Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma

Witzig, Thomas E.; Geyer, Susan; Ghobrial, Irène M.; Inwards, David J.; Fonseca, Rafaël; Kurtin, Paul J.; Ansell, Stephen M.; Luyun, Ronnie F.; Flynn, Patrick J.; Morton, Roscoe F.; Dakhil, Shaker R.; Gross, Howard M.; Kaufmann, Scott H.

doi:10.1200/jco.2005.13.466

Cited by 471 publications

(338 citation statements)

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“…In a phase II clinical trial, the rapamycin derivative temsirolimus revealed significant clinical activity in patients with relapsed mantle cell lymphoma. 40 This drug was shown to hyper-induce autophagy and to elicit synergistic anti-tumour effect with vorinostat at low doses in mantle cell lymphoma cells; 41 (2) chloroquine is a well-known lysosomotropic anti-malarial drug that impairs intralysosomal proteolysis by alkalinizing the vacuolar pH. In myc-overexpressing transgenic mice that model human Burkitt's lymphoma, chloroquine administration prevented the development of myc-induced lymphomas by killing precancerous B lymphocytes through a p53-dependent and caspase-independent death pathway.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

Nicotra

Mercalli

Peracchio³

et al. 2010

Modern Pathology

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The expression of beclin-1, an oncosuppressor monoallelically deleted in 460% epithelial cancers, has been shown to be developmentally regulated in T and B lymphocytes. By interacting with either bcl-2 or class III phosphatidyl-inositol-3-phosphate kinase, beclin-1 regulates apoptosis and autophagy, two processes crucial for lymphatic tissue homeostasis. We analyzed the potential link between beclin-1-mediated autophagy and the malignant behaviour of lymphomas. The tissue expression of beclin-1 was analyzed in a large series of nonHodgkin lymphomas and correlated with patient's clinical outcome. By immunofluorescence, beclin-1 staining showed faintly detectable and diffusely distributed in the cytoplasm (regarded as negative) or confined to the perinuclear region as large and brilliant puncta suggestive of macro-aggregate reactivity (regarded as positive). The positive expression of beclin-1 well correlated with the presence of LC3-positive autophagic vacuoles and was inversely correlated with the expression of bcl-2. Non-Hodgkin lymphomas in which X20% of tumour cells expressed high level of beclin-1 aggregates were associated with a complete (57%) or partial (35%) remission. The 5-year overall survival probability, calculated by the Kaplan-Meier method, was 92% and 42% in beclin-1-expressing non-Hodgkin lymphomas with X20% and o20% positive cells, respectively (log-rank test, Po0.000.1). In Cox multivariate analysis, the level of beclin-1 expression, adjusted for patient's age and pathologic stage, revealed to be significantly correlated with patient's survival (Po0.0001). This is the first demonstration of the involvement of beclin-1 and autophagy in the clinical behaviour of non-Hodgkin lymphomas. The present data are compatible with the hypothesis that non-Hodgkin lymphomas with upregulated autophagy are more responsive to chemotherapy and indicate that beclin-1 could be a valuable independent prognostic factor in this heterogeneous group of tumours. Modern Pathology (2010) 23, 937-950;

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Section: Discussionmentioning

confidence: 99%

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

Nicotra

Mercalli

Peracchio³

et al. 2010

Modern Pathology

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“…Results have been reported from studies in metastatic breast (MBC), renal cell (RCC), 75 small cell lung, (SCLC), 76 endometrial carcinoma, 77 mantle cell lymphoma (MCL), 78 melanoma, 79 and glioblastoma multiforme (GBM). 80,81 The results of these studies are summarized in Table 2.…”

Section: Temsirolimus (Cci-779)mentioning

confidence: 99%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

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The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

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“…Concentrations leading to apoptosis and autophagy are observed only at high concentrations barely compatible with pharmacokinetic exposures that may be reached in the patients. To our knowledge, tumour types highly vulnerable to rapalogues include endometrial cancer (Kanamori et al, 2001;Uegaki et al, 2005;Oza et al, 2006;Colombo et al, 2007;Milam et al, 2007) that frequently displays PTEN loss of function and mantle cell lymphoma (Grewe et al, 1999;Witzig et al, 2005;Ansell et al, 2006) that overexpress cyclin D1. The effects of rapalogues in mantle cell carcinoma are consistent with preclinical studies showing that mTORC1 inhibitors could downregulate cyclin D1 (Aguirre et al, 2004).…”

Section: Differential Review Of Biological Effects Of Mtor Inhibitionmentioning

confidence: 99%

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

et al. 2008

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The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1a-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

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Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma

Cited by 471 publications

References 42 publications

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

Therapeutic targets: MTOR and related pathways

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

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