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Background Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. Methods We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided. Results Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors. Conclusions We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.

Glutamine is the most abundant plasma amino acid and many cancers show altered glutamine metabolism. We evaluated glutamine uptake and metabolism in gliomas using PET imaging and biochemical approaches. We demonstrate that glutamine is a key TCA cycle anaplerotic substrate and is metabolized to generate 2-HG in IDH1-mutant gliomas. PET imaging with18F-labeled glutamine (18F-FGln) showed high uptake in gliomas in vivo but low background uptake in the surrounding brain in RCAS-PDGF/PTEN null and IDH1-mutant glioma animal models, facilitating clear tumor delineation in contrast to that seen with 18F-FDG. We did not observe 18F-FGln uptake in animals with neuroinflammation or animals with a disrupted BBB. Further, 18F-FGln uptake was specifically reduced on chemo/radiation therapy. Finally, 18F-FGln showed high avidity in human glioma with low uptake in the surrounding brain. These data suggest that 18F-FGln is specifically taken up by gliomas, can be used to assess the metabolic state of gliomas in vivo and may serve as a valuable tool in the clinical management of gliomas.

Proneural glioblastoma (GBM) is characterized by PDGF signaling through receptor and/or ligand overexpression or amplification. Despite this, clinical trials using the tyrosine kinase receptor inhibitor Gleveec for GBM have failed. The inability to respond to PDGFR inhibition could either be at the ligand/receptor level where the amount of ligand or receptor is sufficient to promote downstream signaling despite levels of PDGFR inhibition achieved clinically, or due to constitutive activation of downstream pathways making receptor activation less important. In addition to activation of PDGFR signaling, proneural GBMs frequently harbor alterations of tumor suppressor genes CDKN2A, PTEN and TP53. To understand if loss of these tumor suppressor genes drives tumor progression and evolution of independence from PDGF signaling, and thus therapeutic resistance, we used a combination of human and mouse proneural GBMs. Patient-derived primary cell cultures did not respond to PDGFR inhibition with reduction in proliferation when treated with Vatalanib, indicating that tumor cells were PDGF-independent and consistent with failed clinical trials. Despite reduction in receptor phosphorylation with drug treatment, no effects on downstream signaling in the PI3K and MAPK pathways were seen. Using the in vivo mouse RCAS/TVA model of proneural GBM we found that genetic knock down of PDGFRA expression inhibited tumor formation and that simultaneously knocking down expression of CDKN2A, PTEN or TP53 could not eliminate the need for PDGF signaling for tumor initiation. However, loss of CDKN2A and PTEN in PDGF-driven tumors with high PDGFRA expression accelerated tumorigenesis and lead to failure to respond to PDGFR inhibition by Vatalanib in vivo. We propose that PDGF signaling is crucial during tumor initiation but once loss of CDKN2A, PTEN and/or TP53 occurs during tumor evolution, constitutive activation of the PI3K and MAPK pathways occurs making tumor cells independent of upstream activation through PDGFRA.

BACKGROUND: Dexamethasone (DEX) is a mainstay in high-grade glioma (HGG) treatment due to the ability to decrease cerebral edema in the perioperative window and control neurological symptoms during adjuvant therapy. However, DEX has many potential systemic complications and there has been a recent effort at our hospital to more rigorously titrate DEX usage during radiotherapy (RT) with patient symptoms. The purpose of this study was to retrospectively evaluate DEX usage, readmissions, and subjective complaints during radiotherapy. METHODS: We performed an IRB-approved review of patients with pathologist-confirmed HGG from 2010-2013 to identify (i) the DEX dosage throughout RT, (ii) subjective patient complaints, specifically pertaining to fatigue, neuromotor, seizure, nausea, vomiting, headache, and vision, and (iii) readmissions during the treatment process, which are all documented during routine weekly status checks throughout the period of adjuvant RT. RESULTS: We identified 347 HGG patients treated at our institution. We saw no significant differences in pathology distribution, age, performance status, chemotherapy or antiangiogenic therapy use in 2013 compared to 2010-2012. However, 41% of patients in 2013 started RT without DEX, compared to 22% from 2010-2012 (p = .0005), with no increase in the number of patients requiring DEX later during RT to manage their symptoms. The mean total DEX dose during RT was significantly lower in 2013 (3.51 in 2013 vs 4.86 mg/day in 2010-2012, p = 0.0061). Although DEX usage was reduced, we observed no differences in readmissions (4% in 2013 vs 8% 2009-2012, p = 0.33) or subjective complaints (80% of patients in 2013 vs 83% in 2009-2012, p = 0.63). CONCLUSIONS: Our data suggests that HGG patients can be safely managed with lower DEX doses without increased adverse outcomes or patient readmissions. Further studies are needed to more systematically investigate DEX usage during HGG radiotherapy and whether long-term outcomes such as progression and survival are affected.