Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer

I. Garrido-Laguna, A. C. Tan, M. Uson, M. Angenendt, Wen Wee Ma, M. C. Villaroel, M. Zhao, N. V. Rajeshkumar, A. Jimeno, R. Donehower, C. Iacobuzio-Donahue, Michael Barrett, M. A. Rudek, B. Rubio-Viqueira, D. Laheru, M. Hidalgo

Research output: Contribution to journalArticle

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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. 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). 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. 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.

Original languageEnglish (US)
Pages (from-to)649-655
Number of pages7
JournalBritish Journal of Cancer
Volume103
Issue number5
DOIs
StatePublished - Aug 2010
Externally publishedYes

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Sirolimus
Pancreatic Neoplasms
Heterografts
70-kDa Ribosomal Protein S6 Kinases
Neoplasms
gemcitabine
Blood Cells
Survival Rate
Pharmacokinetics
Comparative Genomic Hybridization
Gene Dosage
Phosphatidylinositol 3-Kinases
Pharmaceutical Preparations
Biomarkers
Immunohistochemistry
Gene Expression
Therapeutics
Growth
Genes

Keywords

  • mTOR
  • p70S6K
  • pancreatic cancer
  • sirolimus
  • temsirolimus

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Garrido-Laguna, I., Tan, A. C., Uson, M., Angenendt, M., Ma, W. W., Villaroel, M. C., ... Hidalgo, M. (2010). Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer. British Journal of Cancer, 103(5), 649-655. https://doi.org/10.1038/sj.bjc.6605819

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

In: British Journal of Cancer, Vol. 103, No. 5, 08.2010, p. 649-655.

Research output: Contribution to journalArticle

Garrido-Laguna, I, Tan, AC, Uson, M, Angenendt, M, Ma, WW, Villaroel, MC, Zhao, M, Rajeshkumar, NV, Jimeno, A, Donehower, R, Iacobuzio-Donahue, C, Barrett, M, Rudek, MA, Rubio-Viqueira, B, Laheru, D & Hidalgo, M 2010, 'Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer', British Journal of Cancer, vol. 103, no. 5, pp. 649-655. https://doi.org/10.1038/sj.bjc.6605819
Garrido-Laguna, I. ; Tan, A. C. ; Uson, M. ; Angenendt, M. ; Ma, Wen Wee ; Villaroel, M. C. ; Zhao, M. ; Rajeshkumar, N. V. ; Jimeno, A. ; Donehower, R. ; Iacobuzio-Donahue, C. ; Barrett, Michael ; Rudek, M. A. ; Rubio-Viqueira, B. ; Laheru, D. ; Hidalgo, M. / Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer. In: British Journal of Cancer. 2010 ; Vol. 103, No. 5. pp. 649-655.
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AU - Villaroel, M. C.

AU - Zhao, M.

AU - Rajeshkumar, N. V.

AU - Jimeno, A.

AU - Donehower, R.

AU - Iacobuzio-Donahue, C.

AU - Barrett, Michael

AU - Rudek, M. A.

AU - Rubio-Viqueira, B.

AU - Laheru, D.

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N2 - 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. 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). 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. 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.

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