MTOR inhibitor-based combination therapies for pancreatic cancer

Hassan, Zonera; Schneeweis, Christian; Wirth, Matthias; Veltkamp, Christian; Dantes, Zahra; Feuerecker, Benedikt; Ceyhan, Güralp O.; Knauer, Shirley K.; Weichert, Wilko; Schmid, Roland M.; Stauber, Roland H.; Arlt, Alexander; Krämer, Oliver; Rad, Roland; Reichert, Maximilian; Saur, Dieter; Schneider, Günter

doi:10.1038/bjc.2017.421

Cited by 37 publications

(24 citation statements)

References 58 publications

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“…Primary patient-derived PDAC three-dimensional (3D) organoids were generated from primary resected human PDAC surgical specimen according to the Tuveson protocol described in23 and in the SM&M 24. Generation and culturing of primary-dispersed human PDAC cells is described in25 and SM&M. Written informed consent from the patients for research use was obtained prior to the investigation.…”

Section: Methodsmentioning

confidence: 99%

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Biederstädt

Hassan

Schneeweis

et al. 2020

Gut

Self Cite

104

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ObjectivePancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.DesignWe analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.ResultsWe observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.ConclusionSUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

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Section: Methodsmentioning

confidence: 99%

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Biederstädt

Hassan

Schneeweis

et al. 2020

Gut

Self Cite

104

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“…This may further be explained by mTORC1 being involved in complex negative feedback loops that restrain upstream signalling. More recently developed dual ATP-competitive agents that target mTORC1/mTORC2 have shown favourable results [207,208] with AZD2014 effectively inhibiting PDAC cell division (G1 arrest), proliferation, and invasion in vitro [158,160] and prolonging survival in the KPC mouse model of PDAC [109,208,209]. More recently developed dual ATP-competitive agents that target mTORC1/mTORC2 have shown favourable results [207,208] with AZD2014 effectively inhibiting PDAC cell division (G1 arrest), proliferation, and invasion in vitro [158,160] and prolonging survival in the KPC mouse model of PDAC [109,208,209].…”

Section: Modulation Of the Upstream And Downstream Src Signalling Commentioning

confidence: 99%

“…For example, inhibition of mTORC1 drives activation of PI3K-, AKT-or ERK pathways [205], which in turn limits the efficacy of mTORC-inhibitors as targeted therapies [206]. However there is still some debate as to whether blocking mTORC1/2 leads to the adaptive activation of the PI3K-AKT pathway [209], and consequently whether multiple targeting of this network is required to effectively interfere with both branches of adaptive signalling and to elicit a durable therapeutic response. However there is still some debate as to whether blocking mTORC1/2 leads to the adaptive activation of the PI3K-AKT pathway [209], and consequently whether multiple targeting of this network is required to effectively interfere with both branches of adaptive signalling and to elicit a durable therapeutic response.…”

Section: Modulation Of the Upstream And Downstream Src Signalling Commentioning

confidence: 99%

“…For example, inhibition of mTORC1 drives activation of PI3K-, AKT-or ERK pathways [205], which in turn limits the efficacy of mTORC-inhibitors as targeted therapies [206]. More recently developed dual ATP-competitive agents that target mTORC1/mTORC2 have shown favourable results [207,208] with AZD2014 effectively inhibiting PDAC cell division (G1 arrest), proliferation, and invasion in vitro [158,160] and prolonging survival in the KPC mouse model of PDAC [109,208,209]. However there is still some debate as to whether blocking mTORC1/2 leads to the adaptive activation of the PI3K-AKT pathway [209], and consequently whether multiple targeting of this network is required to effectively interfere with both branches of adaptive signalling and to elicit a durable therapeutic response.…”

Section: Modulation Of the Upstream And Downstream Src Signalling Commentioning

confidence: 99%

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Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

et al. 2019

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Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine‐guided approach.

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“…increased AKT with downregulation of miR-149-3p. With activation of AKT1 and its downstream of mammalian target of rapamycin, mTOR pathway enhancement is implicated in pancreatic cancer formation [28,29]. PI3K signaling affects KRAS activity in PDAC [30,31] and PI3K/AKT/mTOR has recently been targeted in therapeutic treatment of PDAC [32].…”

Section: In Targetscan Analysis Negative Correlations Were Observed mentioning

confidence: 99%

Cancer Simulation from Stage Minus One by Quantum microRNA Language: Lung, Colorectal and Pancreatic Cancers

Fujii¹

2019

Med One

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Background: The second, third, and fourth cases of lethal cause upon cancer are lung cancer, colorectal cancer, and pancreatic cancer, respectively. This trend is not limited to some countries, but is a global problem. To further decrease cancer-related death, early prediction, diagnosis and prognosis of cancer by noninvasive liquid biopsy is an urgent issue for us. It is related with saving lives at a low medical cost and cutting-edged ideas of a neo-medical tool for risk hedge. One of the biomarkers is circulating microRNA (miRNA). miRNA can control gene expression of protein and it is a common factor of tumorigenesis and tumor suppression. Although it has recently been cleared that miRNA panel as a biomarker could be measured and evaluated as an indicator of human diseases, it is remained unclear whether the miRNA biomarker could be evaluated as biological and pathogenic processes, or pharmacologic responses to a therapeutic intervention or not. Methods: To elucidate the implication between miRNA biomarkers and pathogenic processes, time-dependent processes of tumorigenesis in pancreatic, colorectal and lung cancers were investigated through network analysis from minus one stage (or stage zero) of cancer to various cancer stages by algorithm of miRNA entangling target sorting (METS) in silico simulation using quantum miRNA language. Results: We found three different miRNA memory package (MMP) hubs for pathogenic processes among three cancer cases. Conclusions: These computer simulation data suggested that quantum miRNA language would be essential for clinical miRNA biomarker panel to understand its biological, pathological and pharmaceutical characters in cancer.

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MTOR inhibitor-based combination therapies for pancreatic cancer

Abstract: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.

Cited by 37 publications

References 58 publications

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

Cancer Simulation from Stage Minus One by Quantum microRNA Language: Lung, Colorectal and Pancreatic Cancers

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