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. 2010 Aug 24;103(5):649-55.
doi: 10.1038/sj.bjc.6605819. Epub 2010 Jul 27.

Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer

I Garrido-Laguna  1 , A C Tan, M Uson, M Angenendt, W W Ma, M C Villaroel, M Zhao, N V Rajeshkumar, A Jimeno, R Donehower, C Iacobuzio-Donahue, M Barrett, M A Rudek, B Rubio-Viqueira, D Laheru, M Hidalgo
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Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer

I Garrido-Laguna et al. Br J Cancer. .

Abstract

Background: The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic. VSports手机版.

Methods: Temsirolimus (20 mg Kg(-1) daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs). V体育安卓版.

Results: In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies V体育ios版. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects. .

Conclusion: Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker VSports最新版本. .

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Figures (V体育2025版)

Figure 1
Figure 1
Tumour growth inhibition (T/C) in 17 direct pancreatic cancer xenografts treated with temsirolimus. Four xenografts showed tumour regression (negative T/Cs). Bars represent standard deviation.
Figure 2
Figure 2
(A) Sensitive xenografts had focal gains in RAS, or homozygous deletions in PTEN or FHIT, potentially leading to pathway activation. Red colour represents gene copy number gains. Green colour represents gene copy number losses. (B) Tumour regression after treatment with temsirolimus in direct pancreatic cancer xenografts was correlated with baseline phospho-p70S6K. Green dots represent xenografts that experienced tumour regression after temsirolimus treatment. Red dots represent xenografts that experienced tumour growth.
Figure 3
Figure 3
Treatment-related toxicities (n=31).
Figure 4
Figure 4
Activity of p70S6K at 6 h after first dose of sirolimus predicts stable disease on PET-CT evaluation. Patients with stable disease as shown by PET-CT on restaging at 8 weeks had greater inhibition of phospho-p70S6K in PBMC at 6 h than those with disease progression (P=0.01).
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VSports手机版 - References

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