A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913

Chinnaiyan, Prakash; Won, Minhee; Wen, Patrick Y.; Rojiani, Amyn M.; Werner‐Wasik, Maria; Shih, Helen A.; Ashby, Lynn S.; Yu, Hsiang-Hsuan Michael; Stieber, Volker W.; Malone, Shawn; Fiveash, John B.; Mohile, Nimish; Ahluwalia, Manmeet; Wendland, Merideth M; Stella, Philip J.; Kee, Andrew Y.; Mehta, Minesh P.

doi:10.1093/neuonc/nox209

Cited by 116 publications

(85 citation statements)

References 36 publications

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“…In children, H3.1K27M cases tend to be enriched for PI3K/mTOR alterations . In a recent phase II trial of adults with newly diagnosed glioblastoma, the addition of everolimus to radiotherapy and temozolomide did not improve progression‐free survival . A pediatric phase II trial of temsirolimus single agent did not show any objective response in recurrent/refractory pHGG .…”

Section: Biology Of Phgg and Molecularly Directed Therapiesmentioning

confidence: 99%

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

Guerra‐García

Marshall

Cockle

et al. 2019

Pediatric Blood & Cancer

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Pediatric high‐grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.

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Section: Biology Of Phgg and Molecularly Directed Therapiesmentioning

confidence: 99%

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

Guerra‐García

Marshall

Cockle

et al. 2019

Pediatric Blood & Cancer

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show abstract

“…S1B). Ionizing radiation causes double-stranded breaks (DSBs) in 6 DNA and rapidly results in the phosphorylation of histone H2A variant H2AX, which can be readily detected by immunoblot, flow cytometry or immunofluorescence 23 .…”

Section: Nucleotide Metabolites Correlate With Rt-resistance In Gbmmentioning

confidence: 99%

“…Work from The Cancer Genome Atlas (TCGA) and others have defined a diversity of driver alterations in GBM including gene amplifications, mutations, deletions and complex rearrangements of signaling receptors 1, 2 . Unfortunately, targeted therapies against these abnormalities have uniformly lacked efficacy in patients with GBM 3,4,5,6 . These disappointing results may be due to the profound intra-tumoral genomic heterogeneity that also characterizes GBM.…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Zhou

Yao

Scott

et al. 2020

Preprint

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Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance, and new strategies that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we found that purine metabolites strongly correlated with radiation resistance. Inhibiting purine, but not pyrimidine, synthesis radiosensitized GBM cells and patient-derived neurospheres by impairing DNA repair in a nucleoside-dependent fashion. Likewise, administration of exogenous purine nucleosides protected sensitive GBM models from radiation by promoting DNA repair. Combining an FDA-approved inhibitor of de novo purine synthesis with radiation arrested growth in GBM xenograft models and depleted intratumoral guanylates. High expression of the rate-limiting enzyme of de novo GTP synthesis was associated with shorter survival in GBM patients. Together, these findings indicate that inhibiting de novo purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

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“…Meclizine and flunarizine were more toxic than rapamycin ( Figure 3). Rapamycin has been used in multiple GBM clinical trials (21)(22)(23)(24).…”

Section: Piperazine Drugs Kill Gbmscsmentioning

confidence: 99%

“…Flunarizine reduced GBMSC viability to a similar extent ( Fig.4). Both meclizine and flunarizine were significantly more toxic to GBMSCs than rapamycin, a drug that has been used in several GBM clinical trials (21)(22)(23)(24). The IC50's for meclizine, flunarizine, and rapamycin are 5.3µM, 6.8µM, and 14µM respectively.…”

Section: Comparison Of Gbm Cell Viability After Treatment With Meclizmentioning

confidence: 99%

Novel mTORC1 inhibitors kill Glioblastoma stem cells

Sandoval

Tomilov

Datta

et al. 2020

Preprint

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Glioblastoma Multiforme (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. mTORC1 regulates cell proliferation and has been shown by others to have reduced activity in GBMSC.We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed piperazine-mTOR binding strength by two biophysical measurements--biolayer interferometry and field effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. Since mTORC1 is reduced in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy--but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, the tight-binding Meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. These data tend to support a novel clinical strategy for GBM, i.e. the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM, and IDH1-mutant GBM.

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A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913

Cited by 116 publications

References 36 publications

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Novel mTORC1 inhibitors kill Glioblastoma stem cells

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