Targeted Oncology

, Volume 4, Issue 2, pp 135–142

The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents

  • Kamalesh Sankhala
  • Alain Mita
  • Kevin Kelly
  • Devalingam Mahalingam
  • Francis Giles
  • Monica Mita
Review

Abstract

Mammalian target of rapamycin (mTOR) has emerged as an important target for cancer therapy. Rapamycin has a distinct, well-documented toxicity profile and most of the toxicity data has been reported in patients with organ transplantation. Newer mTOR inhibitors have slightly different pharmacokinetic properties, yet they present toxicity profiles similar to rapamycin. Most of these toxicities are mild to moderate in severity and can be managed clinically by dose modification and supportive measures. Mucositis and pneumonitis are the most commonly reported toxicities, but they rarely lead to treatment discontinuation. Pathogenesis of pneumonitis is uncertain, but various hypotheses have been suggested, including cell-mediated immune response to the drug.

Keywords

mTOR inhibitors Toxicity Pulmonary toxicity Hyperlipidemia Mucositis Newer mTOR inhibitors Rapamycin 

References

  1. 1.
    Hennessy BT et al (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4(12):988–1004CrossRefPubMedGoogle Scholar
  2. 2.
    Scaltriti M, Baselga J (2006) The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12(18):5268–5272CrossRefPubMedGoogle Scholar
  3. 3.
    Yu H, Rohan T (2000) Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92(18):1472–1489CrossRefPubMedGoogle Scholar
  4. 4.
    MacDonald AS (2001) A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 71(2):271–280CrossRefPubMedGoogle Scholar
  5. 5.
    Huang S, Houghton PJ (2002) Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 3(2):295–304PubMedGoogle Scholar
  6. 6.
    Hudes G et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281CrossRefPubMedGoogle Scholar
  7. 7.
    Raymond E et al (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22(12):2336–2347CrossRefPubMedGoogle Scholar
  8. 8.
    Mita MM et al (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26(3):361–367CrossRefPubMedGoogle Scholar
  9. 9.
    O'Donnell A et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26(10):1588–1595CrossRefPubMedGoogle Scholar
  10. 10.
    Morelon E et al (2001) Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 72(5):787–790CrossRefPubMedGoogle Scholar
  11. 11.
    Lennon A et al (2001) Interstitial pneumonitis associated with sirolimus (rapamycin) therapy after liver transplantation. Transplantation 72(6):1166–1167CrossRefPubMedGoogle Scholar
  12. 12.
    Atkins MB, Stadler W et al (2002) A randomized double blind phase 2 study of intravenous CCI-779 administered weekly to patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 21:36 AbstractGoogle Scholar
  13. 13.
    Atkins MB et al (2006) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22(5):909–918CrossRefGoogle Scholar
  14. 14.
    Duran I et al (2004) Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 42(12):1875–1880CrossRefGoogle Scholar
  15. 15.
    Pham PT et al (2004) Sirolimus-associated pulmonary toxicity. Transplantation 77(8):1215–1220CrossRefPubMedGoogle Scholar
  16. 16.
    Motzer RJ et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. The Lancet 372(9637):449–456CrossRefGoogle Scholar
  17. 17.
    Brattstrom C et al (1998) Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation 65(9):1272–1274CrossRefPubMedGoogle Scholar
  18. 18.
    Kraemer FB et al (1998) Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways. Metabolism 47(5):555–559CrossRefPubMedGoogle Scholar
  19. 19.
    Massy ZA et al (2000) Hyperlipidaemia and post-heparin lipase activities in renal transplant recipients treated with sirolimus or cyclosporin A. Nephrol Dial Transplant 15(6):928CrossRefPubMedGoogle Scholar
  20. 20.
    Hoogeveen RC et al (2001) Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Transplantation 72(7):1244–250CrossRefPubMedGoogle Scholar
  21. 21.
    Kahan BD (2000) Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 356(9225):194–202CrossRefPubMedGoogle Scholar
  22. 22.
    Hidalgo M et al (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12(19):5755–5763CrossRefPubMedGoogle Scholar
  23. 23.
    23. Yee KW et al Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12(17):5165–5173Google Scholar
  24. 24.
    Fraenkel M et al (2008) mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57(4):945–957CrossRefPubMedGoogle Scholar
  25. 25.
    Tremblay F, Marette A (2001) Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 276(41):38052–38060PubMedGoogle Scholar
  26. 26.
    Galanis E et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 23(23):5294–5304CrossRefPubMedGoogle Scholar
  27. 27.
    Bellmunt J et al (2008) Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 19(8):1387–1392CrossRefPubMedGoogle Scholar
  28. 28.
    Hong JC, Kahan BD (2000) Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 69(10):2085–2090CrossRefPubMedGoogle Scholar
  29. 29.
    Mita MM, Poplin E, Tap WD, Carmona A, Yonemoto L, Wages DS, Bedrosian CL, Rubin EH, Tolcher AW (2008) Deforolimus trial 106- A Phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669). J Clin Oncol 26:3509 abstractCrossRefGoogle Scholar
  30. 30.
    Kneteman N, Babini R et al (2000) Sirolimus immunosuppression for liver transplantation in the presence of malignancy. XVIII International Congress of the Transplantation Society: AbstractGoogle Scholar
  31. 31.
    Stallone G et al (2005) Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 352(13):1317–1323CrossRefPubMedGoogle Scholar
  32. 32.
    Stallone G et al (2008) Kaposi's sarcoma and mTOR: a crossroad between viral infection neoangiogenesis and immunosuppression. Transpl Int 21(9):825–832CrossRefPubMedGoogle Scholar
  33. 33.
    Kahan BD, Camardo JS (2001) Rapamycin: clinical results and future opportunities. Transplantation 72(7):1181–1193CrossRefPubMedGoogle Scholar
  34. 34.
    Groth CG et al (1999) Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European renal transplant study group. Transplantation 67(7):1036–1042CrossRefPubMedGoogle Scholar
  35. 35.
    Kreis H et al (2000) Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 69(7):1252–1260CrossRefPubMedGoogle Scholar
  36. 36.
    Morales JM, Wramner H, Kreis D et al (2000) Sirolimus vs cyclosporin: a comparision of renal function over two years. XVIII International Congress of the Transplantation Society 140:0428 AbstractGoogle Scholar
  37. 37.
    Chan S et al (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23(23):5314–5322CrossRefPubMedGoogle Scholar
  38. 38.
    Witzig TE et al (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23(23):5347–5356CrossRefPubMedGoogle Scholar
  39. 39.
    Amato RJ et al (2006) A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). J Clin Oncol (Meeting Abstracts) 24((18_suppl)):4530Google Scholar
  40. 40.
    Chawla SP, Staddon AP, Schuetze SM, D'Amato GZ, Blay JY, Sankhala KK, Daly ST, Rivera VM, Demetri GD (2006) Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas. J Clin Oncol 24(18S):9505Google Scholar
  41. 41.
    Rizzieri DA et al (2008) A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 14(9):2756–2762CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Kamalesh Sankhala
    • 1
  • Alain Mita
    • 1
  • Kevin Kelly
    • 1
  • Devalingam Mahalingam
    • 1
  • Francis Giles
    • 1
  • Monica Mita
    • 1
  1. 1.Institute for Drug DevelopmentCancer Therapy and Research Center at the University of Texas Health Science CenterSan AntonioUSA

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