Phase III Study to Evaluate Temsirolimus Compared With Investigator's Choice Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

Heß, Georg; Herbrecht, Raoul; Romaguera, Jorge; Verhoef, Gregor; Crump, Michael; Gisselbrecht, Christian; Laurell, Anna; Offner, Fritz; Strahs, Andrew; Berkenblit, Anna; Hanushevsky, Orysia; Clancy, Jill S.; Hewes, Becker; Moore, Laurence; Coiffier, Bertrand

doi:10.1200/jco.2008.20.7977

Cited by 595 publications

(457 citation statements)

References 33 publications

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“…Recent studies show that most cases of MCL exhibit constitutive activation of PI3K/Akt/mTOR pathways, which promotes tumour proliferation and survival. In agreement with this, relapsed or refractory MCL patients in a Phase III clinical study have shown a better response to treatment with the specific mTOR inhibitor temsirolimus than the investigator's choice therapy [60]. These data warrant the use of mTOR inhibitors in HIV-associated MCL.…”

Section: Lymphomassupporting

confidence: 54%

mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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Section: Lymphomassupporting

confidence: 54%

mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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“…CCI-779 (Torisel ® ) has been approved for advanced renal cell carcinoma (Motzer et al, 2007) and relapsed or refractory mantle cell lymphoma (Hess et al, 2009). Cytostatic effects of CCI-779 on tumour cells (Geoerger et al, 2001;Dudkin et al, 2001) could complement the genotoxic activity of radiation therapy in upfront treatment of glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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“…Inhibitiors of mTOR (rapamycin, temsirolimus, everolimus) may increase apoptosis and decrease proliferation rate by causing G1 arrest in the cell cycle 126 . Single agent temsirolimus has been shown to have clinical activity in phase II trials, and a randomized phase III trial [127][128][129] . Alternative mTOR inhibitor everolimus is currently in phase II trials 130,131 .…”

Section: Emerging New Drugs To Improve Results In the Near Futurementioning

confidence: 99%