An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in<i>Pten</i><sup>+/−</sup>mice

Podsypanina, Katrina; Lee, Richard T.; Politis, Christopher; Hennessy, Ian; Crane, Allison; Puc, Janusz; Neshat, Mehran S.; Wang, Hong; Yang, Lin; Gibbons, Jacqueline A.; Frost, Phil; Dreisbach, Valley; Blenis, John; Gaciong, Zbigniew; Fisher, Peter; Sawyers, Charles L.; Hedrick-Ellenson, Lora; Parsons, Ramon

doi:10.1073/pnas.171060098

Cited by 561 publications

(379 citation statements)

References 45 publications

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“…A potential complication in the use of rapamycin in anti-cancer therapies is that in many cases, the effect of rapamycin is cytostatic and does not kill cancer cells (Neshat et al, 2001;Podsypanina et al, 2001;Law et al, 2002). We reported previously that under conditions of serum withdrawal, rapamycin induces apoptosis in MDA-MB-231 breast cancer cells (Chen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Although there have been some successes, clinical trials with rapamycin and rapamycin derivatives such as CCI-779 and RAD-001 have been largely disappointing (Sawyers, 2003;Guertin and Sabatini, 2005). One of the problems with the use of rapamycin as an anti-cancer drug is that in most cases, rapamycin is cytostatic rather than cytotoxic and induces G 1 cell cycle arrest, rather than apoptosis (Neshat et al, 2001;Podsypanina et al, 2001;Law et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Defective TGF-β signaling sensitizes human cancer cells to rapamycin

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

et al. 2007

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“…6,43,125 Rapamycin, an inhibitor of mTOR kinase, and its analogs CCI-779 and RAD001 have been shown to have significant in vitro and in vivo antiproliferative activity against a broad range of human cancers. [126][127][128][129] Several rapamycin analogs have already been approved for use in transplant patients as immunosuppressants. 130 RAD001 and CCI-779 are currently in phase I and II trials, respectively, as anticancer agents.…”

Section: Molecular Biomarkers Based On Akt Activitiesmentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

112

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The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

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“…Preclinical models have suggested enhanced antitumoural activity of mTOR inhibition in PTEN-deficient tumours (Neshat et al, 2001;Podsypanina et al, 2001) and translational studies have revealed that activation of the PI3K/AKT/mTOR pathway is associated with reduced survival of glioma patients (Chakravarti et al, 2004). Consequently, this signalling pathway has been subjected to a number of single-or multi-targeted therapies including the mTOR inhibitor rapamycin or its derivatives, the 'rapalogs' everolimus (RAD001), deforolimus (AP23573), and temsirolimus (CCI-779) (Faivre et al, 2006).…”

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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An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity inPten^+/−mice

Cited by 561 publications

References 45 publications

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

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An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity inPten+/−mice

Cited by 561 publications

References 45 publications

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

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Product

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An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity inPten^+/−mice