Inhibition of mTORC1 in pediatric low-grade glioma depletes glutathione and therapeutically synergizes with carboplatin

Poore, Brad; Yuan, Ming; Arnold, Antje; Price, Antoinette; Alt, Jesse; Rubens, Jeffrey; Slusher, Barbara S.; Eberhart, Charles G.; Raabe, Eric H.

doi:10.1093/neuonc/noy150

Cited by 23 publications

(17 citation statements)

References 50 publications

(60 reference statements)

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“…These could include e.g. the inhibition of other MAPK-related survival pathways like AKT/mTOR [38], or the use of senolytic drugs [37], both of which remain to be introduced into the clinical treatment of pLGGs. PD was observed in 3/11 (27%) of the patients who stopped trametinib, within 4 months after EOT.…”

Section: Discussionmentioning

confidence: 99%

Response to trametinib treatment in progressive pediatric low-grade glioma patients

et al. 2020

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Introduction A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. Methods In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. Results We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Conclusions Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

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Section: Discussionmentioning

confidence: 99%

Response to trametinib treatment in progressive pediatric low-grade glioma patients

et al. 2020

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“…Furthermore, demonstration of synergy between everolimus and carboplatin in pediatric LGG cell lines and slowed tumor growth in the in vivo pediatric LGG models support its potential utility in future multiagent protocols. 49 Lastly, a separate recently completed Phase II study of everolimus by the Pacific Neuro-Oncology Consortium requiring tissue at enrollment may provide further insight into its relevance for molecular subtypes of pediatric…”

Section: Discussionmentioning

confidence: 99%

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low‐grade glioma

Wright

Yao

London

et al. 2020

Pediatric Blood & Cancer

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Background: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive lowgrade glioma (LGG). Methods: Everolimus was administered at 5 mg/m 2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. Results: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or

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“…In the study, when mTOR signaling was suppressed, the MAPK pathway was activated and the sensitivity to carboplatin increased. Inhibition of mTOR signaling was confirmed to increase the efficacy of carboplatin in glioma cells by reducing the glutathione pool [ 142 ]. As a basis for this, tumorigenesis in glioblastoma multiforme is associated with abnormal PI3K/AKT/mTOR signaling, and inhibition of mTOR signaling induces the activity of MAPK(pERK1/2) and MEK1/2 [ 143 ].…”

Section: Resistance Mechanism Of Platinum-based Anticancer Drugs In Brain Tumorsmentioning

confidence: 99%

Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas

Jeon

Lee

Kim

et al. 2021

IJMS

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Although there are many patients with brain tumors worldwide, there are numerous difficulties in overcoming brain tumors. Among brain tumors, glioblastoma, with a 5-year survival rate of 5.1%, is the most malignant. In addition to surgical operations, chemotherapy and radiotherapy are generally performed, but the patients have very limited options. Temozolomide is the most commonly prescribed drug for patients with glioblastoma. However, it is difficult to completely remove the tumor with this drug alone. Therefore, it is necessary to discuss the potential of anticancer drugs, other than temozolomide, against glioblastomas. Since the discovery of cisplatin, platinum-based drugs have become one of the leading chemotherapeutic drugs. Although many studies have reported the efficacy of platinum-based anticancer drugs against various carcinomas, studies on their effectiveness against brain tumors are insufficient. In this review, we elucidated the anticancer effects and advantages of platinum-based drugs used in brain tumors. In addition, the cases and limitations of the clinical application of platinum-based drugs are summarized. As a solution to overcome these obstacles, we emphasized the potential of a novel approach to increase the effectiveness of platinum-based drugs.

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Inhibition of mTORC1 in pediatric low-grade glioma depletes glutathione and therapeutically synergizes with carboplatin

Cited by 23 publications

References 50 publications

Response to trametinib treatment in progressive pediatric low-grade glioma patients

Response to trametinib treatment in progressive pediatric low-grade glioma patients

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low‐grade glioma

Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas

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