”

“…CED was carried out as described by Biddlestone-Thorpe et al 4 with the following modifications. Briefly, a 1-cm midsagittal skin incision was made on the head, and the skull exposed.…”

“…2 Similar results and significant survival improvements of mice bearing orthotopic GB have been reported in two US-and one UKbased studies. [3][4][5] A relationship between tumor response to ATM inhibitors and low levels of TP53 tumor suppressor expression has been described 2,4 but these results have not been confirmed. 3 We take a further step forward in our route toward the clinical application of ATM inhibitors describing the pharmacokinetics of KU60019, its pharmacodynamics over an adult orthotopic GB and its effectiveness on pediatric high-grade gliomas (HGG).…”

“…[1). To specifically target GB-initiating cells (GIC), we 2 and others [3][4][5] have identified a new radiosensitizing procedure. This is based on the capacity of ATM inhibitors such as KU60019 to specifically stimulate proliferation of quiescent GIC.…”