mTOR signaling and drug development in cancer (original) (raw)
Lane, H. A. & Breuleux, M. Optimal targeting of the mTORC1 kinase in human cancer. Curr. Opin. Cell Biol.21, 219–229 (2009). ArticleCASPubMed Google Scholar
Abraham, R. T. & Eng, C. H. Mammalian target of rapamycin as a therapeutic target in oncology. Expert Opin. Ther. Targets12, 209–222 (2008). ArticleCASPubMed Google Scholar
Marone, R., Cmiljanovic, V., Giese, B. & Wymann, M. P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta1784, 159–185 (2008). ArticleCASPubMed Google Scholar
Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell110, 177–189 (2002). ArticleCASPubMed Google Scholar
Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol.14, 1296–1302 (2004). ArticleCASPubMed Google Scholar
Copp, J., Manning, G. & Hunter, T. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res.69, 1821–1827 (2009). ArticleCASPubMedPubMed Central Google Scholar
Garcia, J. A. & Danielpour, D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol. Cancer Ther.7, 1347–1354 (2008). ArticleCASPubMedPubMed Central Google Scholar
Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol.14, 1650–1656 (2004). ArticleCASPubMed Google Scholar
Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest.118, 3065–3074 (2008). CASPubMedPubMed Central Google Scholar
O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res.66, 1500–1508 (2006). ArticleCASPubMedPubMed Central Google Scholar
Bjornsti, M. A. & Houghton, P. J. Lost in translation: dysregulation of cap-dependent translation and cancer. Cancer Cell5, 519–523 (2004). ArticleCASPubMed Google Scholar
Bjornsti, M. A. & Houghton, P. J. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer4, 335–348 (2004). ArticleCASPubMed Google Scholar
Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov.5, 671–688 (2006). ArticleCASPubMed Google Scholar
Grünwald, V. et al. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res.62, 6141–6145 (2002). PubMed Google Scholar
Aguirre, D. et al. Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis9, 797–805 (2004). ArticleCASPubMed Google Scholar
deGraffenried, L. A. et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin. Cancer Res.10, 8059–8067 (2004). ArticleCASPubMed Google Scholar
Dancey, J. in ASCO Educational Book 2000 68–75 (Lippincott Williams & Wilkins, Alexandria, Virginia, 2000). Google Scholar
Yu, K. et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res.69, 6232–6240 (2009). ArticleCASPubMed Google Scholar
Breuleux, M. et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol. Cancer Ther.8, 742–753 (2009). ArticleCASPubMedPubMed Central Google Scholar
Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med.8, 128–135 (2002). ArticleCASPubMed Google Scholar
Zhong, H., Hanrahan, C., van der Poel, H. & Simons, J. W. Hypoxia-inducible factor 1alpha and 1beta proteins share common signaling pathways in human prostate cancer cells. Biochem. Biophys. Res. Commun.284, 352–356 (2001). ArticleCAS Google Scholar
Zhong, H. et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res.60, 1541–1545 (2000). CASPubMed Google Scholar
Edinger, A. L., Linardic, C. M., Chiang, G. G., Thompson, C. B. & Abraham, R. T. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res.63, 8451–8460 (2003). CASPubMed Google Scholar
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell22, 159–168 (2006). ArticleCASPubMed Google Scholar
Cloughesy, T.F. et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med.5, e8 (2008). ArticlePubMedPubMed CentralCAS Google Scholar
Shor, B. 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.68, 2934–2943 (2008). ArticleCASPubMed Google Scholar
Foster, D. A. & Toschi, A. Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle8, 1026–1029 (2009). ArticleCASPubMed Google Scholar
O'Donnell, A. et al. 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, 1588–1595 (2008). ArticleCASPubMed Google Scholar
Tabernero, J. et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol.26, 1603–1610 (2008). ArticleCASPubMed Google Scholar
Fouladi, M. et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. J. Clin. Oncol.25, 4806–4812 (2007). ArticleCASPubMed Google Scholar
Hess, G. et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol.27, 3822–3829 (2009). ArticleCASPubMed Google Scholar
Ellard, S. et al. A randomized phase II study of two different schedules of RAD001C in patients with recurrent/metastatic breast cancer [abstract]. J. Clin. Oncol.25, a3513 (2007). Google Scholar
Raymond, E. 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.22, 2336–2347 (2004). ArticleCASPubMed Google Scholar
Geoerger, B. 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.61, 1527–1532 (2001). CASPubMed Google Scholar
Brattström, C. et al. Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers. Ther. Drug Monit.22, 537–544 (2000). ArticlePubMed Google Scholar
Filler, G., Bendrick-Peart, J. & Christians, U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther. Drug Monit.30, 138–142 (2008). ArticleCASPubMed Google Scholar
Kirchner, G. I., Meier-Wiedenbach, I. & Manns, M. P. Clinical pharmacokinetics of everolimus. Clin. Pharmacokinet.43, 83–95 (2004). ArticleCASPubMed Google Scholar
Neuhaus, P., Klupp, J. & Langrehr, J. M. mTOR inhibitors: an overview. Liver Transpl.7, 473–484 (2001). ArticleCASPubMed Google Scholar
Duran, I. et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur. J. Cancer42, 1875–1880 (2006). ArticleCASPubMed Google Scholar
Gibbons, J. J. 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]. Proc. Ame. Assoc. Cancer Res.40, a2000 (1999). Google Scholar
Clackson, T. et al. Broad anti-tumor activity of AP23573, an mTOR inhibitor in clinical development [abstract]. Proc. Am. Soc. Clin. Oncol.22, a882 (2003). Google Scholar
Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet372, 449–456 (2008). ArticleCASPubMed Google Scholar
Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med.356, 2271–2281 (2007). ArticleCASPubMed Google Scholar
Monaco, A. P. The role of mTOR inhibitors in the management of posttransplant malignancy. Transplantation87, 157–163 (2009). ArticleCASPubMed Google Scholar
Krymskaya, V. P. & Goncharova, E. A. PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects. Cell Cycle8, 403–413 (2009). ArticleCASPubMed Google Scholar
Sampson, J. R. Therapeutic targeting of mTOR in tuberous sclerosis. Biochem. Soc. Trans.37, 259–264 (2009). ArticleCASPubMed Google Scholar
Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med.358, 140–151 (2008). ArticleCASPubMedPubMed Central Google Scholar
Davies, D. M. et al. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N. Engl. J. Med.358, 200–203 (2008). ArticleCASPubMed Google Scholar
Marsh, D. J. et al. Rapamycin treatment for a child with germline PTEN mutation. Nat. Clin. Pract. Oncol.5, 357–361 (2008). ArticleCASPubMed Google Scholar
Del Bufalo, D. et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res.66, 5549–5554 (2006). ArticleCASPubMed Google Scholar
Dal Col, J. et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood111, 5142–5151 (2008). ArticleCASPubMed Google Scholar
Witzig, E. et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed non-hodgkin lymphoma (NHL) and Hodgkin Disease (HD) [abstract]. Haematologica94 (Suppl. 2), a1081 (2009). Google Scholar
Smith, S. M. et al. Activity of single agent temsirolimus (CCI-779) in non-mantle cell non-Hodgkin lymphoma subtypes [abstract]. J. Clin. Oncol.26, a8514 (2008). Article Google Scholar
Witzig, T. E. et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol.23, 5347–5356 (2005). ArticleCAS Google Scholar
Ansell, S. M. et al. Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: A phase II trial in the North Central Cancer Treatment Group [abstract]. J. Clin. Oncol.24, a2732 (2006). Google Scholar
Oza, A. M. et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer--NCIC IND 160 [abstract]. J. Clin. Oncol.24, a3003 (2006). Google Scholar
Chawla, S. P. et al. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas [abstract]. J. Clin. Oncol.24, a9505 (2006). Google Scholar
Okuno, S. H. et al. A multicenter phase 2 consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS) [abstract]. J. Clin. Oncol.24, a9504 (2006). Google Scholar
Duran, I. et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br. J. Cancer95, 1148–1154 (2006). ArticleCASPubMedPubMed Central Google Scholar
Yao, J. C. et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J. Clin. Oncol.26, 4311–4318 (2008). ArticlePubMedPubMed Central Google Scholar
Oza, A. M. et al. A phase II study of temsirolimus (CCI-779) in patients with metastatic and/or locally advanced recurrent endometrial cancer previously treated with chemotherapy: NCIC CTG IND 160b [abstract]. J. Clin. Oncol.26, a5516 (2008). Article Google Scholar
Colombo, N. et al. A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer [abstract]. J. Clin. Oncol.25, a5516 (2007). Google Scholar
Pandya, K. J. et al. A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J. Thorac. Oncol.2, 1036–1041 (2007). ArticlePubMed Google Scholar
Owonikoko, T. K. et al. Phase II study of RAD001 (Everolimus) in previously treated small cell lung cancer (SCLC) [abstract]. J. Clin. Oncol.26, a19017 (2008). Article Google Scholar
Soria, J. C. et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann. Oncol.20, 1674–1681 (2009). ArticlePubMed Google Scholar
Wolpin, B. M. et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J. Clin. Oncol.27, 193–198 (2009). ArticleCASPubMedPubMed Central Google Scholar
Garrido-Laguna, I. et al. Preclinical identification of biomarkers of response to mTOR inhibitors and subsequent application in a phase II trial of sirolimus in pancreatic cancer patients refractory to gemcitabine [abstract]. J. Clin. Oncol.27, a4612 (2009). Google Scholar
Margolin, K. et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer104, 1045–1048 (2005). ArticleCASPubMed Google Scholar
Rao, R. D. et al. N0377: Results of NCCTG phase II trial of the mTOR inhibitor RAD-001 in metastatic melanoma [abstract]. J. Clin. Oncol.25, a8530 (2007). ArticleCAS Google Scholar
Chang, S. M. et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest. New Drugs23, 357–361 (2005). ArticleCASPubMed Google Scholar
Galanis, E. et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol.23, 5294–5304 (2005). ArticleCAS Google Scholar
Rizzieri, D. A. et al. 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, 2756–2762 (2008). ArticleCASPubMed Google Scholar
Yee, K. W. 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, 5165–5173 (2006). ArticleCASPubMed Google Scholar
Hartford, C. M. et al. A Phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clin. Cancer Res.15, 1428–1434 (2009). ArticleCASPubMedPubMed Central Google Scholar
Hidalgo, M. et al. 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, 5755–5763 (2006). ArticleCASPubMed Google Scholar
Mita, M. M. et al. 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, 361–367 (2008). ArticleCASPubMed Google Scholar
Ma, W. W. et al. [18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy. J. Clin. Oncol.27, 2697–2704 (2009). ArticleCASPubMedPubMed Central Google Scholar
Cejka, D. et al. FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo. Br. J. Cancer100, 1739–1745 (2009). ArticleCASPubMedPubMed Central Google Scholar
Salvesen, H. B. et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc. Natl Acad. Sci. USA106, 4834–4839 (2009). Article Google Scholar
Lane, H. The potential of mTOR inhibitors for the treatment of human cancers [abstract]. AACR Meeting Abstracts 2007, SY21–01 (2007).
Manegold, P. C. et al. Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (everolimus) increases radiosensitivity in solid cancer. Clin. Cancer Res.14, 892–900 (2008). ArticleCASPubMed Google Scholar
Murphy, J. D. et al. Inhibition of mTOR radiosensitizes soft tissue sarcoma and tumor vasculature. Clin. Cancer Res.15, 589–596 (2009). ArticleCASPubMed Google Scholar
Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell6, 117–127 (2004). ArticleCASPubMed Google Scholar
Casa, A. J., Dearth, R. K., Litzenburger, B. C., Lee, A. V. & Cui, X. The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Front. Biosci.13, 3273–3287 (2008). ArticleCASPubMed Google Scholar
Lu, C. H. et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin. Cancer Res.13, 5883–5888 (2007). ArticleCASPubMed Google Scholar
La Monica, S. et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem. Pharmacol.78, 460–468 (2009). ArticleCASPubMed Google Scholar
Reardon, D. A. et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J. Neurooncol.96, 219–230 (2010). ArticleCASPubMed Google Scholar
Kreisl, T. N. et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J. Neurooncol.92, 99–105 (2009). ArticleCASPubMed Google Scholar
Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol. Cell. Biol.22, 7004–7014 (2002). ArticleCASPubMedPubMed Central Google Scholar
El-Hashemite, N., Walker, V., Zhang, H. & Kwiatkowski, D. J. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res.63, 5173–5177 (2003). CASPubMed Google Scholar
Fischer, P. et al. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma [abstract]. J. Clin. Oncol.26, a16020 (2008). Article Google Scholar
Giessinger, S. et al. A phase I study with a daily regimen of the oral mTOR inhibitor RAD001 (Everolimus) plus sorafenib for patients with metastatic renal cell cancer (MRCC) [abstract]. J. Clin. Oncol.26, a14603 (2008). Article Google Scholar
Merchan, J. R. et al. Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: Phase I safety and activity results [abstract]. J. Clin. Oncol.25, a5034 (2007). Google Scholar
Patnaik, A. et al. A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies [abstract]. J. Clin. Oncol.25, a3512 (2007). Google Scholar
Rosenberg, J. E. et al. Phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma [abstract]. J. Clin. Oncol.26, a5109 (2008). Article Google Scholar
Merchan, J. R. et al. Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): Safety and activity in RTKI refractory RCC patients [abstract]. J. Clin. Oncol.27, a5039 (2009). Article Google Scholar
Houghton, P. Targeting the IGF-1/mTOR pathway. AACR Meeting Abstracts 2008, PL05–03 (2008).
Kurmasheva, R. T., Easton, J. B. & Houghton, P. J. Combined targeting of mTOR and the insulin-like growth factor pathway. ASCO Educational Book2008, 460–464 (2008). Article Google Scholar
McDaid, H. M. et al. Combined MEK and mTOR suppression is synergistic in human NSCLC and is mediated via inhibition of protein translation [abstract]. J. Clin. Oncol.25, a10615 (2007). Google Scholar
Meier, F. et al. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death and abrogates invasive growth of melanoma cells [abstract]. J. Clin. Oncol.26, a20033 (2008). Article Google Scholar
Carracedo, A., Baselga, J. & Pandolfi, P. P. Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors. Cell Cycle7, 3805–3809 (2008). ArticleCASPubMed Google Scholar
Atkins, M. B. et al. 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, 909–918 (2004). ArticleCASPubMed Google Scholar
Amato, R. J., Jac, J., Giessinger, S., Saxena, S. & Willis, J. P. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer115, 2438–2446 (2009). ArticleCASPubMed Google Scholar
Chan, S. et al. 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, 5314–5322 (2005). ArticleCASPubMed Google Scholar
Farag, S. S. et al. Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): Preliminary results [abstract]. J. Clin. Oncol.24, a7616 (2006). Google Scholar
Yee, K. W. L. et al. A phase II study of temsirolimus (CCI-779) in patients with advanced leukemias [abstract]. Blood (ASH Annual Meeting Abstracts)104, a4523 (2004). Google Scholar