Recent clinical trials of mTOR-targeted cancer therapies

Reviews on Recent Clinical Trials

Volumn 6, Issue 1, 2011, Pages 24-35

  Don, Aruni S Arachchige ^a   Zheng, X F Steven ^a  

^a RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

Author keywords

ATP competitive mTORC1 2 inhibitors; Cancer clinical trials; Dual PI3K mTOR inhibitors; mTOR; mTOR targeted therapeutics; Rapamycins

Indexed keywords

[1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; ABI 009; ALPHA INTERFERON; AZD 8055; BEVACIZUMAB; BGT 226; EVEROLIMUS; GEFITINIB; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; NVPBEZ 235; OCTREOTIDE; OSI 027; PACLITAXEL; RAPAMYCIN; RAPAMYCIN DERIVATIVE; RIDAFOROLIMUS; TEMSIROLIMUS; TRASTUZUMAB; UNCLASSIFIED DRUG; XL 765;

ADVANCED CANCER; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; APHTHOUS ULCER; ARTICLE; ASTHENIA; BREAST CANCER; CANCER CHEMOTHERAPY; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; DESQUAMATION; DIARRHEA; DRUG EFFICACY; DRUG ERUPTION; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; ENDOMETRIUM CANCER; ENDOMETRIUM CARCINOMA; FATIGUE; GLIOBLASTOMA; GLIOMA; HUMAN; HYPERGLYCEMIA; HYPERTRIGLYCERIDEMIA; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; LYMPHOMA; MANTLE CELL LYMPHOMA; METASTASIS; MONOTHERAPY; MUCOSA INFLAMMATION; NAUSEA; NEUROENDOCRINE DISEASE; NEUROENDOCRINE TUMOR; NEUTROPENIA; OSTEOSARCOMA; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN TARGETING; RECURRENT CANCER; SIDE EFFECT; SIGNAL TRANSDUCTION; SOFT TISSUE SARCOMA; SOLID TUMOR; STOMACH CANCER; THROMBOCYTOPENIA;

ANTIBIOTICS, ANTINEOPLASTIC; CLINICAL TRIALS AS TOPIC; HUMANS; NEOPLASMS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME;

EID: 78650929230     PISSN: 15748871     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488711793980147     Document Type: Article

References (98)

1. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007; 12(3-4): 112-24.
2. Bai X, Jiang Y. Key factors in mTOR regulation. Cell Mol Life Sci 2010; 67(2): 239-53.
3. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17(6): 596-603.
4. 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): 1122-8.
5. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptorindependent pathway that regulates the cytoskeleton. Curr Biol 2004; 14(14): 1296-302.
6. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6(9): 729-34.
7. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12(1): 9-22.
8. EMEA/COMP/195543/2008. European Medicines Agency, public summary of positive opinion for orphan designation of temsirolimus for the treatment of mantle cell lymphoma. http: //www.emea.europa.eu/pdfs/human/comp/opinion/19554308en.pdf, 2009.
9. Sancak Y, Peterson TR, Shaul YD, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008; 320(5882): 1496-501.
10. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 2008; 10(8): 935-45.
11. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010; 141(2): 290-303.
12. Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004; 6(1): 91-9.
13. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30(2): 214-26.
14. Brugarolas J, Lei K, Hurley RL, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18(23): 2893-904.
15. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005; 102(23): 8204-9.
16. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098-101.
17. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene 2006; 25(48): 6436-46.
18. Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999; 21(1): 99-102.
19. Li SY, Rong M, Grieu F, Iacopetta B. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 2006; 96(1): 91-5.
20. Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 2005; 65(23): 10669-73.
21. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275(5308): 1943-7.
22. Risinger JI, Hayes AK, Berchuck A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 1997; 57(21): 4736-8.
23. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15(4): 356-62.
24. Delmonte A, Sessa C. Molecule-targeted agents in endometrial cancer. Curr Opin Oncol 2008; 20(5): 554-9.
25. Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005; 173(6): 1853-62.
26. Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev 2005; 69(1): 79-100.
27. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 2006; 21(4): 521-31.
28. Yeung RS, Xiao GH, Jin F, Lee WC, Testa JR, Knudson AG. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci USA 1994; 91(24): 11413-6.
29. Kwiatkowski DJ. Tuberous sclerosis: from tubers to mTOR. Ann Hum Genet 2003; 67(Pt 1): 87-96.
30. Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987; 316(24): 1511-4.
31. Couch FJ, Wang XY, Wu GJ, Qian J, Jenkins RB, James CD. Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res 1999; 59(7): 1408-11.
32. Wong AS, Kim SO, Leung PC, Auersperg N, Pelech SL. Profiling of protein kinases in the neoplastic transformation of human ovarian surface epithelium. Gynecol Oncol 2001; 82(2): 305-11.
33. Sorrells DL, Meschonat C, Black D, Li BD. Pattern of amplification and overexpression of the eukaryotic initiation factor 4E gene in solid tumor. J Surg Res 1999; 85(1): 37-42.
34. Sorrells DL, Jr., Ghali GE, De Benedetti A, Nathan CA, Li BD. Progressive amplification and overexpression of the eukaryotic initiation factor 4E gene in different zones of head and neck cancers. J Oral Maxillofac Surg 1999; 57(3): 294-9.
35. Haydon MS, Googe JD, Sorrells DS, Ghali GE, Li BD. Progression of eIF4e gene amplification and overexpression in benign and malignant tumors of the head and neck. Cancer 2000; 88(12): 2803-10.
36. Wang S, Lloyd RV, Hutzler MJ, et al. Expression of eukaryotic translation initiation factors 4E and 2alpha correlates with the progression of thyroid carcinoma. Thyroid 2001; 11(12): 1101-7.
37. Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 1999; 18(15): 2507-17.
38. Berkel HJ, Turbat-Herrera EA, Shi R, de Benedetti A. Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol Biomarkers Prev 2001; 10(6): 663-6.
39. Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer 2000; 82(1): 161-6.
40. Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 1995; 377(6548): 441-6.
41. Thoreen CC, Sabatini DM. Rapamycin inhibits mTORC1, but not completely. Autophagy 2009; 5(5): 725-6.
42. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22(2): 159-68.
43. Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008; 5(1): e8.
44. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98(18): 10314-9.
45. Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/-mice. Proc Natl Acad Sci USA 2001; 98(18): 10320-5.
46. Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002; 62(17): 5027-34.
47. Jimeno A, Rudek MA, Kulesza P, et al. Pharmacodynamic-guided modified continuous reassessment method-based, dose-finding study of rapamycin in adult patients with solid tumors. J Clin Oncol 2008; 26(25): 4172-9.
48. Lane HA, Breuleux M. Optimal targeting of the mTORC1 kinase in human cancer. Curr Opin Cell Biol 2009; 21(2): 219-29.
49. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther 2007; 82(4): 381-8.
50. Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 2009; 35(2): 148-59.
51. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356(22): 2271-81.
52. Bhatia S, Thompson JA. Temsirolimus in patients with advanced renal cell carcinoma: an overview. Adv Ther 2009; 26(1): 55-67.
53. Le Tourneau C, Faivre S, Serova M, Raymond E. mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? Br J Cancer 2008 Oct 21; 99(8): 1197-203.
54. Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006; 95(9): 1148-54.
55. Ray M, Fleming G. Management of advanced-stage and recurrent endometrial cancer. Semin Oncol 2009; 36(2): 145-54.
56. Gadducci A, Tana R, Cosio S, Fanucchi A, Genazzani AR. Molecular target therapies in endometrial cancer: from the basic research to the clinic. Gynecol Endocrinol 2008; 24(5): 239-49.
57. Lu KH, Wu W, Dave B, et al. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res 2008; 14(9): 2543-50.
58. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27(13): 2278-87.
59. Argatoff LH, Connors JM, Klasa RJ, Horsman DE, Gascoyne RD. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood 1997; 89(6): 2067-78.
60. Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 2007; 7(10): 750-62.
61. Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 2006; 7(4): 285-94.
62. Hess G, Herbrecht R, Romaguera J, 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 2009; 27(23): 3822-9.
63. Coiffier B, Ribrag V. Exploring mammalian target of rapamycin (mTOR) inhibition for treatment of mantle cell lymphoma and other hematologic malignancies. Leuk Lymphoma 2009; 50(12): 1916-30.
64. Udvardy M. Therapy of mantle cell lymphoma. Orv Hetil 2009; 150(50): 2253-7.
65. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372(9637): 449-56.
66. Doi T, Muro K, Boku N, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 2010; 28(11): 1904-10.
67. Arkenau HT. Gastric cancer in the era of molecularly targeted agents: current drug development strategies. J Cancer Res Clin Oncol 2009; 135(7): 855-66.
68. Hede K. Gastric cancer: trastuzumab trial results spur search for other targets. J Natl Cancer Inst 2009; 101(19): 1306-7.
69. Tanaka S, Arii S. Molecularly targeted therapy for hepatocellular carcinoma. Cancer Sci 2009; 100(1): 1-8.
70. Mahalingam D, Sankhala K, Mita A, Giles FJ, Mita MM. Targeting the mTOR pathway using deforolimus in cancer therapy. Future Oncol 2009; 5(3): 291-303.
71. ARIAD Pharmaceuticals Inc. Positive clinical results from ridaforolimus Phase 2 trial in sarcoma 2009; Available at from: http://www.ariad.com/wt/tertiarypage/ridaforolimus
72. Hartford CM, Desai AA, Janisch L, 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 2009; 15(4): 1428-34.
73. 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): 5755-63.
74. Goudar RK, Shi Q, Hjelmeland MD, et al. Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 2005; 4(1): 101-12.
75. Chang SM, Kuhn J, Wen P, et al. Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzymeinducing antiepileptic drugs. Invest New Drugs 2004; 22(4): 427-35.
76. Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005; 23(23): 5294-304.
77. Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006; 12(3 Pt 1): 860-8.
78. Miller KD. Recent translational research: antiangiogenic therapy for breast cancer - where do we stand? Breast Cancer Res 2004; 6(3): 128-32.
79. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12(4): 395-402.
80. Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett 2006; 232(2): 123-38.
81. ARIAD Pharmaceuticals I. ARIAD announces preliminary data from two ongoing clinical trials of its investigational mTOR inhibitor, ridaforolimus, in combination with targeted drugs. News release, 2009.
82. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97(4): 934-59.
83. Yao JC. Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract Res Clin Endocrinol Metab 2007; 21(1): 163-72.
84. Yao JC, Hoff PM. Molecular targeted therapy for neuroendocrine tumors. Hematol Oncol Clin North Am 2007; 21(3): 575-81.
85. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced lowto intermediategrade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008; 26(26): 4311-8.
86. Huang S, Houghton PJ. Mechanisms of resistance to rapamycins. Drug Resist Updat 2001; 4(6): 378-91.
87. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009; 37(Pt 1): 217-22.
88. Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7(7): 1851-63.
89. Folkes AJ, Ahmadi K, Alderton WK, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin -4-yl-thieno(3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 2008; 51(18): 5522-32.
90. Garlich JR, De P, Dey N, et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 2008; 68(1): 206-15.
91. Brachmann S, Fritsch C, Maira SM, Garcia-Echeverria C. PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr Opin Cell Biol 2009; 21(2): 194-8.
92. Park S, Chapuis N, Bardet V, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 2008; 22(9): 1698-706.
93. Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006; 9(5): 341-9.
94. Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycinresistant functions of mTORC1. J Biol Chem 2009; 284(12): 8023-32.
95. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2009; 2(67): 24.
96. Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7(2): e38.
97. George S, Bukowski RM. Role of everolimus in the treatment of renal cell carcinoma. Ther Clin Risk Manag 2009; 5(5): 699-706.
98. White DA, Camus P, Endo M, et al. Non-infectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010; 182(3): 396-403.