Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study

Lau, David K.; Tay, Rebecca; Yeung, Yvonne; Chionh, Fiona; Mooi, Jennifer; Murone, Carmel; Skrinos, Effie; Price, Timothy; Mariadason, John M.; Tebbutt, Niall C.

doi:10.1038/s41416-018-0021-1

Cited by 39 publications

(37 citation statements)

References 29 publications

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“…A phase I study reported that Everolimus achieved 50% disease-control-rate in a subgroup of 22 advanced CCA patients ( [104], Table 2). Subsequently a phase II study, in which patients with advanced CCA were enrolled, used Everolimus as a treatment option reporting an OS of 9.5 months [105]. At the same time in a phase II Italian study with Everolimus 39 patients with advanced and pre-treated CCA had progression-free survival (PFS) of 3.2 months, and OS of 7.7 months [106] while an Australian phase II study with Everolimus, conducted on patients with advanced CCA, showed objective response rate of 12 % and PFS of 6.0 months.…”

Section: Pi3k-akt-mtor Signaling Pathwaymentioning

confidence: 99%

“…At the same time in a phase II Italian study with Everolimus 39 patients with advanced and pre-treated CCA had progression-free survival (PFS) of 3.2 months, and OS of 7.7 months [106] while an Australian phase II study with Everolimus, conducted on patients with advanced CCA, showed objective response rate of 12 % and PFS of 6.0 months. Recently in 27 unselected patients, Everolimus displayed clinical activity as first-line monotherapy in advanced CCA with PFS of 5.5 months and OS of 9.5 months [105]. In another phase II study that aimed to evaluate the activity of Everolimus in 10 patients with PIK3CA amplification/mutation or PTEN loss refractory solid cancer, only one patient with CCA with PTEN loss experienced disease control ( [107], Table 2).…”

Section: Pi3k-akt-mtor Signaling Pathwaymentioning

confidence: 99%

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Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Pastore

Lori

Gentilini

et al. 2020

Cells

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Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.

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Section: Pi3k-akt-mtor Signaling Pathwaymentioning

confidence: 99%

Section: Pi3k-akt-mtor Signaling Pathwaymentioning

confidence: 99%

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Pastore

Lori

Gentilini

et al. 2020

Cells

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“…6,16 In line with this, there are already clinical trials using Everolimus for cancer therapies. 17 In the present work, we however, report that the potent anti- reported to activate the Rac pathway, which culminates in morphological and migratory responses of the endothelium. 10,18,19 These findings are somehow reminiscent of our recent data in brain tumors highlighting the propagation of adhesion and migration cues via extracellular vesicles.…”

Section: Discussionmentioning

confidence: 55%

Inhibition of mTOR in head and neck cancer cells alters endothelial cell morphology in a paracrine fashion

Duarte

André-Grégoire

Trillet

et al. 2018

Molecular Carcinogenesis

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Head and neck squamous cell carcinoma (HNSCC) represent aggressive classes of tumors with a high mortality rate. The mammalian target of rapamycin (mTOR) pathway is instrumental in their initiation and expansion. Although results from pre-clinical models promise mTOR targeting as a potent novel therapeutic approach, its impact on the tumor microenvironment, such as endothelial cells is only scarcely investigated. Here, we first confirmed the effects of mTOR pharmacological inhibition on cell viability, clonogenicity, and proliferation in HNSCC human cell lines, HN26, and HN30. While Everolimus and Torin1 potently blunted mTOR-based proliferation of HN26 and HN30 lines, endothelial cells were left intact. To further explore the possibility of a paracrine bystander action of HNSCC-treated cells on endothelial cells, conditioned medium from Everolimus- and Torin1-challenged HN26 and HN30 cells were collected and applied to naive human endothelial cells. Although endothelial cell viability was again not modified, morphology and mobility were changed. Indeed, spreading of endothelial cells was altered upon challenge with mTOR-pretreated tumor conditioned-media, as measured via cell impedance and imagery. Interestingly, this was associated with an augmentation of focal adhesion kinase (FAK) active phosphorylation and enhanced migratory behavior. From a molecular standpoint, the production of vascular endothelial growth factor was elevated in treated HNSCC cells and might contribute to FAK phosphorylation. Although mTOR inhibition in tumor cells did hinder their growth, it also favors the release of factors that subsequently enable endothelial cell migration. Further studies will address how this paracrine action may affect tumor-driven angiogenesis upon pharmacological treatments.

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“…RADIANT-4 (NCT01524783) [62,63] Tuberous sclerosis complex NCT00457808 [47] ; NCT00490789 [48,49] ; NCT00411619 [50] ; NCT00126672 [51] ; EXIST-1 (NCT00789828) [52] ; [53] Potential clinical benefit Biliary tract cancer RADiChol study (NCT00973713) [64] ; EUDRACT 2008-007152-94 [125] Thyroid cancer (in patients refractory to other agents) NCT01263951 [126] ; NCT00936858 [127] No clinical benefit seen Gastric cancer GRANITE-1, NCT00879333 [ mTORC1 activity also cross-talks with, as well as negatively regulates, the catabolic process of autophagy. While rapamycin treatment is often less effective at re-activating autophagy in mammalian cells than in yeast [80] , mTORC1 inhibition could permit some reactivation of autophagy in cancer cells, thus allowing them to recycle macromolecules more effectively, maintain homeostasis and survive.…”

Section: Cancer/disease Type Study and Reference Food And Drug Adminimentioning

confidence: 99%

Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics

Bhaoighill¹,

Dunlop²

2019

CDR

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Delineating the contributions of specific cell signalling cascades to the development and maintenance of tumours has greatly informed our understanding of tumorigenesis and has advanced the modern era of targeted cancer therapy. It has been revealed that one of the key pathways regulating cell growth, the phosphatidylinositol 3-kinase/ mechanistic target of rapamycin (PI3K/mTOR) signalling axis, is commonly dysregulated in cancer. With a specific, well-tolerated inhibitor of mTOR available, the impact of inhibiting this pathway at the level of mTOR has been tested clinically. This review highlights some of the promising results seen with mTOR inhibitors in the clinic and assesses some of the challenges that remain in predicting patient outcome following mTOR-targeted therapy.

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Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study

Abstract: In unselected patients, everolimus demonstrated clinical activity as first-line monotherapy in advanced BTC.

Cited by 39 publications

References 29 publications

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Inhibition of mTOR in head and neck cancer cells alters endothelial cell morphology in a paracrine fashion

Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics

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