Targeting mTOR pathways in human malignancies

Current Pharmaceutical Design

Volumn 18, Issue 19, 2012, Pages 2766-2777

  Fasolo, Angelica ^a   Sessa, Cristiana ^a  

^a SAN RAFFAELE HOSPITAL   (Italy)

Author keywords

Deforolimus; Dual kinase PI3K mTOR inhibitors; Everolimus; Mammalian target of rapamycin; Mantle cell lymphoma; mTORC1 mTORC2 inhibitors; Renal cell carcinoma; Temsirolimus

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; ALPHA INTERFERON; ANTINEOPLASTIC AGENT; AZD 8055; BEVACIZUMAB; BGT 226; EVEROLIMUS; GDC 0980; GSK 2126458; LETROZOLE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PACLITAXEL; PF 04691502; PHOSPHATIDYLINOSITOL 3 KINASE; PKI 587; RIDAFOROLIMUS; TEMSIROLIMUS; TRASTUZUMAB; UNCLASSIFIED DRUG; XL 765; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE;

ADJUVANT THERAPY; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ASTHENIA; B CELL LYMPHOMA; BLOOD BRAIN BARRIER; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER SURVIVAL; DIARRHEA; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG MECHANISM; DRUG SAFETY; DRUG SCREENING; DRUG WITHDRAWAL; DYSPNEA; FATIGUE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTRANSAMINASEMIA; IN VITRO STUDY; IN VIVO STUDY; KIDNEY CARCINOMA; LARGE CELL LYMPHOMA; LIVER CELL CARCINOMA; LYMPHOMA; MANIC DEPRESSIVE PSYCHOSIS; MANTLE CELL LYMPHOMA; MOLECULARLY TARGETED THERAPY; NAUSEA; NAUSEA AND VOMITING; NEUROENDOCRINE TUMOR; NEUTROPENIA; NONHUMAN; PANCREATIC NEUROENDOCRINE TUMOR; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PRIORITY JOURNAL; RASH; RECOMMENDED DRUG DOSE; REVIEW; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SOLID TUMOR; STOMACH CANCER; STOMATITIS; THROMBOCYTOPENIA; TUMOR REGRESSION;

EID: 84862528335     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212800626210     Document Type: Review

References (125)

1. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. Fermentation, isolation and characterization. J Antibiot 1975; 28: 727-32.
2. Vezina 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 (1975) 28: 721-6.
3. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem (1998) 31: 335-40.
4. Schreiber SL. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science (1991) 251: 283-7.
5. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int (2001) 59: 3-16.
6. Huang S, Bjornsti M, Houghton PJ. Rapamycins. Mechanism of action and cellular resistance. Cancer Biol Ther 2003; 2: 222-32
7. Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Expert Opin Investig Drugs 2008; 17: 1717-34.
8. Fasolo A, Sessa C. Current and future directions in mTOR inhibitors development. Expert Opin Investig Drugs 2011; 20: 381-94.
9. Vivanco I, Sawyers CL. The Phosphatidylinositol 3-Kinase-Akt pathway in human cancer. Nat Rev Cancer (2002) 2: 489-501.
10. Tee AR, Manning BD, Roux PP, et al. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signalling by acting as a CTPase-activating protein complex toward Rheb. Curr Biol 2003; 13: 1259-68.
11. Silvera D, Formenti SC, Schneider RJ. Translational control in cancer. Nat rev cancer 2010; 10: 254-66
12. Strimpakos AS, Karapangiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 2009; 35: 148-59.
13. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
14. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098-101.
15. Sarbassov DD, et al.: Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptorindependent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-302.
16. Jacinto E, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122-8.
17. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identifi cation of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12 rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA 1995; 92: 4947-51.
18. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12 rapamycin complex interacting with the binding domain of human FRAP. Science 1996; 273: 239-42.
19. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6: 729-34.
20. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signalling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 2007; 13: 3109-14.
21. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22: 159-68.
22. Harrington LS, Findlay GM, Gray A, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signalling via regulation of IRS proteins. J Cell Biol 2004; 166: 213-23.
23. Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 2010; 30: 908-21.
24. O'Reilly KE, Rojo F, She QB, Solit D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signalling and activates Akt. Cancer Res 2006; 66: 1500-8.
25. Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006; 2: 358-364.
26. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2009; 2: pe-24
27. Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 2009; 8: 3831-7
28. Choo AY, Blenis J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 2009; 8: 567-72.
29. Yu K, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 2010; 70: 621-31.
30. Feldman ME, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7: e38.
31. Yuan R. Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009; 27: 2: 45.
32. Guba M, Von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumour growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128-35.
33. Humar R, Kiefer FN, Berns H, et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) dependent signaling. FASEB J 2002; 16: 771-80.
34. Guba M, Breitenbuch VP, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumour growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128-35.
35. Yu K, Toral-Barza L, Discafani C, et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001; 8: 249-58.
36. Dudkin L, Dilling MB, Cheshire PJ, et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001; 7: 1758-64.
37. Grunwald V, Degraffenried L, Russel D, Friedrichs We, Ray Rb, Hidalgo M. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 2002; 62: 6141-45.
38. Geoerger B, Kerr K, 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 2001; 61: 1527-32.
39. Degraffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol 2004; 15: 1510-6.
40. 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; 19: 5755-63.
41. Wu L, Birle DC, Tannock IF: Effects of the mTOR inhibitor CCI 779 used alone or during chemotherapy on human prostate cancer xenografts. Proc Am Assoc Cancer Res 2004; 45: 3849
42. Gibbons JJ, Discafani C, Peterson R. The effect of CCI-779, a novel macrolide anti-tumor 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.
43. Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents. From bench to clinic. Curr Opin Invest Drugs 2002; 3: 295-304.
44. Beuvink I, O'reilly T, Zumstein S, et al. Antitumor activity of RAD001, an orally active rapamycin derivative. Pro Am Assoc Cancer Res 2001; 42: 366.
45. Schuler W, Sedrani R, Cottens S, et al. RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation (1997) 64: 36-42.
46. 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. Transplantation 2003; 75: 1710-7.
47. Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis and prolongs survival in an ovarian cancer model. Clin Cancer Res (2007) 13: 4261-70.
48. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumour cells to DNA-damage induced apoptosis through inhibition of p21 translation. Cell 2005; 120: 747-59.
49. O'Reilly T, Vaxelaire J, Muller M, et al. In vivo activity of RAD001, an o rally active rapamycin derivative, in experimental tumor models. Proc Am Assoc Cancer Res 2002; 43: 71.
50. Pollock R, Keats JA, Tang H, Rivera VM, Metcalf CA III, Clackson T. Cell shrinkage, cell cycle arrest and anti-angiogenesis underlie the anti-tumor activity of the mTOR inhibitor AP23573. Presented at the 15th EORTC-NCI-AACR Symposium on Molecular Targets Cancer Therapeut 2003; Abstr B160.
51. 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: 2336-47.
52. Fetterly GJ, Mita MM, Britten CD, et al. Pharmacokinetics of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008; 26. Abstract 14555.
53. 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 2008; 26. Abstract 3509.
54. Coppin C. Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Biologics 2010; 4: 91-101.
55. O'Donnell A, Faivre S, Burris HA III, 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 2008; 26: 1588-95.
56. Tanaka C, O'Reilly T, Kovarik JM, et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26: 1596-602.
57. Tabernero J, Rojo F, Calvo E, et al. Doseand 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 2008; 26: 1603-10.
58. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14: 4726-34.
59. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 202; 1: 237-46.
60. Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate binding and HIF1 to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002; 1: 247-55.
61. Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 1998; 8: 588-94
62. Erler JT, Cawthorne CJ, Williams KJ, et al. Hypoxia-mediated down regulation of Bid and Bax in tumors occurs via hypoxia inducible factor 1-dependent and independent mechanisms and contributes to drug resistance. Mol Cell Biol 2004; 24: 2875-89
63. Unruh A, Ressel A, Mohamed HG, et al. The hypoxia-inducible factor-1 is a negative factor for tumor therapy. Oncogene 2003; 22: 3213-20
64. Maxwell PH, Dachs GU, Gleadle JM, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997; 94: 8104-9.
65. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Anti-angiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006; 66: 5549-54.
66. Mayerhofer M, Aichberger KJ, Florian S, et al. Identification of mTOR as a novel bifunctional target in chronic myeloid leukaemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. FASEB J 2005; 19: 960-2.
67. Wan X, Shen N, Mendoza A, Khanna C, Helman LJ. CCI-779 inhibits rhabdomiosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/HIF-1 /VEGF signalling. Neoplasia 2006; 8: 394-401.
68. Furge KA, Mackeigan JP, Teh BT. Kinase targets in renal-cell carcinomas: reassessing the old and discovering the new. Lancet Oncol 2010; 11: 571-8.
69. 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: 909-18.
70. Hudes G, Carducci M, Tomczak P, et al. For the Global ARCC Trial: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356: 2271-81.
71. Dutcher JP, Szczylik C, Tannir N, et al. Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN). J Clin Oncol 2007: 25. Abstract 5033.
72. NCT00631371: Study Comparing Bevacizumab + Temsirolimus Vs Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects. [http://www.clinicaltrials.gov]. Accessed July 15, 2009.
73. Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009; 115: 2438-46.
74. Motzer RJ, Escudier B, Oudard S, et al. For the RECORD-1 Study Group: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372: 449-56.
75. Motzer R, Escudier B, Oudard S, et al. Updated data from a phase III randomized trial of everolimus (RAD001) versus placebo in metastatic renal cell carcinoma (mRCC). ASCO 2009 Genitourinary Cancers Symposium. Abstract 278.
76. De Reijke TM, Bellmunt J, van Poppel H, Marreaud S, Aapro M. EORTC-GU group expert opinion on metastatic renal cell cancer. Eur J Cancer 2009, 45: 765-73.
77. Soulieres D. Review of guidelines on the treatment of metastatic renal cell carcinoma. Curr Oncol 2009; 16(S1): S67-70
78. Escudier B, Kataja V. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20(S4): iv81-iv82.
79. NCT00719264: Safety and Efficacy of Bevacizumab Plus RAD001 Versus Interferon Alfa-2a and Bevacizumab in Adult Patients With Kidney Cancer (L2201) [http://www.clinicaltrials.gov]. Accessed August 11, 2009.
80. NCT00903175: Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-Line and Second-Line Treatment of Patients With Metastatic Renal Cell Carcinoma (RECORD3) [http://www.clinicaltrials.gov]. Accessed July 21, 2009.
81. Bertoni F, Zucca E, Cotter FE. Molecular basis of mantle cell lymphoma. Br J Haematol 2004; 124: 130-40
82. Dal Col J, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008; 111: 5142-51.
83. Ansell SM, Inwards DJ, Rowland KM, et al. Low-dose, singleagent temsirolimus for relapsed mantle cell lymphoma. A phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008; 113: 508-14.
84. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator's choice of therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009, 27: 3822-9
85. Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in Non-Mantle Cell Non-Hodgkin's Lymphoma Subtypes: the University of Chicago Phase II Consortium. J Clin Oncol 2010; 28: 1-7.
86. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010; 28: 69-76.
87. 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: 4311-8.
88. Yao JC, Rindi G, Evans DB. Pancreatic endocrine tumors. In: De-Vita VT, Lawrence TS, Rosenberg SA, eds. Cancer: principles and practice of oncology. 8th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins, 2008: 1702-21.
89. Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 2010; 28: 245-55.
90. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-23
91. Gligorov J, Azria D, Namer M, Khayat D, Spano JP. Novel therapeutic strategies combining antihormonal and biological targeted therapies in breast cancer: Focus on clinical trials and perspectives. Crit Rev Hematol Oncol 2007, 64: 115-28.
92. Chawla SP, Tolcher AW, Staddon AP, et al. Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: update of phase II trial. J Clin Oncol (Meeting Abstracts) 2007; 25: 10076.
93. Mita MM, Britten CD, Poplin E, et al. Deforolimus trial 106A Phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669). J Clin Oncol (Meeting Abstracts) 2008; 26: 3509.
94. Slomovitz B.M., Brown J., Johnston T.A., Mura D. A Phase II study of everolimus and letrozole in patients with advanced or recurrent endometrial cancer. J Clin Oncol 2011: 29. Abstract 5012.
95. Oza AM, Poveda A, Clamp AR, et al. A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotheraphy (C) in female adult patients with advanced endometrial carcinoma. J Clin Oncol 2011: 29. Abstract 5009.
96. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 2008; 27: 5527-41.
97. Janes MR, Fruman DA. Targeting TOR dependence in cancer. Oncotarget 2010; 1: 69-76.
98. Yu K, Toral-Barza L, Shi C, Zhang WG, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009; 69: 6232-40.
99. Di Nicolantonio F, Arena S, Tabernero J, et al. Deragulation of the PI3K and KRAS signalling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010; 8: 2858-6
100. Garcia-Echeverria, Sellers C. Drug discovery approaches targheting the PI3K/Akt pathway in cancer. Oncogene 2008; 27: 5511-26
101. 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: 194-8.
102. Foukas LC, Claret M, Okkenhaug K, et al. Critical role for the p110a phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 2006, 441: 366-70.
103. Vanhaesebroeck B, Leevers SJ, Ahmadi K, et al. "Synthesis and function of 3-phosphorylated inositol lipids," Annual Review of Biochemistry 2001; 70: 535-602.
104. Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective and orally bioavailable ATP-competitive mammalian target of Rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010; 70: 288-98.
105. 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. Proc Am Soc Clin Oncol 2010; 28: 3006.
106. Papadopoulos KP, Markman B, Tabernero J, et al. A phase I doseescalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD)of a novel PI3K inhibitor, XL765, administered orally to patients with advanced solid tumors. Proc Am Soc Clin Oncol 2008; 26: 3510.
107. Nghiemphu PL, Omuro AM, Cloughesy T, et al. A phase I safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients with newly diagnosed malignant glioma. Proc Am Soc Clin Oncol 2010, 28: 3085.
108. Cohen RB, Janne PA, Engelman JA, et al. A phase I safety and pharmacokinetic study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2010, 28: 3015.
109. Brana I, LoRusso P, Baselga J, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients with advanced malignancies. Proc Am Soc Clin Oncol 2010, 28: 3030.
110. Venkatesan AM, Dehnhardt CM, Santos ED, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem 2010; 53: 2636-45.
111. Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidilynositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851-63.
112. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signalling and inhibits the grwth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-30.
113. Burris H, Rodon J, Sharma S, et al. Firs-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients with advanced solid tumors. J Clin Oncol 2010, 28: 3005.
114. NCT00600275 A Phase I/II, Multi-center, Open-label Study of BGT226, Administered Orally in Adult Patients With Advanced Solid Malignancies Including Patients With Advanced Breast Cancer. [http://www.clinicaltrials.gov]. Accessed January 11, 2008
115. 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: 206-15.
116. Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1benzopyran-4-one (LY294002). J Biol Chem 1994; 269: 5241-8.
117. Chiorean EG, Mahadevan D, Harris WB, et al. Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly iv in patients with refractory solid tumors. J Clin Oncol 2009; 27: 2558
118. Durden, et al. A Novel Pan-PI3K/Akt Inhibitor, SF1126, Inhibits In vitro Growth of Multiple Myeloma Cells. Blood (ASH Annual Meeting Abstracts) 2007; 110: 4806.
119. David E, Peng X, Barwick BG, Kaufman JL, Garlich JR, Lonial S. SF1126, a Novel PI3K Inhibitor Results in Downstream Inhibition of the PI3K Axis and Displays Sequence Specific Synergy When Combined with Bortezomib in Multiple Myeloma Cells. Blood (ASH Annual Meeting Abstracts) 2008; 112: 5167.
120. Lonial S, Harvey RD, Francis D, et al. Preliminary results of a phase I study of the pan-PI3K kinase inhibitor SF1126 in patients with relapsed and refractory mieloma. Blood (ASH Annual Meeting Abstracts) 2009; 114: 3879.
121. NCT00927823 A Phase 1, Open-Label, Dose-Escalation Study To Evaluate Safety, Pharmacokinetics, And Pharmacodynamics Of The PI3K/MTOR Inhibitor PF-04691502 In Adult Patients With Advanced Malignant Solid Tumors [http://www.clinicaltrials.gov]. Accessed June 23, 2009
122. Cheng H, Bagrodia S, Bailey, et al. Discovery of the highly potent PI3K/mTOR dual inhibitor PF-04691502 through structure based drug design. Med Chem Commun 2010; 1: 139-44.
123. Dolly S, Wagner AJ, Bendell JC, et al. A firs-in-human, phase I study to evaluate the dual PI3K/mTOR inhibitor GDC-0980 administered QD in patients with advanced solid tumors or non Hodgkin's lymphoma. J Clin Oncolol 2010; 28: 3079.
124. Knight SD, Adams ND, Burgess JL, et al. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med Chem Lett 2010; 1: 39-43.
125. NCT00972686: A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK2126458 in Subjects With Solid Tumors or Lymphoma [http://www.clinicaltrials.gov]. Accessed September 3, 2009