Medulloblastoma drugs in development: Current leads, trials and drawbacks

Wen, Jiachen; Hadden, M. Kyle

doi:10.1016/j.ejmech.2021.113268

Cited by 12 publications

(14 citation statements)

References 168 publications

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“…A preclinical study that used a different PI3K inhibitor, called pilaralisib (SAR245408), had a similar conclusion [ 50 ]. In addition, the Sonic hedgehog (SHH) pathway, which is intertwined with the PI3K/Akt/mTOR signaling pathway, has been involved in medulloblastoma-targeted therapy [ 5 , 16 ]. Some of these medications were FDA-approved for basal cell cancer, such as vismodegib (GDC-0449 and Sonidegib (NVP-LDE225) [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

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Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Alammar

Nassani

Alshehri

et al. 2021

IJMS

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Medulloblastoma is a common fatal pediatric brain tumor. More treatment options are required to prolong survival and decrease disability. mTOR proteins play an essential role in the disease pathogenesis, and are an essential target for therapy. Three generations of mTOR inhibitors have been developed and are clinically used for immunosuppression and chemotherapy for multiple cancers. Only a few mTOR inhibitors have been investigated for the treatment of medulloblastoma and other pediatric tumors. The first-generation mTOR, sirolimus, temsirolimus, and everolimus, went through phase I clinical trials. The second-generation mTOR, AZD8055 and sapanisertib, suppressed medulloblastoma cell growth; however, limited studies have investigated possible resistance pathways. No clinical trials have been found to treat medulloblastoma using third-generation mTOR inhibitors. This systematic review highlights the mechanisms of resistance of mTOR inhibitors in medulloblastoma and includes IDO1, T cells, Mnk2, and eIF4E, as they prolong malignant cell survival. The findings promote the importance of combination therapy in medulloblastoma due to its highly resistant nature.

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Section: Resultsmentioning

confidence: 99%

“…The aggressive nature of the medulloblastoma, genetic variation, and the tendency to develop resistance necessitate an update to the conventional treatment [ 5 , 6 ]. Resistance has been observed against mTOR inhibitor-targeted therapy in medulloblastoma.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Alammar

Nassani

Alshehri

et al. 2021

IJMS

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“…Medulloblastoma (MB) is a highly malignant neuroepithelial tumor of the central nervous system and is a common solid tumor in children ( Li M. et al, 2021 ; Wen and Hadden, 2021 ), particularly those under 10 years of age ( Hammoud et al, 2020 ; Danilenko et al, 2021 ). MB is difficult to treat because of its rapid growth, incomplete surgical excision, and tendency to disseminate with the cerebrospinal fluid ( Caimano et al, 2021 ).…”

Section: Roles and Significance Of Circrnas In Pediatric Malignant Solid Tumorsmentioning

confidence: 99%

Emerging Role and Mechanism of circRNAs in Pediatric Malignant Solid Tumors

Shen

Liu

et al. 2022

Front. Genet.

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Circular RNAs (circRNAs) are non-coding RNAs with covalent closed-loop structures and are widely distributed in eukaryotes, conserved and stable as well as tissue-specific. Malignant solid tumors pose a serious health risk to children and are one of the leading causes of pediatric mortality. Studies have shown that circRNAs play an important regulatory role in the development of childhood malignant solid tumors, hence are potential biomarkers and therapeutic targets for tumors. This paper reviews the biological characteristics and functions of circRNAs as well as the research progress related to childhood malignant solid tumors.

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“…clinically ineffective (40). However, AKT, PDK and PP2A have all been implicated as potential targets for future MB therapies (40,41).…”

Section: Medulloblastoma (Mb) Is Another Brain Tumor In Which Kinase Inhibitors Have Been Provenmentioning

confidence: 99%

Development of Actionable Targets of Multi-kinase Inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

Denisova

Merisaari

Huhtaniemi

et al. 2022

Preprint

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Kinase inhibitor tolerance of human glioblastoma is an unmet clinical challenge and a mechanistic enigma. Here, we demonstrate that glioblastoma cell tolerance to multi-kinase inhibition can be reverted by reactivation of Protein Phosphatase 2A (PP2A). To characterize kinase targets of clinical stage multi-kinase inhibitor UCN-01 synergizing with PP2A reactivation, we established a strategy, named Actionable Targets of Multi-kinase Inhibitors (AToMI). AToMI revealed AKT and mitochondrial pyruvate dehydrogenase kinases (PDK1-4) as the co-targets for UCN-01-elicited synthetic lethality with PP2A reactivation. Notably, heterogeneous glioblastoma and medulloblastoma models were tolerant to AKT and PDK1-4 inhibitor monotherapies, and their combinations, but were effectively inhibited by triplet therapy including pharmacological PP2A reactivation. Mechanistically, overcoming the kinase therapy tolerance by the triplet therapy could be explained by combinatorial effects on signaling rewiring between AKT and PDK1-4, decrease in mitochondrial oxidative phosphorylation, and BH3-only protein mediated apoptosis priming. The brain-penetrant triplet combination had a significant in vivo efficacy in intracranial glioblastoma and medulloblastoma models. Collectively, we present a generalizable approach to identify actionable co-targets of multi-kinase inhibitors and demonstrate that overcoming of the kinase inhibitor tolerance in brain tumor cells requires triplet targeting of AKT, PDK1-4, and PP2A.

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Medulloblastoma drugs in development: Current leads, trials and drawbacks

Cited by 12 publications

References 168 publications

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Emerging Role and Mechanism of circRNAs in Pediatric Malignant Solid Tumors

Development of Actionable Targets of Multi-kinase Inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells

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