Targeted therapy for sarcomas

Biologics: Targets and Therapy

Volumn 8, Issue , 2014, Pages 91-105

  Forscher, Charles ^a   Mita, Monica ^a   Figlin, Robert ^a  

^a CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

mTor inhibition; Sarcoma; Targeted agents; Tyrosine kinase inhibitors

Indexed keywords

ANAPLASTIC LYMPHOMA KINASE; BEVACIZUMAB; CEDIRANIB; CRIZOTINIB; CYCLIN DEPENDENT KINASE 4; DASATINIB; DENOSUMAB; EVEROLIMUS; FIGITUMUMAB; GANITUMAB; IMATINIB; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY R1507; N (6,7 DIHYDRO 6 OXO 5H DIBENZ[B,D]AZEPIN 7 YL) 2,2 DIMETHYL N' (2,2,3,3,3 PENTAFLUOROPROPYL)PROPANEDIAMIDE; NILOTINIB; OSTEOCLAST DIFFERENTIATION FACTOR; PALBOCICLIB; PAZOPANIB; PLATELET DERIVED GROWTH FACTOR ALPHA RECEPTOR; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; PROTEIN MDM2; R 1507; REGORAFENIB; RIDAFOROLIMUS; SOMATOMEDIN B RECEPTOR; SOMATOMEDIN C RECEPTOR; SORAFENIB; SUNITINIB; TEMOZOLOMIDE; TEMSIROLIMUS; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR E3 FUSION PROTEIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN; VISMODEGIB;

ALVEOLAR SOFT PART SARCOMA; ANGIOGENESIS; ANGIOSARCOMA; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER SURVIVAL; CARCINOGENESIS; CHONDROSARCOMA; CHORDOMA; DERMATOFIBROSARCOMA PROTUBERANS; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; EWING SARCOMA; GASTROINTESTINAL STROMAL TUMOR; GENE FUSION; GENE MUTATION; GENE TRANSLOCATION; HEDGEHOG; HEMANGIOENDOTHELIOMA; HUMAN; INTRACELLULAR SIGNALING; LEIOMYOSARCOMA; LIPOSARCOMA; LUNG NON SMALL CELL CANCER; METASTASIS; MOLECULARLY TARGETED THERAPY; ONCOGENE C KIT; OSTEOCLASTOMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PIGMENTED VILLONODULAR SYNOVITIS; PLASMA CELL GRANULOMA; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; SARCOMA; SOFT TISSUE SARCOMA; SOLITARY FIBROUS TUMOR; SYNOVIAL SARCOMA; TREATMENT DURATION; TREATMENT RESPONSE;

EID: 84897837428     PISSN: 11775475     EISSN: 11775491     Source Type: Journal    
DOI: 10.2147/BTT.S26555     Document Type: Review

References (121)

1. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344(14):1052-1056.
2. van Oosterom AT, Judson I, Verweij J, et al; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Safety and effcacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 27 2001;358(9291): 1421-1423.
3. Demetri GD, von Mehren M, Blanke CD, et al. Effcacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-480.
4. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26(4):620-625.
5. Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol. 2007;25(13):1760-1764.
6. Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26(33):5360-5367.
7. Debiec-Rychter M, Sciot R, Le Cesne A, et al; EORTC Soft Tissue and Bone Sarcoma Group; Italian Sarcoma Group; Australasian GastroIntestinal Trials Group. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42(8):1093-1103.
8. Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007;25(9):1107-1113.
9. Le Cesne A, Ray-Coquard I, Bui BN, et al; French Sarcoma Group. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol. 2010;11(10):942-949.
10. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338.
11. George S, von Mehren M, Heinrich MC, et al. A multicenter phase II study of regorafenib in patients (pts) with advanced gastrointestinal stromal tumor (GIST), after therapy with imatinib (IM) and sunitinib (SU). J Clin Oncol. 2011;29(15 May 20 Supplement): 10007.
12. Demetri GD, Reichardt P, Kang YK, et al. Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial. J Clin Oncol. 2012;30:Abstract LBA10008.
13. Adenis A, Le Cesne A, Nguyen BB, et al. Masitinib mesylate in imatinib-resistant advanced GIST: a randomized phase II trial. J Clin Oncol. 2012;30:Abstract 10007.
14. Le Cesne A, Blay J Y, Bui BN, et al. Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intes-tinal stromal tumour (GIST). Eur J Cancer. 2010;46(8): 1344-1351.
15. Trent JC, Walthen K, von Mehren M, et al. A phase II study of dasat-inib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol. 2011;29:Abstract 10006.
16. Schöffski P, Reichardt P, Blay JY, et al. A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol. 2010;21(10): 1990-1998.
17. Dematteo R P, Ballman K V, Antonescu CR, et al; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 28;373(9669): 1097-1104.
18. Joensuu H, Eriksson M, Hatrmann K, et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). Proc Am Soc Clin Oncol. 2011;Abstract LBA1.
19. Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/ adjuvant imatinib mesylate (IM) for advanced primary and metastatic/ recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009;99(1): 42-47.
20. McAuliffe JC, Hunt KK, Lazar AJ, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Ann Surg Oncol. 2009;16(4):910-919.
21. Rutkowski P, Van Glabbeke M, Rankin CJ, et al; European Organisation for Research and Treatment of Cancer Soft Tissue/ Bone Sarcoma Group; Southwest Oncology Group. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol. 2010;28(10): 1772-1779.
22. Kérob D, Porcher R, Vérola O, et al. Imatinib mesylate as a preopera-tive therapy in dermatofbrosarcoma: results of a multicenter phase II study on 25 patients. Clin Cancer Res. 2010;16(12):3288-3295.
23. Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer. 2004;101(9):2086-2097.
24. Stacchiotti S, Longhi A, Ferraresi V, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol. 2012;30(9):914-920.
25. Mercier F, Guiot MC, Bojanowski M W. Treatment of chordoma with imatinib complicated by intracranial hemorrhage: a case showing dissociation between biological effect and therapeutic outcome. J Neurooncol. 2012;107(2):435-437.
26. Stacchiotti S, Tamborini E, Marrari A, et al. Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin Cancer Res. 2009;15(3): 1096-1104.
27. Stacchiotti S, Negri T, Zaffaroni N, et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol. 2011;22(7):1682-1690.
28. Gardner K, Judson I, Leahy M, et al. Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma. J Clin Oncol. 2009;27:15s, Abstract 10523.
29. National Cancer Institute. Phase II study of cediranib (AZD2171) in patients with alveolar soft part sarcoma. Available from: http://clinicaltrials.gov/show/NCT00942877.NLMidentifer:NCT00942877. Accessed July 25, 2013.
30. Park MS, Patel SR, Ludwig JA, et al. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fbrous tumor. Cancer. 2011;117(21):4939-4947.
31. Stacchiotti S, Negri T, Palassini E, et al. Sunitinib malate and fgitu-mumab in solitary fbrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther. 2010;9(5):1286-1297.
32. Ray-Coquard I, Italiano A, Bompas E, et al; French Sarcoma Group (GSF/GETO). Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO). Oncologist. 2011;7(2):260-266.
33. Maki RG, D'Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009;27(19):3133-3140.
34. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24(1): 257-263.
35. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009;27(19): 3126-3132.
36. Van Der Graaf WT, Blay JY, Chawla S P, et al; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886.
37. Blay JY, El Sayadi H, Thiesse P, Garret J, Ray-Coquard I. Complete response to imatinib in relapsing pigmented villonodular synovitis/ tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 2008;19(4): 821-822.
38. Gelderblom H, Pérol D, Chevreau C, et al. An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment. J Clin Oncol. 2013;31:Abstract 10516.
39. Butrynski JE, D'Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18):1727-1733.
40. Scotlandi K, Picci P. Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opin Oncol. 2008;20(4):419-427.
41. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004;24(16):7275-7283.
42. Pappo AS, Patel S, Crowley J, et al. Activity of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R), in patients (pts) with recurrent or refractory Ewing's sarcoma family of tumors (ESFT): Results of a phase II SARC study. J Clin Oncol. 2010;28:15s, Abstract 10000.
43. Tap WD, Demetri G, Barnette P, et al. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30(15):1849-1856.
44. Olmos D, Postel-Vinay S, Molife LR, et al. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody fgitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 2010;11(2):129-135.
45. Juergens H, Daw NC, Geoerger B, et al. Preliminary effcacy of the anti-insulin-like growth factor type 1 receptor antibody fgitumumab in patients with refractory Ewing sarcoma. J Clin Oncol. 2011;29(34): 4534-4540.
46. Subbiah V, Naing A, Brown RE, et al. Targeted morphoproteomic profling of Ewing's sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures. PLoS One. 6 2011;6(4):e18424.
47. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010;11(3):275-280.
48. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012;18(16):4415-4424.
49. Dickson MA, Tap WD, Keohan ML, et al. Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplifed Well-Differentiated or Dedifferentiated Liposarcoma. J Clin Oncol. 2013;31(16):2024-2028.
50. Italiano A, Le Cesne A, Cassier PA, et al. GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma Group (FSG)/French and US. National Cancer Institutes phase II collaborative study. J Clin Oncol. 2013;30:Abstract 10005.
51. Gounder MM, Dickson MA, Wu N, et al. A frst-in-human, phase Ib combination study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a Notch inhibitor, RO4929097, in patients with advanced sarcoma. J Clin Oncol. 2013;30:Abstract 10004.
52. Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975;28(10): 721-726.
53. Baker H, Sidorowicz A, Sehgal SN, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. J Antibiot (Tokyo). 1978;31(6):539-545.
54. Eng C P, Sehgal SN, Vézina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo). 1984;37(10):1231-1237.
55. Wiederrecht GJ, Sabers CJ, Brunn GJ, Martin MM, Dumont FJ, Abraham RT. Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells. Prog Cell Cycle Res. 1995;1:53-71.
56. Steck PA, Pershouse MA, Jasser SA, et al. Identifcation of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15(4): 356-362.
57. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-defcient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A. 2001;98(18):10314-10319.
58. Fruman DA, Wood MA, Gjertson CK, Katz HR, Burakoff SJ, Bierer BE. FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells. Eur J Immunol. 1995;25(2): 563-571.
59. Sekulić A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60(13):3504-3513.
60. Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 1997;16(12):3693-3704.
61. Gingras AC, Raught B, Sonenberg N. EIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem. 1999;68:913-963.
62. Sabatini DM. MTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729-734.
63. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10(3):457-468.
64. Zeng Z, Sarbassov Dos D, Samudio IJ, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007;109(8):3509-3512.
65. Kim DH, Sarbassov DD, Ali SM, et al. MTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163-175.
66. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177-189.
67. Yonezawa K, Tokunaga C, Oshiro N, Yoshino K. Raptor, a binding partner of target of rapamycin. Biochem Biophys Res Commun. 2004;313(2):437-441.
68. Harris TE, Lawrence JC Jr. TOR signaling. Sci STKE. 2003; 2003(212):e15.
69. Nojima H, Tokunaga C, Eguchi S, et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem. 2003;278(18):15461-15464.
70. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124(3):471-484.
71. Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat. 2008;11(3):63-76.
72. Kim DH, Sarbassov DD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895-904.
73. Frias MA, Thoreen CC, Jaffe JD, et al. MSin1 is necessary for Akt/ PKB phosphorylation, and its isoforms defne three distinct mTORC2s. Curr Biol. 2006;16(18):1865-1870.
74. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defnes a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296-1302.
75. Wullschleger S, Loewith R, Oppliger W, Hall MN. Molecular organization of target of rapamycin complex 2. J Biol Chem. 2005;280(35): 30697-30704.
76. Pearce LR, Huang X, Boudeau J, et al. Identifcation of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J. 2007;405(3):513-522.
77. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122-1118.
78. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671-688.
79. Kurmasheva RT, Huang S, Houghton PJ. Predicted mechanisms of resistance to mTOR inhibitors. Br J Cancer. 2006;95(8):955-960.
80. Ricci R, Maggiano N, Castri F, et al. Role of PTEN in gastrointestinal stromal tumor progression. Arch Pathol Lab Med. 2004;128(4): 421-425.
81. Saito T, Oda Y, Kawaguchi K, et al. PTEN/MMAC1 gene mutation is a rare event in soft tissue sarcomas without specifc balanced translocations. Int J Cancer. 2003;104(2):175-178.
82. Wan X, Helman LJ. Levels of PTEN protein modulate Akt phosphoryla-tion on serine 473, but not on threonine 308, in IGF-II-overexpressing rhabdomyosarcomas cells. Oncogene. 2003;22(50):8205-8211.
83. Gibbons JJ, Discafani C, Peterson R, 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 in vivo. Proc Am Assoc Cancer Res. 1999;40:301, Abstract 2000.
84. Hidalgo M, Buckner JC, Erlichman C, 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. 2006;12(19):5755-5763.
85. 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. 2004;22(12): 2336-2347.
86. Atkins MB, Hidalgo M, Stadler WM, 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. 2004;22(5):909-918.
87. Hudes G, Carducci M, Tomczack P, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of frst-line, poor-risk patients with advanced renal cell carcinoma (adv RCC). J Clin Oncol. 2006;24(18S June 20 Supplement):LBA4.
88. Chan S, Scheulen ME, Johnston 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. 2005;23(23):5314-5322.
89. Carpenter JT, Roché H, Campone M, et al. Randomized 3-arm, phase 2 study of temsirolimus (CCI-779) in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2005;23(16S June 1 Supplement):564.
90. Galanis E, Buckner JC, Maurer MJ, et al; North Central Cancer Treatment Group. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol. 2005;23(23):5294-5304.
91. Fourouzesh B, Buckner J, Adjei A, et al. Phase I, bioavailability and pharmacokinetic study of oral dosage of CCI-779 administered to patients with advanced solid malignancies. Proceedings of the 13th EORTC-NCI-AACr symposium. Eur J Cancer. 2002;38(Suppl 7); S54, Abstract 168.
92. O'Reilly T, Vaxelaire J, Muller M. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. Proc Am Assoc Cancer Res. 2002:43:Abstract 359.
93. Lane HA, Schnell C, Theuer A, et al. Antiangiogenic activity of RAD001, an orally active anticancer agent. Proc Amer Assoc Cancer Res. 2002;43:184.
94. O'Donnell A, Faivre S, Judson I, et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumors. Proc Am Soc Clin Oncol. 2003;22:200:Abstract 803.
95. Amato RJ, Misellati A, Khan M, Chiang S. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). J Clin Oncol. 2006;24(18S June 20 Supplement):4530.
96. Lerut E, Roskams T, Goossens E, et al. Molecular pharmacodynamic (MPD) evaluation of dose and schedule of RAD001 (everolimus) in patients with operable prostate carcinoma (PC). J Clin Oncol. 2005;23(16S June 1 Supplement):3071.
97. Reardon D, Quinn JA, Rich JN, et al. A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma. J Clin Oncol. 2006;24(18S June 20 Supplement):1580.
98. Yao JC, Phan A, Chang DZ, et al. Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in advanced low grade neu-roendocrine carcinoma (LGNET). J Clin Oncol. 2007;25(18S June 20 Supplement):4503.
99. Milton DT, Kris MG, Azzoli CG, et al. Phase I/II trial of geftinib and RAD001 (everolimus) in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2005;23(16S June 1 Supplement):7104.
100. Clackson T, Metcalf CA, Rivera VM, et al. Broad anti-tumor activity of ap23573, an mTOR inhibitor in clinical development. Proc Am Soc Clin Oncol. 2003;22(220):Abstract 882.
101. Mita M, Rowinsky EK, Goldston ML, et al. Phase I, pharmacoki-netic (PK) and pharmacodynamic (PD) study of AP23573, an mTOR inhibitor administered IV daily X5 every other week in patients with refractory or advanced malignancies. J Clin Oncol. 2004;22(14S):Abstract 3076.
102. Desai AA, Janish L, Berk LR, et al. A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis. J Clin Oncol. 2004;22(14S July 15 Supplement):3150.
103. Perotti A, Maur M, Viganò L, et al. Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to defne the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE). J Clin Oncol. 2006;24(No 18S June 20 Supplement):3065.
104. Feldman E, Giles F, Roboz G, et al. A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol. 2005;23(16S June 1 Supplement):6631.
105. Chawla S P, Tolcher AW, Staddon A 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. J Clin Oncol. 2006;24(18S June 20 Supplement):9505.
106. Blay JY, van Glabbeke M, Verweij J, et al. Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy. Eur J Cancer. 2003;39(1): 64-69.
107. Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005;23(3):576-584.
108. Le Cesne A, Judson I, Crowther D, et al. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 2000;18(14):2676-2684.
109. Van Glabbeke M, Verweij J, Judson I, Nielsen OS; EORTC Soft Tissue and Bone Sarcoma Group. Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer. 2002;38(4):543-549.
110. Sankhala KK, Chawla S P, Iagaru A, et al. Early response evaluation of therapy with AP23573 (an mTOR inhibitor) in sarcoma using [18F]2-fuoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan. J Clin Oncol. 2005;23(16S June 1 Supplement):9028.
111. Chawla SP, Blay J, Ray-Coquard IL, et al. Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical beneft from prior standard cytotoxic chemotherapy (CT). J Clin Oncol. 2011;29:Abstract 10005.
112. Okuno SH, Mahoney MR, Bailey HH, et al. A multicenter phase 2 consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS). J Clin Oncol. 2006;24(18S June 20 Supplement):9504.
113. Schuetze SM, Baker LH, Maki RG. Sirolimus reduced tumor-related morbidity and resulted in biochemical and radiographic response in patients with progressive sarcoma. J Clin Oncol. 2006;24(18S June 20 Supplement):9503.
114. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24(29):4764-4774.
115. van Oosterom A, Reichardt P, Blay J-Y, et al. A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: study update. J Clin Oncol. 2005;23(16S June 1 Supplement):9033.
116. Schwartz GK, Tap WD, Qin LX, et al. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol. 2013;14(4):371-382.
117. Quek R, Wang Q, Morgan JA, et al. Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and fgitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res. 2011;17(4):871-879.
118. Leob DM, DeLorenzo KA, Chen ARS, et al. A dose-fnding study of temsirolimus and liposomal doxorubicin for patients with advanced soft tissue or bone sarcoma. J Clin Oncol. 2011;29:Abstract 10026.
119. Movva S, Bocklage T, Schmit B, et al. Phase I study of irinotecan and temsirolimus in patients with refractory sarcomas. J Clin Oncol. 2011;29:Abstract 10027.
120. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivas-cular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010;28(5):835-840.
121. Italiano A, Delcambre C, Hostein I, et al. Treatment with the mTOR inhibitor temsirolimus in patients with malignant PEComa. Ann Oncol. 2010;21(5):1135-1137.