mTOR kinase inhibitors as a treatment strategy in hematological malignancies

References

• 1  Peng T, Golub TR, Sabatini DM. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell. Biol.22,5575–5584 (2002).
  Medline CASGoogle Scholar
• 2  Vezina C, Kudelski A, Sehgal SN. Rapamycin (AYU-22,989) a new antifugal antibiotic. Taxonomy of the producing streptomycyte and isolation of the active principle. J. Antibiot.28,721–726 (1975).
  Medline CASGoogle Scholar
• 3  Smolewski P. Investigating mammalian target of rapamycin inhibitors for their anticancer properties. Expert Opin. Investig. Drugs15(10),1201–1227 (2006).
  Medline CASGoogle Scholar
• 4  Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumorigenesis and targeted antitumor therapy. Cell Mol. Biol. Lett.10(3),479–498 (2005).
  Medline CASGoogle Scholar
• 5  Tremblay F, Brûlé S, Hee-Um S et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc. Natl Acad. Sci. USA104(35),14056–14061(2007).
  Medline CASGoogle Scholar
• 6  Zick Y. Role of Ser/Thr kinases in the uncoupling of insulin signaling. Intl J. Obes. Relat. Metab. Disord.27 Suppl 3,S56–60 (2003).
  Medline CASGoogle Scholar
• 7  Brown EJ, Albers MW, Shin TB et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature369(6483),756–758 (1994).
  Medline CASGoogle Scholar
• 8  Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene23(18),3151–3171 (2004).
  Medline CASGoogle Scholar
• 9  Jacinto E, Loewith R, Schmidt A et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol.6(11),1122–1128 (2004).
  Medline CASGoogle Scholar
• 10  Frias MA, Thoreen CC, Jaffe JD et al. mSin1 is necessary for Akt/PKB phosphorylation and its isoforms define three distinct mTORC2s. Curr. Biol.16(18),1865–1870 (2006).
  Medline CASGoogle Scholar
• 11  Sarbassov DD, Ali SM, Kim DH et al. Rictor, a novel binding partner of mTOR, defines a rapamycin sensitive and raptor independent pathway that regulates the cytoskeleton. Curr. Biol.14,1296–1302 (2004).
  Medline CASGoogle Scholar
• 12  Woo SY, Kim DH, Jun CB et al. PRR5, a novel component of mTOR complex 2, regulates platelet derived growth factor receptor beta expression and signaling. J. Biol. Chem.282(35),25604–25612 (2007).
  Medline CASGoogle Scholar
• 13  Pearce LR, Huang X, Boudeau J et al. Identification of Protor as a novel Rictor binding component of mTOR complex 2. J. Biochem.405(3),513–522 (2007).
  CASGoogle Scholar
• 14  Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H et al. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J. Biol. Chem.282(32),23708–23715 (2007).
  Medline CASGoogle Scholar
• 15  Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum and glucocorticoid induced protein kinase 1 (SGK1). J. Biochem.416(3),375–385 (2008).
  CASGoogle Scholar
• 16  Liu L, Luo Y, Chen L et al. Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J. Biol. Chem.285(49),38362–38373 (2010).
  Medline CASGoogle Scholar
• 17  Hannan KM, Brandenburger Y, Jenkins A et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell. Biol.23,8862–8877 (2003).
  Medline CASGoogle Scholar
• 18  Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer4,335–348 (2004).
  Medline CASGoogle Scholar
• 19  Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin as therapy for hematologic malignancies. Cancer100,657–666 (2004).
  Medline CASGoogle Scholar
• 20  Xu L, Salloum D, Medlin PS et al. Phospholipase D mediates nutrient input to mammalian target of rapamycin complex 1 (mTORC1). J. Biol. Chem.286(29),25477–22586 (2011).
  Medline CASGoogle Scholar
• 21  Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signalling, growth, migration and apoptosis. J. Cell Sci.114,2375–2384 (2001).
  Medline CASGoogle Scholar
• 22  Jozwiak J, Jozwiak S, Grzela T, Lazarczyk M. Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway. Neuromolecular Med.7,287–296 (2005).
  Medline CASGoogle Scholar
• 23  Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem.280,32081–32089 (2005).
  Medline CASGoogle Scholar
• 24  Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res.65,2755–2760 (2005).
  Medline CASGoogle Scholar
• 25  Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr. Biol.15,702–713 (2005).
  Medline CASGoogle Scholar
• 26  Ellisen LW. Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle4,1500–1502 (2005).
  Medline CASGoogle Scholar
• 27  Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr. Opin. Oncol.16(6),564–575 (2004).
  Medline CASGoogle Scholar
• 28  Yellen P, Saqcena M, Salloum D et al. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle15(10),3948–3956 (2011).
  Google Scholar
• 29  Janus A, Linke A, Cebula B, Robak T, Smolewski P. Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine. Anticancer Drugs20,693–701 (2009).
  Medline CASGoogle Scholar
• 30  Guba M, von Breitenbuch P, Steinbauer M et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med.8(2),128–135 (2002).
  Medline CASGoogle Scholar
• 31  Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs17(5),487–494 (2006).
  Medline CASGoogle Scholar
• 32  Boehm A, Aichberger KJ, Mayerhofer M et al. Targeting of mTPR in AML is associated with decreased growth of leukemic cells and downregulation of VEGF. Blood (ASH Annual Meeting Abstracts)104,2544 (2004).
  Google Scholar
• 33  Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Annu. Oncol.19,1387–1392 (2008).
  Medline CASGoogle Scholar
• 34  Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol. Ther.2,169–177 (2003).
  Google Scholar
• 35  Costa LJ. Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin’s lymphoma. Cancer Treat. Rev.33(1),78–84 (2007).
  Medline CASGoogle Scholar
• 36  MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin. Ther.22(Suppl. B),B101–B121 (2000).
  Medline CASGoogle Scholar
• 37  Meier-Kriesche HU, Kaplan B. Toxicity and efficacy of sirolimus: relationship to whole-blood concentrations. Clin. Ther.22(Suppl. B),B93–B100 (2000).
  Medline CASGoogle Scholar
• 38  Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood102(3),972–980 (2003).
  Medline CASGoogle Scholar
• 39  Recher C, Dos Santos C, Demur C, Payrastre B. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle4(11),1540–1549 (2005).
  Medline CASGoogle Scholar
• 40  Yee KW, Zeng Z, Konopleva M 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),5165–5173 (2006).
  Medline CASGoogle Scholar
• 41  Rizzieri DA, Feldman E, Dipersio JF et al. A Phase II 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),2756–2762 (2008).
  Medline CASGoogle Scholar
• 42  Récher C, Beyne-Rauzy O, Demur C et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood105(6),2527–2534 (2005).
  Medline CASGoogle Scholar
• 43  Xu Q, Thompson JE, Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood106(13),4261–4268 (2005).
  Medline CASGoogle Scholar
• 44  Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P. Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia19(12),2153–2158 (2005).
  Medline CASGoogle Scholar
• 45  Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia22(12),2159–2168 (2008).
  Medline CASGoogle Scholar
• 46  Smolewski P, Cebula B, Wierzbicka D et al. Rapamycin, inhibitor of mTOR kinase, sensitizes leukemia cells to fludarabine-induced apoptosis, but protects survival of normal lymphocytes. Presented at: 46th Annual Meeting of American Society of Hematology. San Diego, USA, December 2004. Blood104(11),4497 (2004).
  Google Scholar
• 47  Boehm A, Mayerhofer M, Herndlhofer S et al. Evaluation of in vivo antineoplastic effects of rapamycin in patients with chemotherapy-refractory AML. Eur. J. Intern. Med.20(8),775–778 (2009).
  Medline CASGoogle Scholar
• 48  Brown VI, Fang J, Alcorn K et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. Natl Acad. Sci. USA100,15113–15118 (2003).
  Medline CASGoogle Scholar
• 49  Crazzolara R, Cisterne A, Thien M, Hewson J, Bradstock K, Bendall L. The mTOR inhibitor RAD001 improves survival in preclinical models of primary human ALL. Blood (ASH Annual Meeting [Abstracts 110]) (2007).
  Google Scholar
• 50  Saydam G, Bertino JR, Erickan-Abali E. mTOR inhibition leads to increased sensitivity to methotrexate. Presented at: AACR 96th Annual Meeting. Los Angeles, CA, USA, 9 June 2005 (Abstract 3303).
  Google Scholar
• 51  Teachey DT, Sheen C, Hall J et al. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood112,2020–2023 (2008).
  Medline CASGoogle Scholar
• 52  Luger S, Perl AE, Kemner A et al. A Phase I dose escalation study of the mTOR inhibitor sirolimus and MEC chemotherapy targeting signal transduction in leukemic stem cells for acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts)108,161 (2006).
  Google Scholar
• 53  Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br. J. Haematol.145,569–580 (2009).
  Medline CASGoogle Scholar
• 54  Gu L, Zhou C, Liu H, Gao J, Li Q, Mu D, Ma Z. Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis. J. Exp. Clin. Cancer Res.29,150 (2010).
  MedlineGoogle Scholar
• 55  Kharas MG, Deane JA, Wong S et al. Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood103,4268–4275 (2004).
  Medline CASGoogle Scholar
• 56  Kharas MG, Janes MR, Scarfone VM et al. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J. Clin. Invest.118,3038–3050 (2008).
  Medline CASGoogle Scholar
• 57  Janes MR, Limon JJ, So L et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat. Med.16,205–213 (2010).
  Medline CASGoogle Scholar
• 58  Mayerhofer M, Aichberger KJ, Florian S et al. Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. FASEB J.19(8),960–962 (2005).
  Medline CASGoogle Scholar
• 59  Sillaber C, Mayerhofer M, Böhm A et al. Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. Eur. J. Clin. Invest.38,43–52 (2008).
  Medline CASGoogle Scholar
• 60  Dunn C, Croom KF. Everolimus: a review of its use in renal and cardiac transplantation. Drugs66(4),547–570 (2006).
  Medline CASGoogle Scholar
• 61  Nashan B. Review of the proliferation inhibitor everolimus. Expert Opin. Investig. Drugs11,1845–1857 (2002).
  Medline CASGoogle Scholar
• 62  American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am. J. Health Syst. Pharm.63,1172–1193 (2006).
  Google Scholar
• 63  Sedrani R, Cottens S, Kallen J, Schuler W. Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant. Proc.30(5),2192–2194 (1998).
  Medline CASGoogle Scholar
• 64  Formica RN, Lorberb KM, Friedmanb AL. et al. The evolving experience using everolimus in clinical transplantation. Transplant Proc.36(2),S495–S499 (2004).
  MedlineGoogle Scholar
• 65  Majewski M, Korecka M, Joergensen J et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation75,1710–1717 (2003).
  Medline CASGoogle Scholar
• 66  Götze KS, Hoffmann D, Schätzl HM, Peschel C, Fend F, Decker T. Fatal Epstein-Barr virus-associated lymphoproliferative disorder following treatment with a novel mTOR inhibitor for relapsed chronic lymphocytic leukemia cells. Haematologica92,1282–1283 (2007).
  MedlineGoogle Scholar
• 67  Haritunians T, Mori A, O’Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia21,333–339 (2007).
  Medline CASGoogle Scholar
• 68  Raymond E, Alexandre J, Faivre S 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).
  Medline CASGoogle Scholar
• 69  Saunders P, Cisterne A, Weiss J, Bradstock KF, Bendall LJ. The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia. Haematologica96,69–77 (2011).
  Medline CASGoogle Scholar
• 70  Decker T, Hipp S, Ringshausen I et al. Rapamycin-induced G1-arrest in cycling B-CLL cells is associated with reduced expression of cyklin D3, cyklin E, Cyclin A, and survivin. Blood101,278–285 (2003).
  Medline CASGoogle Scholar
• 71  Decker C, Sandherr M, Goetze K, Oelsner M, Ringshausen I, Peschel C. A pilot trial of the mTOR inhibitor RAD001 in patients with advanced B-CLL. Annu. Hematol.88(3),221–227 (2009).
  Medline CASGoogle Scholar
• 72  Zent CS, LaPlant BR, Johnston PB et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer116,2201–2207 (2010).
  MedlineGoogle Scholar
• 73  Smith MS, Pro B, Cisneros A et al. Activity of single agent temsirolimus in non-mantle cell non-Hodgkin lymphoma subtypes. J. Clin. Oncol. (ASCO Annual Meeting)26(Suppl. 8514), (2008).
  Google Scholar
• 74  Mancini M, Corradi V, Petta S, Martinelli G, Barbieri E, Santucci MA. mTOR inhibitor RAD001 (everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. Leuk. Res.34,641–648 (2010).
  Medline CASGoogle Scholar
• 75  Minami Y, Minami M, Kuwatsuka Y et al. Treatment with mTOR inhibitor, everolimus (RAD001) overcomes resistance to imatinib in Ph-leukemia quiescent or T315I-mutated cells. Presented at: 51st ASH Annual Meeting. 5–8 December 2009 (Abstract No 3277).
  Google Scholar
• 76  Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med.356,2271–2281 (2007).
  Medline CASGoogle Scholar
• 77  Del Bufalo D, Ciuffreda L, Trisciuoglio D et al. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res.66,5549–5554 (2006).
  Medline CASGoogle Scholar
• 78  Yee KW, Garcia-Manero G, Thomas D et al. A Phase II study of temsirolimus (CCI-779) in patients with advanced leukemias. Blood (ASH Annual Meeting Abstracts)104,4523 (2004).
  Google Scholar
• 79  Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert. Opin. Investig. Drugs17(12),1947–1954 (2008).
  Medline CASGoogle Scholar
• 80  Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert. Opin. Investig. Drugs.17,1947–1954 (2008).
  Medline CASGoogle Scholar
• 81  Mita MM, Mita AC, Chu QS 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).
  Medline CASGoogle Scholar
• 82  Mita MM, Britten CD, Poplin E et al. Deforolimus trial 106- A Phase I trial evaluating 7 regimens of oral deforolimus (AP23573, MK-8669). J. Clin. Oncol.26, Abstract 3509 (2008).
  Google Scholar
• 83  Fetterly J, Mita MM, Britten CD et al. Pharmacokinetics of oral deforolimus (AP23573, MK-8669). J. Clin. Oncol. ASCO Annual Meeting Proceedings26, No 15S, 14555 (2008).
  Google Scholar
• 84  Thoreen CC, Sabatini DM. Rapamycin inhibits mTORC1, but not completely. Autophagy5,725–726 (2009).
  Medline CASGoogle Scholar
• 85  Dowling RJ, Topisirovic I, Alain T et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science328(5982),1172–1176 (2010).
  Medline CASGoogle Scholar
• 86  O’Reilly KE, Rojo F, She QB et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res.66(3),1500–1508 (2006).
  MedlineGoogle Scholar
• 87  Papa V, Tazzari PL, Chiarini F et al. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia22(1),147–160 (2008).
  Medline CASGoogle Scholar
• 88  Rahmani M, Anderson A, Habibi JR et al. The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways. Blood114(20),4507–4516 (2009).
  Medline CASGoogle Scholar
• 89  Ghobrial IM, Roccaro A, Hong F et al. Clinical and translational studies of a Phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom’s macroglobulinemia. Clin. Cancer Res.16(3),1033–1041 (2010).
  Medline CASGoogle Scholar
• 90  Park S, Chapuis N, Tamburini J et al. Role of the PI3K/AKT and mTOR signalling pathways in acute myeloid leukemia. Haematologica95(5),819–828 (2010).
  Medline CASGoogle Scholar
• 91  Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr. Oncol. Rep.11(2),102–110 (2009).
  Medline CASGoogle Scholar
• 92  van Blitterswijk WJ, Verhei M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr. Pharm. Design14,2061–2074 (2008).
  Medline CASGoogle Scholar
• 93  Chiarini F, Del Sole M, Mongiorgi S et al. The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia22(6),1106–1116 (2008).
  Medline CASGoogle Scholar
• 94  Tazzari PL, Tabellini G, Ricci F et al. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor perifosine in acute myelogenous leukemia cells. Cancer Res.68(22),9394–9403 (2008).
  Medline CASGoogle Scholar
• 95  Crul M, Rosing H, de Klerk GJ et al. Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumors. Eur. J. Cancer38(12),1615–1621 (2002).
  Medline CASGoogle Scholar
• 96  Baumann P, Mandl-Weber S, Oduncu F et al. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp. Cell. Res.315(3),485–497 (2009).
  Medline CASGoogle Scholar
• 97  Park S, Chapuis N, Bardet V et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide PI-103 kinase and mTOR, has antileukemic activity in AML. Leukemia22(9),1698–1706 (2008).
  Medline CASGoogle Scholar
• 98  Tan DS, Dumez H, Olmos D et al. First-in-human Phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma. Presented at: American Society of Clinical Oncology Annual Meeting. Chicago, IL, USA, 4–8 June 2010 (Abstract 3006).
  Google Scholar
• 99  Hoang B, Frost P, Shi Y et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood116(22),4560–4568 (2010).
  Medline CASGoogle Scholar
• 100  Feldman ME, Apsel B, Uotila A et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol.7(2),e38 (2009).
  MedlineGoogle Scholar
• 101  Deforolimus (AP23573) in treatment of sarcoma – SUCCEED (sarcoma Multi-center clinical evaluation of the efficacy of deforolimus) study (2008). http://clinicaltrials.gov
  Google Scholar