Local intracerebral Inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy <i>in vivo</i>

Reste, Pierre-Jean Le; Pineau, Raphaël; Voutetakis, Konstantinos; Samal, Juhi; Jégou, Gwénaële; Lhomond, Stéphanie; Gorman, Adrienne M.; Samali, Afshin; Patterson, John B.; Zeng, Qingping; Pandit, Abhay; Aubry, Marc; Soriano, Nicolas; Etcheverry, Amandine; Chatziioannou, Aristotelis; Mosser, Jean; Avril, Tony; Chevet, Éric

doi:10.1101/841296

Cited by 8 publications

(11 citation statements)

References 28 publications

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“…The most common and aggressive malignancy in brain tumors is Glioblastoma Multiforme (GBM) ( Duwa et al, 2019;Gong et al, 2019;Le Reste et al, 2020;Rahn et al, 2020). Currently, surgical resection, chemotherapy, and radiation therapy are mainly used for treatment, but the tumor often regrowth and the survival rate of GBM patients is low (Jeong et al, 2008;Floyd et al, 2015;Hotchkiss & Sampson, 2021).…”

Section: Intracranial Tumor Therapymentioning

confidence: 99%

PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application

Zhang²,

Sun³

et al. 2021

Drug Delivery

308

106

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Biodegradable microspheres have been widely used in the field of medicine due to their ability to deliver drug molecules of various properties through multiple pathways and their advantages of low dose and low side effects. Poly (lactic-co-glycolic acid) copolymer (PLGA) is one of the most widely used biodegradable material currently and has good biocompatibility. In application, PLGA with a specific monomer ratio (lactic acid and glycolic acid) can be selected according to the properties of drug molecules and the requirements of the drug release rate. PLGA-based biodegradable microspheres have been studied in the field of drug delivery, including the delivery of various anticancer drugs, protein or peptide drugs, bacterial or viral DNA, etc. This review describes the basic knowledge and current situation of PLGA biodegradable microspheres and discusses the selection of PLGA polymer materials. Then, the preparation methods of PLGA microspheres are introduced, including emulsification, microfluidic technology, electrospray, and spray drying. Finally, this review summarizes the application of PLGA microspheres in drug delivery and the treatment of pulmonary and ocularrelated diseases.

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Section: Intracranial Tumor Therapymentioning

confidence: 99%

PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application

Zhang²,

Sun³

et al. 2021

Drug Delivery

308

106

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“…Second, we administered RT in one single dose and we did not perform concomitant chemotherapy, contrarily to the fractionated RT regimens associated with low-dose concomitant chemotherapy usually administered to patients [2]. As we already demonstrated by us and other groups, fractionated RT and concomitant TMZ in mice is feasible; therefore, we are currently implementing these therapies in our treatment pipeline [16,21]. Third, GBM patients are very often treated with corticosteroids in order to reduce brain edema.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we treated NS/CT-2A tumor bearing mice with a fluorescence-guided surgical resection of the tumor mass combined with focal RT and oral TMZ. Tumor resection alone or in combination with other treatments has been anecdotally implemented in the preclinical settings (some examples in [16][17][18]). However, to the best of our knowledge, this is the first study where fluorescence-guided surgical resection has been combined with focal RT targeted to the tumor cavity and its close surroundings and with oral TMZ.…”

Section: Discussionmentioning

confidence: 99%

“…The surgical removal of brain tumors was performed on day 14 after tumor cell inoculation. To induce fluorescence in the brain tumors, mice received with 5mg/kg fluorescein (Sigma) dissolved in 100µl of 0.9% NaCl solution (Braun) via tail vein injection immediately before surgery, as previously described [16]. Mice were then placed under general anesthesia with 2% isoflurane (Baxter), administered with penicillin and 5% glucose solution IP (Table 1, Figure 2) and transferred on a stereotactic frame (Stoelting) below the surgical microscope (Leica Microsystems).…”

Section: Ip: Intraperitoneallymentioning

confidence: 99%

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Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model

Riva

Bevers

Wouters

et al. 2021

Preprint

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Introduction: Contrarily to clinical trials, where glioblastoma (GBM) patients are usually heavily pre-treated (surgery, radio-therapy (RT) and temozolomide (TMZ)) before receiving the experimental therapies, in preclinical GBM studies experimental treatments have mostly been administered as monotherapy or combined with a very limited part of the clinical standard of care. This discrepancy can explain the failed clinical translation of preclinically successful treatments. This study is aimed at evaluat-ing the feasibility and survival impact of the clinical standard of care in glioma-bearing mice. Methods. Neurospheres CT-2A tumor-bearing mice were treated with fluorescence-guided tumor resection, focal RT and oral TMZ. Results: The implementation of postoperative intensive care treatment reduced surgical mortality by approximately 50% and increased experimental cost-effectiveness. Partial and total tumor resection significantly prolonged survival, the latter showing the strongest effect. Mice treated with surgery combined with RT or with RT and TMZ survived significantly longer than un-treated controls. Conclusions: Implementing the current GBM clinical standard of care in preclinical research is feasible and it leads to results in line with those obtained in patients. Systematic preclinical evaluation of the efficacy of experimental therapies in combination with standard of care treatments could improve the translational impact of next generation GBM animal studies.

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“…This pertains to the possibility that targeting IRE1 activity could lead to sensitisation of tumours to current therapies as cancer cells would exhibit reduced capacity to cope with the hostile environment. Indeed, such studies have been performed in triple-negative breast cancer (TNBC) showing that the inhibition of IRE1 RNase activity with salicylaldehyde MKC8866 increased paclitaxel-dependent attenuation of TNBC development in mouse xenograft models [7] or in glioblastoma multiforme (GBM) models [8]. Further to this, MKC8866 treatment greatly enhanced the efficacy of docetaxel in regressing MYC-overexpressing tumours in breast cancer PDX models [9].…”

Section: Introductionmentioning

confidence: 99%

Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1 activity

et al. 2020

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Inositol‐requiring enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein‐folding demand. To cope with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here, we report the discovery of the FDA‐approved compounds methotrexate, cefoperazone, folinic acid and fludarabine phosphate as IRE1 inhibitors. These were identified through a structural exploration of the IRE1 kinase domain using IRE1 peptide fragment docking and further optimisation and pharmacophore development. The inhibitors were verified to have an impact on IRE1 activity in vitro and were tested for their ability to sensitise human cell models of glioblastoma multiforme (GBM) to chemotherapy. We show that all molecules identified sensitise glioblastoma cells to the standard‐of‐care chemotherapy temozolomide (TMZ).

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Local intracerebral Inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo

Cited by 8 publications

References 28 publications

PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application

PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application

Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model

Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1 activity

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