Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma

Eckerdt, Frank; Clymer, Jessica; Bell, Jonathan B.; Beauchamp, Elspeth M.; Blyth, Gavin T.; Goldman, Stewart; Platanias, Leonidas C.

doi:10.1038/s41598-019-49299-3

Cited by 26 publications

(17 citation statements)

References 59 publications

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“…The antineoplastic effects of alpelisib can be enhanced by pharmacological mTOR inhibition in breast cancer 34 , 55 and medulloblastoma 63 . Here we provide evidence that also in GSCs concomitant mTOR inhibition potentiates the antineoplastic effects of PI3Kα inhibition.…”

Section: Discussionmentioning

confidence: 99%

Combined PI3Kα-mTOR Targeting of Glioma Stem Cells

Eckerdt

Bell

Gonzalez

et al. 2020

Sci Rep

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Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.

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Section: Discussionmentioning

confidence: 99%

Combined PI3Kα-mTOR Targeting of Glioma Stem Cells

Eckerdt

Bell

Gonzalez

et al. 2020

Sci Rep

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“…With that said, simultaneous targeting of SMO and GLI has been shown to provide synergistic inhibitory effects on various cancers, including multiple myeloma [ 250 , 251 ], medulloblastoma [ 252 ], and glioblastoma [ 253 ]. Additionally, a combination of SMO inhibitors with inhibitors targeting other oncogenic targets, such as PI3K/AKT/mTOR [ 254 , 255 , 256 , 257 ], EGFR [ 258 ], DNA methyltransferases [ 83 ], and interleukin 6 [ 259 ], resulted in synergistic inhibition of cancer cell growths. Such combinations included the use of SMO or GLI inhibitors with drugs targeting oncogenic drivers of noncanonical GLI activation, which allows for the simultaneous targeting of compensatory noncanonical GLI activation and other Hh-unrelated key cancer targets.…”

Section: Current Challenges and Future Perspective For Using Smo/gli Inhibitors In Clinical Settingsmentioning

confidence: 99%

The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

et al. 2021

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The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.

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“…and PI3K inhibition has demonstrated efficacy against medulloblastoma cells and tumors [131,130]. In preclinical in vivo studies, this effect was enhanced with concurrent mTOR inhibition, and the percentage of stem cells was decreased with combined PI3K/ mTOR inhibition [132]. Further studies have shown that Akt inhibition with perifosine can re-sensitize medulloblastoma nestin + stem cells to radiation treatment [129].…”

Section: Targeted Agentsmentioning

confidence: 99%

Overview and recent advances in the targeting of medulloblastoma cancer stem cells

Paul

Zage

2021

Expert Review of Anticancer Therapy

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Introduction: Medulloblastoma, an embryonal small round blue cell tumor primarily arising in the posterior fossa, is the most common malignancy of the central nervous system in children and requires intensive multi-modality therapy for cure. Overall 5-year survival is approximately 75% in children with primary disease, but outcomes for relapsed disease are very poor. Recent advances have identified molecular subgroups with excellent prognosis, with 5-year overall survival rates >90%, and subgroups with very poor prognosis with overall survival rates <50%. Molecular subtyping has allowed for more sophisticated risk stratification of patients, but new treatments for the highest risk patients have not yet improved outcomes. Targeting cancer stem cells may improve outcomes, and several candidate targets and novel drugs are under investigation. Areas covered: We discuss medulloblastoma epidemiology, biology, treatment modalities, risk stratification, and molecular subgroup analysis, links between subgroup and developmental biology, cancer stem cell biology in medulloblastoma including previously described cancer stem cell markers and proposed targeted treatments in the current literature. Expert opinion: The understanding of cancer stem cells in medulloblastoma will advance therapies targeting the most treatment-resistant cells within the tumor and therefore reduce the incidence of treatment refractory and relapsed disease.

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Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma

Cited by 26 publications

References 59 publications

Combined PI3Kα-mTOR Targeting of Glioma Stem Cells

Combined PI3Kα-mTOR Targeting of Glioma Stem Cells

The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

Overview and recent advances in the targeting of medulloblastoma cancer stem cells

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