A phase I-II study of everolimus (RAD001) in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)

Dumez, Herlinde; Reichard, Peter S.; Blay, Jean‐Yves; Schöffski, Patrick; Morgan, Jon; Ray-Coquard, I. L.; Hollaender, Norbert; Jappe, Annette; Demetri, G. D.

doi:10.1200/jco.2008.26.15_suppl.10519

Cited by 12 publications

(10 citation statements)

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“…Temsirolimus has failed to demonstrate meaningful activity as monotherapy in these tumors, as evidenced by a phase II trial in which PFS was only 2 months [83]. Everolimus, on the contrary, may have synergistic activity with imatinib mesylate in gastrointestinal stromal tumors (GIST) [84]. Phase I/II data of this combination in patients who progressed with imatinib mesylate alone showed a modest improvement in PFS [84].…”

Section: Sarcomasmentioning

confidence: 99%

Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies

Khokhar

Altman

Platanias

2011

Current Opinion in Oncology

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The rapalogs are the first mTOR inhibitors to show promising, yet modest, antitumor effects. To fully exploit the potential of targeting this pathway, it will be important to better understand the mechanisms of action and precise targets of the various inhibitors. Moreover, definition of biomarkers of susceptibility and identification of predictors and/or correlates to drug resistance will substantially advance this area.

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Section: Sarcomasmentioning

confidence: 99%

Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies

Khokhar

Altman

Platanias

2011

Current Opinion in Oncology

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“…The updated results also suggested that GIST patients may benefit from combined treatment in case of first-and second-line treatment failure. However, randomized studies are needed to demonstrate the benefit associated with the combined therapy [74].…”

Section: Everolimusmentioning

confidence: 99%

The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas

Vemulapalli¹,

Mita²,

Alvarado³

et al. 2011

Targ Oncol

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The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma.

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“…Fifty patients were treated and clinical activity was observed even in patients who have progressed on a bevacizumab-based regimen, with a disease control rate of 46%, suggesting that the combination therapy may overcome resistance to bevacizumab [159]. Trials combining different doses of everolimus with gemcitabine, capecitabine, and imatinib, in patients with advanced gastrointestinal malignancies are ongoing [160][161][162].…”

Section: Colorectal Cancermentioning

confidence: 99%

Clinical activity of mammalian target of rapamycin inhibitors in solid tumors

et al. 2011

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The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is vital for cell metabolism, growth, and proliferation. mTOR is frequently upregulated in many tumor types and hence has become an important target in cancer treatment. Sirolimus and its derivatives (rapalogs) interact with the intracellular receptor FK506 binding protein 12 (FKBP12), forming a complex with high affinity for mTOR and thus disrupting its activity. Rapalogs are being evaluated extensively in cancer patients with different formulations and schedules. Significant clinical activity has led to their approval for the treatment of kidney cancer, mantle cell lymphoma, and subependymal giant cell astrocytoma; however, despite increasing knowledge about cancer cell biology, their activity in other malignancies is unclear. Further research is needed to identify optimal dosage, administration and targeted combination as well as the subset of patients likely to respond to mTOR/PI3K inhibition. This review focuses on a discussion of the pathway, its implications in cancer biology and results of clinical trials of rapalogs alone or in combination, organizing them by common malignancy type.

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A phase I-II study of everolimus (RAD001) in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)

Cited by 12 publications

References 0 publications

Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies

Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies

The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas

Clinical activity of mammalian target of rapamycin inhibitors in solid tumors

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