Sunitinib, sorafenib and mTOR inhibitors in renal cancer

Journal of B.U.ON.

Volumn 12, Issue SUPPL. 1, 2007, Pages

  Radulovic, Sinisa ^a   Bjelogrlic, Snezana K ^a  

^a INSTITUTE FOR ONCOLOGY AND RADIOLOGY OF SERBIA   (Serbia)

Author keywords

Rrenal cell carcinoma; Sorafenib; Sunitinib; Tem sirolimus

Indexed keywords

ALPHA INTERFERON; ANTIHYPERTENSIVE AGENT; BEVACIZUMAB; CISPLATIN; CYCLOSPORIN; CYTOKINE; CYTOTOXIC AGENT; DOCETAXEL; DOXORUBICIN; ERLOTINIB; EVEROLIMUS; FLUOROURACIL; GEMCITABINE; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PACLITAXEL; PLACEBO; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; RAPAMYCIN; SORAFENIB; SUNITINIB; TEMSIROLIMUS; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN RECEPTOR 3; VON HIPPEL LINDAU PROTEIN;

ABDOMINAL DISTENSION; ADVANCED CANCER; AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ANOREXIA; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ASTHENIA; BIPOLAR DISORDER; BREAST ADENOCARCINOMA; BREAST CANCER; BREAST TUMOR; CANCER IMMUNOTHERAPY; CANCER INHIBITION; CHEMOTHERAPY INDUCED EMESIS; CLEAR CELL CARCINOMA; CLINICAL TRIAL; COLON CANCER; COLON TUMOR; CONFERENCE PAPER; CONSTIPATION; DIARRHEA; DISEASE FREE SURVIVAL; DOSAGE SCHEDULE COMPARISON; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ERUPTION; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG POTENTIATION; DRUG TARGETING; DRUG WITHDRAWAL; DYSPEPSIA; FATIGUE; GASTROINTESTINAL SYMPTOM; GENE MUTATION; GENE OVEREXPRESSION; GENETIC RISK; HAND FOOT SYNDROME; HISTOPATHOLOGY; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTENSION; HYPERTRIGLYCERIDEMIA; HYPOPHOSPHATEMIA; KIDNEY CANCER; KIDNEY CARCINOMA; LUNG METASTASIS; LUNG NON SMALL CELL CANCER; LYMPHOCYTOPENIA; MACULOPAPULAR RASH; MAXIMUM TOLERATED DOSE; MELANOMA; MONOTHERAPY; MUCOSA INFLAMMATION; NAUSEA; NEPHRECTOMY; NEUTROPENIA; NONHUMAN; OVERALL SURVIVAL; PANCREATITIS; PERIPHERAL EDEMA; PNEUMONIA; PROGNOSIS; RECOMMENDED DRUG DOSE; SENSORY NEUROPATHY; SIDE EFFECT; SKIN DISCOLORATION; SKIN TOXICITY; SOLID TUMOR; SQUAMOUS CELL CARCINOMA; STOMATITIS; SURVIVAL RATE; THROMBOCYTOPENIA; TRIACYLGLYCEROL LIPASE BLOOD LEVEL; TUMOR REGRESSION; UPREGULATION;

ANGIOGENESIS INHIBITORS; BENZENESULFONATES; CARCINOMA, RENAL CELL; DRUG RESISTANCE, NEOPLASM; HUMANS; INDOLES; KIDNEY NEOPLASMS; PATIENT SELECTION; PRACTICE GUIDELINES AS TOPIC; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; PYRIDINES; PYRROLES; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; SIROLIMUS; TREATMENT OUTCOME; TUMOR MARKERS, BIOLOGICAL;

EID: 36749016244     PISSN: 11070625     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Conference Paper

References (103)

1. Thrasher JB, Paulson DF. Prognostic factors in renal cancer. Urol Clin Northern 1993; 20: 247-262.
2. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996; 335: 865-875.
3. Motzer RJ, Mazumdar M, Bacik J, Russo P, Berg WJ, Metz EM. Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol 2000; 19: 1929-1935.
4. Coppin C, Porzolt F, Autenrieth M, Kurnpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cohrane Database Syst Rev 2004; CD001425.
5. Storkel S, Eble JN, Adlakha K et al. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80: 987-989.
6. Soung SP, Rao J, Cheng L, Cote RJ. Classical pathology versus molecular pathology in renal cell carcinoma. Curr Urol Rep 2007; 8: 5-11.
7. Lonser RR, Glenn GM, Walther M et al. von Hippel-Lindau disease. Lancet 2003; 361: 2059-2067.
8. Maher ER, Yates JR, Harries R et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77: 1151-1163.
9. Yao M, Yoshida M, Kishida T et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 2002; 94: 1569-1575.
10. Kondo K, Yao M, Yoshida M et al. Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters. Genes Chromosomes Cancer 2002; 34: 58-68.
11. Schraml P, Struckmann K, Hatz F et al. VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J Pathol 2002; 196: 186-193.
12. Kibel A, Itiopoulos O, DeCaprio JA, Kaelin WG, Jr. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 1995; 269: 1444-1446.
13. Kamura T, Koepp DM, Conrad MN et al. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 1999; 284: 657-661.
14. Clifford SC, Astuti D, Hooper L, Maxwell PH, Ratcliffe PJ, Maher ER. The pVHL-associated SCF ubiquitin ligase complex: molecular genetic analysis of elongin B and C, Rbx1 and HIF-1 alpha in renal cell carcinoma. Oncogene 2001; 20: 5067-5074.
15. Iwai K, Yamanaka K, Kamura T et al. Identification ofthe von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci USA 1999; 96: 12436-12441.
16. Ivan M, Kondo K, Yang H et al. HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292: 464-468.
17. Yu F, White SB, Zhao Q, Lee FS. HIF-1 alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natt Acad Sci USA 2001; 99: 9630-9635.
18. Jaakkola P, Mole DR, Tian YM et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292: 468-472.
19. Epstein AC, Gleadle JM, McNeill LA et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001; 107: 43-54.
20. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF- I alpha in normoxia. EMBO J 2003; 22: 4082-4090.
21. Ivan M, Haberberger T, Gervasi DC et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA 2002; 99: 13459-13464.
22. Bruick RK, McKnight SL. A conserved family ofprolyl-4-hydroxylases that modify HIF. Science 2001; 294: 1337-1340.
23. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor I alpha (HIF-1 alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003; 23: 9361-9374.
24. Kim WY, Kaelin WG, Jr. Molecular pathways in renal cell carcinoma - rationale for targeted treatment. Semin Oncol 2006; 33: 588-595.
25. Giaccia AJ, Simon MC, Johnson R. The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes Dev 2004; 18: 2183-2194.
26. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353-364.
27. Harris AL. Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38-47.
28. Veikkola T, Alitalo K. VEGFs, receptors and angiogenesis. Semin Cancer Biol 1999; 9: 211-220.
29. Saaristo A, Karpanen T, Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene 2000; 19: 6122-6129.
30. Dibb NJ, Dilworth SM, Mol CD. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer 2004; 4: 718-727.
31. Bjamegard M, Enge M, Norlin J et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 2004; 131: 1847-1857.
32. Lindblom P, Gerhardt H, Liebner S et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 2003; 17: 1835-1840.
33. Erler JT, Bennewith KL, Nicolau M et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440: 1222-1226.
34. Ananth S, Knebelmann B, Gruning W et al. Transforming growth factor beta1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma. Cancer Res 1999; 59: 2210-2216.
35. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005; 8: 179-183.
36. Bjelogrlic SK, Srdic T, Radulovic S. Mammalian target of rapamycin is a promising target for novel therapeutic strategy against cancer. J BUON 2006; 11: 267-276.
37. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and independent pathways. Cancer Cell 2003; 4: 147-158.
38. Liu MY, Poellinger L, Walker CL. Up-regulation of hypoxia-inducible factor 2alpha in renal cell carcinoma associated with loss of Tsc-2 tumor suppressor gene. Cancer Res 2003; 63:2675-2680.
39. Hudson CC, Liu M, Chiang GG et al. Regulation of hypoxia-inducible factor 1 alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22: 7004-7014.
40. Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003; 278: 29655-29660.
41. Zhong H, Chiles K, Feldser D et al. Modulation of hypoxia-inducible factor 1 alpha 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 2000; 60: 15 41-1545.
42. El Hashemite N, Walker V, Zhang H, Kwiatkowski DJ. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res 2003; 63: 5173-5177.
43. Thomas GV, Tran C, Mellinghoff IK et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006; 12: 122-127.
44. Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 1997; 10: 537-544.
45. Schmidt L, Duh FM, Chen F et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997; 16: 68-73.
46. Schmidt L, Junker K, Nakaigawa N et al. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 1999; 18:2343-2350.
47. Zhang YW, Vande Woude GF. HGF/SF-met signaling in the control of branching morphogenesis and invasion. J Cell Biochem 2003; 88: 408-417.
48. Rosario M, Birchmeier W. How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol 2003; 13: 328-335.
49. Corso S, Comoglio PM, Giordano S. Cancer therapy: can the challenge be MET? Trends Mol Med 2005; 11: 284-292.
50. Lee JH, Han SU, Cho H et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 2000; 19:4947-4953.
51. Ma PC, Kijima T, Maulik G et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 2003; 63: 6272-6281.
52. Di Renzo MF, Olivero M, Martone T et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 2000; 19:1547-1555.
53. Lehtonen R, Kiuru M, Vanharanta S et al. Biallelic inactivation of famarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol 2004; 164: 17-22.
54. Morris MR, Maina E, Morgan NV et al. Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma. J Clin Pathol 2004; 57: 706-711.
55. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5: 343-354.
56. Isaacs JS, Jung YJ, Mole DR et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005; 8: 143-153.
57. Selak MA, Armour SM, McKenzie ED et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005; 7: 77-85.
58. Nickerson ML, Warren MB, Toro JR et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2002; 2:157-164.
59. Toro JR, Glenn G, Duray P et al. Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999; 135: 1195-1202.
60. Roth JS, Rabinowitz AD, Benson M, Grossman ME. Bilateral renal cell carcinoma in the Birt-Hogg-Dube syndrome. J Am Acad Dermatol 1993; 29: 1055-1056.
61. Yamazaki K, Sakamoto M, Ohta T, Kanai Y, Ohki M, Hirohashi S. Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene 2003; 22: 847-852.
62. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002; 8: 2255-2257.
63. Wilhelm SM, Carter C, Tang L et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-7109.
64. Strumberg D, Awada A, Hirte H et al. Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? Eur J Cancer 2006; 42: 548-556.
65. Awada A, Hendlisz A, Gil T et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 2005; 92: 1855-1861.
66. Moore M, Hirte HW, Siu L et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 2005; 16: 1688-1694.
67. Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005; 23: 965-972.
68. Ratain MJ, Eisen T, Stadler WM et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 2505-2512.
69. Kane RC, Farrell AT, Saber H et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 2006; 12: 7271-7278.
70. Escudier B, Szczylik C, Eisen T et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 2005; 23: #4510 (abstr).
71. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17:2530-2540.
72. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 2005; 315: 971-979.
73. Mendel DB, Laird AD, Xin X et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003; 9: 327-337.
74. Pawson T. Regulation and targets of receptor tyrosine kinases. Eur J Cancer 2002; 38 (Suppl 5): S3-10.
75. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
76. Mendel DB, Laird AD, Xin X et al. Development of a preclinical pharmacokinetic/pharmacodynwnic relationship for the angiogenesis inhibitor SU11248, a selective inhibitor of VEGF and PDGF receptor tyrosine kinase in clinical development. Proc Am Soc Clin Oncol 2002; 20: #94 (abstr).
77. Abrams TJ, Murray LJ, Pesenti E et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2003; 2: 1011-1021.
78. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003; 2: 471-478.
79. Krystal GW, Honsawek S, Kiewlich D et al. Indolinone tyrosine kinase inhibitors block Kit activation and growth of small cell lung cancer cells. Cancer Res 2001; 61: 3660-3668.
80. Faivre S, Delbaldo C, Vera K et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24: 25-35.
81. Rosen L, Mulay M, Long J et al. Phase I trial of SU011248, a novel tyrosine kinase inhibitor in advanced solid tumors. Proc Am Soc Clin Oncol 2003; 22: #765 (abstr).
82. Raymond E, Faivre S, Vera K et al. Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. Proc Am Soc Clin Oncol 2003; 22: #769 (abstr).
83. Motzer RJ, Michaelson MD, Redman BG et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 16-24.
84. Motzer RJ, Rini BI, Michaelson MD et al. Phase 2 trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma (RCC). J Clin Oncol 2005; 23: 94508 (abstr).
85. Motzer RJ, Rini BI, Bukowski RM et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 295:2516-2524.
86. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115-124.
87. Douros J, Suffness M. New antitumor substances of natural origin. Cancer Treat Rev 1981; 8: 63-87.
88. Houchens DP, Ovejera AA, Riblet SM, Slagel DE. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 1983; 19:799-805.
89. Gibbons JJ, Discafani C, Peterson R, Hernandez R, Skotnicki J, Frost P. The effect of CCI-779, a novel macrolide antitumor agent, on the growth of human tumor cells in vitro and in nude mouse xenograft in vivo. Proc Am Assoc Cancer Res 2000; 40: #301 (abstr).
90. Geoerger B, Kerr Y, Tang CB 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 200 1; 61: 1527-1532.
91. Luan FL, Ding R, Sharma VK, Chon WJ, Lagman M, Suthanthiran M. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003; 63: 917-926.
92. 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: 2336-2347.
93. Hidalgo M, Buckner JC, Erlichman C et al. Aphase 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: 5755-5763.
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 tumours. Proc Am Soc Clin Oncol 2003; 21: #803 (abstr).
95. 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: 909-918.
96. Smith JW, Ko Y-J, Dutcher J et al. Update of a phase 1 study of intravenous CCI-779 given in combination with interferon-alpha to patients with advanced renal cell carcinoma. J Clin Oncol 2004; 22: #4513 (abstr).
97. Hodes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: 2271-2281.
98. Lane HA, Boulay A, Hattenberger M et al. The orally active rapamycin derivative RAD001 has potential as an antitumor agent with a broad antiproliferative activity: PTEN as a molecular determinant of response. Proc Am Assoc Cancer Res 2003; 44: #1608 (abstr).
99. Boulay A, Stephan C, Zumstein-Mecker S etal. Phospho-Akt levels as a potential biomarker of in vitro sensitivity of tumor cell lines to the mTOR pathway inhibitor RAD001. Clin Cancer Res 2003; 9: #B 170 (abstr).
100. O'Railly T, Vaxelaire J, Heinz-Herbert M, Hattenberger M, Lane HA. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. Proc Am Assoc Cancer Res 2002; 43: #359 (abstr).
101. Tabemero J, Rojo F, Burris H et al. Aphase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule ofthe oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid tumors. J Clin Oncol 2005; 23: #3007 (abstr).
102. Porter LL, Burris HA, Jones SF et al. Summary of results in patients with metastatic renal cell carcinoma (RCC) from phase 1 studies of RAD001 (everolimus). J Clin Oncol 2006; 24: #14599 (abstr).
103. Jac J, Giessinger S, Khan M, Willis J, Chiang S, Amato R. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). J Clin Oncol 2007; 25: #5107 (abstr).