Elsevier

Seminars in Oncology

Volume 36, Supplement 3, December 2009, Pages S46-S58
Seminars in Oncology

Evaluating Temsirolimus Activity in Multiple Tumors: A Review of Clinical Trials

https://doi.org/10.1053/j.seminoncol.2009.10.010Get rights and content

Activation of mammalian target of rapamycin (mTOR) signaling occurs in a wide variety of human tumors and can lead to increased susceptibility to mTOR inhibitors. Temsirolimus, a novel analog of rapamycin, has shown promising preclinical and early clinical anti-tumor activity in various solid and hematologic tumor types, either alone or in combination with chemotherapy or other targeted agents. Randomized phase III trials have already demonstrated significant clinical benefits of treatment with single-agent temsirolimus in advanced renal cell carcinoma and relapsed and/or refractory mantle cell lymphoma. Other malignancies studied in the phase I and II trial settings include glioblastoma, breast cancer, endometrial cancer, non-Hodgkin lymphomas, and multiple myeloma. This article reviews a comprehensive collection of the clinical trial results reported to date for temsirolimus in various solid and hematologic malignancies, as well as current strategies being tested in ongoing trials. The findings with temsirolimus in multiple tumors provide a valuable framework for future development of temsirolimus and other mTOR inhibitors.

Section snippets

Temsirolimus Activity in Preclinical Tumor Models

mTOR activity is enhanced by genetic alterations and aberrant activity of oncogenes, tumor-suppressor genes, and growth factors that are characteristic of a number of solid and hematologic malignancies (eg, PI3K/Akt pathway activation, PTEN inactivation, cyclin D1 overexpression, and c-myc).1, 2, 3, 4 Numerous preclinical studies have shown anti-tumor activity of temsirolimus in a variety of human solid tumor types. These include RCC,5, 6 breast cancer,7, 8, 9 lung cancer,10, 11, 12, 13

Renal Cell Carcinoma

The results of phase II and III trials of temsirolimus for patients with advanced RCC, which led to its approval for this indication, are reviewed in detail in this supplement by Hudes et al. Briefly, a phase II study characterized safety, pharmacokinetics, and anti-tumor activity of temsirolimus at three flat doses (25 mg, 75 mg, or 250 mg weekly) in patients with cytokine-refractory advanced RCC.40 The objective response rate was 7% (one complete response, seven partial responses) and minor

Mantle Cell Lymphoma

MCL is a subset of non-Hodgkin lymphoma that is characterized by a chromosomal translocation, t(11;14)(q13;q32). This translocation results in overexpression of cyclin D, which is regulated at the translational level by mTOR, suggesting the potential for mTOR inhibition as a novel treatment approach.82 Temsirolimus was shown to have significant anti-tumor activity in relapsed or refractory MCL in two phase II studies83, 84 and in a subsequent phase III randomized study,85 which are reviewed in

Conclusions

mTOR is now well recognized as a therapeutic target for many solid and hematologic malignancies. As the first mTOR inhibitor approved for an oncology indication, temsirolimus has demonstrated significant overall survival and progression-free survival benefits in patients with advanced RCC. More recently, temsirolimus treatment led to improved progression-free survival compared with investigator's choice of therapy in patients with relapsed and/or refractory MCL. Temsirolimus monotherapy

References (91)

  • Y. Shi et al.

    Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6

    J Biol Chem

    (2002)
  • S.S. Farag et al.

    Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma

    Leuk Res

    (2009)
  • M.A. Bjornsti et al.

    The TOR pathway: a target for cancer therapy

    Nat Rev Cancer

    (2004)
  • J.E. Dancey

    Therapeutic targets: mTOR and related pathways

    Cancer Biol Ther

    (2006)
  • R.A. Figlin

    Mechanisms of disease: survival benefit of temsirolimus validates a role for mTOR in the biology of advanced renal cell carcinoma

    Nat Clin Pract Oncol

    (2008)
  • F. Meric-Bernstam et al.

    Targeting the mTOR signaling network for cancer therapy

    J Clin Oncol

    (2009)
  • G.V. Thomas et al.

    Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

    Nat Med

    (2006)
  • J.J. Gibbons

    CCI-779 potentiates the inhibitory effect of the anti-angiogenesis drug interferon-alpha on the growth of a human renal cell carcinoma in nude miceRPT-49843

    (2006)
  • J.J. Gibbons et al.

    The effect of CCI-779, a novel macrolide anti-tumor agent, on the growth of human tumor cells in vitro and in nude mouse xenografts in vivo [abstract 2000]

    Proc Am Assoc Cancer Res

    (2000)
  • D. Del Bufalo et al.

    Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus

    Cancer Res

    (2006)
  • K. Yu et al.

    mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer

    Endocr Relat Cancer

    (2001)
  • M. Wislez et al.

    Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras

    Cancer Res

    (2005)
  • C. Wu et al.

    Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

    Mol Cancer

    (2005)
  • B.R. Bastos et al.

    Overcoming cisplatin resistance with mTOR inhibition in small cell lung cancer: a phase I-II trial design [abstract 14673]

    J Clin Oncol, 2008 ASCO Annual Meeting Proceedings Part I

    (2008)
  • M. Wangpaichitr et al.

    Biochemical determinants for mTOR inhibitor sensitivity in lung cancer cell lines [abstract 2968]

    Proceedings of the 99th Annual Meeting of the American Association of Cancer Research

    (2008)
  • D. Ito et al.

    In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer

    Int J Cancer

    (2006)
  • L. Dudkin et al.

    Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition

    Clin Cancer Res

    (2001)
  • B. Geoerger et al.

    Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy

    Cancer Res

    (2001)
  • L. Wu et al.

    Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts

    Cancer Res

    (2005)
  • C. Thallinger et al.

    CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotransplantation model

    Pharmacology

    (2007)
  • C.F. Hui et al.

    Rapamycin and CCI-779 suppress the growth of hepatocellular carcinoma cells [abstract 4071]

    Proceedings of the 99th Annual Meeting of the American Association of Cancer Research

    (2007)
  • J. Rodon et al.

    Antitumor effects of sorafenib, bevacizumab and cetuximab as single agents or in combination with an MEK, mTOR or bcl-2 inhibitor, in a SNU-398 human hepatocellular tumor xenograft model [abstract 1332]

    Proceedings of the 99th Annual Meeting of the American Association of Cancer Research

    (2008)
  • T. Nishikawa et al.

    Antiproliferative effects of a novel mTOR inhibitor (temsirolimus) in esophageal cancer cells [abstract 1493]

    Proceedings of the 99th Annual Meeting of the American Association of Cancer Research

    (2008)
  • C.A. Nathan et al.

    Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer

    Cancer Res

    (2007)
  • A. Jimeno et al.

    Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy

    Br J Cancer

    (2007)
  • O. Ekshyyn et al.

    CCI-779 a promising radiosensitizer for head and neck squamous cell carcinoma when compared to cisplatin [abstract 420]

    Proceedings of the 99th Annual Meeting of the American Association of Cancer Research

    (2008)
  • Y. Shi et al.

    Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779

    Cancer Res

    (2002)
  • H. Yan et al.

    Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis

    Cancer Res

    (2006)
  • L.K. Francis et al.

    Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma

    Clin Cancer Res

    (2006)
  • B. Shor et al.

    A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis

    Cancer Res

    (2008)
  • M.S. Neshat et al.

    Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR

    Proc Natl Acad Sci U S A

    (2001)
  • K. Podsypanina et al.

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

    Proc Natl Acad Sci U S A

    (2001)
  • A.J. Pantuck et al.

    Prognostic relevance of the mTOR pathway in renal cell carcinoma

    Cancer

    (2007)
  • E. Raymond et al.

    Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer

    J Clin Oncol

    (2004)
  • M. Hidalgo et al.

    A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously for 5 days every 2 weeks to patients with advanced cancer

    Clin Cancer Res

    (2006)
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    STATEMENT OF CONFLICT OF INTEREST: Dr Dancey is a Consultant and has received past honoraria from Wyeth*; at the time this supplement was prepared, Drs Curiel and Purvis were employees of Wyeth Research.* (*Wyeth was acquired by Pfizer Inc in October 2009.)

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