MTOR inhibitors in advanced breast cancer: Ready for prime time?

Cancer Treatment Reviews

Volumn 39, Issue 7, 2013, Pages 742-752

  Martin, Lesley Ann ^a   André, Fabrice ^b,c   Campone, Mario ^d   Bachelot, Thomas ^e   Jerusalem, Guy ^f  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b Universite Paris Sud   (France)

^c INSTITUT GUSTAVE ROUSSY   (France)

^d UMR INSERM U892 CNRS 6299   (France)

^e UNIVERSITÉ LYON 1   (France)

^f UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

Advanced breast cancer; Endocrine resistance; Estrogen receptor; Everolimus; Exemestane; Human epidermal growth factor receptor 2; MTOR inhibitor; Progesterone receptor

Indexed keywords

ANASTROZOLE; AROMATASE INHIBITOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ESTROGEN RECEPTOR; EVEROLIMUS; EXEMESTANE; FIBROBLAST GROWTH FACTOR RECEPTOR 1; FULVESTRANT; INSULIN RECEPTOR; LETROZOLE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; NAVELBINE; PACLITAXEL; PROGESTERONE RECEPTOR; PROTEIN SERINE THREONINE KINASE; RAPAMYCIN; S6 KINASE; TAMOXIFEN; TEMSIROLIMUS; TRASTUZUMAB;

ANTIPROLIFERATIVE ACTIVITY; BREAST CANCER; BREAST METASTASIS; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER HORMONE THERAPY; CANCER PATIENT; CANCER RESISTANCE; CANCER THERAPY; CELL MOTILITY; CELL PROLIFERATION; CELL SURVIVAL; DNA SEQUENCE; ENZYME PHOSPHORYLATION; GENE OVEREXPRESSION; HUMAN; INTRACELLULAR SIGNALING; MULTICENTER STUDY (TOPIC); ONCOGENE; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTMENOPAUSE; PROGRESSION FREE SURVIVAL; PROMOTER REGION; PROTEIN PROTEIN INTERACTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; UPREGULATION; VISCERAL METASTASIS;

ADVANCED BREAST CANCER; ENDOCRINE RESISTANCE; ESTROGEN RECEPTOR; EVEROLIMUS; EXEMESTANE; HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR-2; MTOR INHIBITOR; PROGESTERONE RECEPTOR;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BREAST NEOPLASMS; DRUG EVALUATION, PRECLINICAL; FEMALE; HUMANS; NEOPLASM STAGING; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR, ERBB-2; RECEPTORS, ESTROGEN; RECEPTORS, PROGESTERONE; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; TRANSLATIONAL MEDICAL RESEARCH; TREATMENT OUTCOME;

EID: 84881555744     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2013.02.005     Document Type: Review

References (100)

1. Cardoso F., Costa A., Norton L., et al. 1st international consensus guidelines for advanced breast cancer (ABC 1). Breast 2012, 21:242-252.
2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer. Version I. 2012. 2012 [accessed 09.08.12]. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.
3. Shaw R.J., Cantley L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006, 441:424-430.
4. Cortes J., Saura C., Bellet M., et al. HER2 and hormone receptor-positive breast cancer - blocking the right target. Nat Rev Clin Oncol 2011, 8:307-311.
5. Bjornstrom L., Sjoberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 2005, 19:833-842.
6. Yamnik R.L., Digilova A., Davis D.C., Brodt Z.N., Murphy C.J., Holz M.K. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem 2009, 284:6361-6369.
7. Arteaga C.L., Sliwkowski M.X., Osborne C.K., Perez E.A., Puglisi F., Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2012, 9:16-32.
8. Gijsen M., King P., Perera T., et al. HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer. PLoS Biol 2010, 8:e1000563.
9. Hsieh A.C., Moasser M.M. Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 2007, 97:453-457.
10. deGraffenried L.A., Friedrichs W.E., Russell D.H., et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res 2004, 10:8059-8067.
11. Sadler T.M., Gavriil M., Annable T., Frost P., Greenberger L.M., Zhang Y. Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus. Endocr Relat Cancer 2006, 13:863-873.
12. Beeram M., Tan Q.T., Tekmal R.R., Russell D., Middleton A., DeGraffenried L.A. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 2007, 18:1323-1328.
13. Boulay A., Rudloff J., Ye J., et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005, 11:5319-5328.
14. Miller T.W., Perez-Torres M., Narasanna A., et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 2009, 69:4192-4201.
15. Yue W., Fan P., Wang J., Li Y., Santen R.J. Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells. J Steroid Biochem Mol Biol 2007, 106:102-110.
16. Santen R.J., Song R.X., Masamura S., et al. Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells. Adv Exp Med Biol 2008, 630:19-34.
17. Johnston S.R. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 2010, 16:1979-1987.
18. Nicholson R.I., Staka C., Boyns F., Hutcheson I.R., Gee J.M. Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy. Endocr Relat Cancer 2004, 11:623-641.
19. Gee J.M., Harper M.E., Hutcheson I.R., et al. The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 2003, 144:5105-5117.
20. Massarweh S., Osborne C.K., Creighton C.J., et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 2008, 68:826-833.
21. Treeck O., Wackwitz B., Haus U., Ortmann O. Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol Oncol 2006, 102:292-299.
22. Eichhorn P.J., Gili M., Scaltriti M., et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008, 68:9221-9230.
23. Gayle S.S., Arnold S.L., O'Regan R.M., Nahta R. Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 2012, 12:151-162.
24. Miller T.W., Forbes J.T., Shah C., et al. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res 2009, 15:7266-7276.
25. Garcia-Garcia C., Ibrahim Y.H., Serra V., et al. Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 2012, 18:2603-2612.
26. Riggio M., Polo M.L., Blaustein M., et al. PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer. Carcinogenesis 2012, 33:509-518.
27. Miller T.W., Rexer B.N., Garrett J.T., Arteaga C.L. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011, 13:224.
28. Maruyama N., Miyoshi Y., Taguchi T., Tamaki Y., Monden M., Noguchi S. Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 2007, 13:408-414.
29. Loi S., Haibe-Kains B., Majjaj S., et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A 2010, 107:10208-10213.
30. Perez-Tenorio G., Alkhori L., Olsson B., et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 2007, 13:3577-3584.
31. Baselga J., Semiglazov V., van Dam P., et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009, 27:2630-2637.
32. Ellis M.J., Lin L., Crowder R., et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 2010, 119:379-390.
33. Karlsson E., Waltersson M.A., Bostner J., et al. High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1. Genes Chromosomes Cancer 2011, 50:775-787.
34. Noh W.C., Kim Y.H., Kim M.S., et al. Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables. Breast Cancer Res Treat 2008, 110:477-483.
35. Kim E.K., Kim H.A., Koh J.S., et al. Phosphorylated S6K1 is a possible marker for endocrine therapy resistance in hormone receptor-positive breast cancer. Breast Cancer Res Treat 2011, 126:93-99.
36. Cleator S.J., Ahamed E., Coombes R.C., Palmieri C. A 2009 update on the treatment of patients with hormone receptor-positive breast cancer. Clin Breast Cancer 2009, 9(Suppl. 1):S6-S17.
37. Higgins M.J., Baselga J. Targeted therapies for breast cancer. J Clin Invest 2011, 121:3797-3803.
38. Dodwell D., Wardley A., Johnston S. Postmenopausal advanced breast cancer: options for therapy after tamoxifen and aromatase inhibitors. Breast 2006, 15:584-594.
39. Bergh J., Jonsson P.E., Lidbrink E.K., et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012, 30:1919-1925.
40. Dodwell D., Coombes G., Bliss J.M., Kilburn L.S., Johnston S. Combining fulvestrant (Faslodex) with continued oestrogen suppression in endocrine-sensitive advanced breast cancer: the SoFEA trial. Clin Oncol (R Coll Radiol) 2008, 20:321-324.
41. Johnston S, Kilburn LS, Ellis P, et al. Fulvestrant alone or with concomitant anastrozole vs exemestane following progression on non-steroidal aromatase inhibitor: first results of the SoFEa trial (CRUKE/03/021 & CRUK/09/007) (ISRCTN44195747). Presented at: 8th European Breast Cancer Conference, March 21-24, 2012, Vienna, Austria [Abstract 2LBA].
42. Afinitor (everolimus) [summary of product characteristics]. Nuremberg, Germany: Novartis Pharma GmbH., 2012 [accessed 08.28.12]. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001038/WC500022814.pdf.
43. Torisel (temsirolimus) [summary of product characteristics]. Catania, Italy: Wyeth Lederle S.p.A., a subsidiary of Pfizer Inc., 2012 [accessed 08.28.12]. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000799/WC500039912.pdf.
44. Rapamune (sirolimus) [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals, a subsidiary of Pfizer Inc., 2012 [accessed 09.08.12]. http://labeling.pfizer.com/showlabeling.aspx?id=139.
45. Bhattacharyya G.S., Biswas J., Singh J.K., et al. Reversal of tamoxifen resistance (hormone resistance) by addition of sirolimus (mTOR inhibitor) in metastatic breast cancer. Eur J Cancer 2011, 47(Suppl. 2). [Abstract 16LBA].
46. Bachelot T., Bourgier C., Cropet C., et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012, 30:2718-2724.
47. Hortobagyi GN, Piccart M, Rugo H, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial. Presented at: CTRC-AACR San Antonio Breast Cancer Symposium, December 6-10, 2011, San Antonio, TX [Abstract S3-7].
48. Baselga J., Roche H., Fumoleau P. Treatment of postmenopausal women with locally advanced or metastatic breast cancer with letrozole alone or in combination with temsirolimus: a randomized, 3-arm, phase 2 study. Breast Cancer Res Treat 2005, 94(Suppl. 1):S62. [Abstract 1068].
49. Chow L.W.C., Sun Y., Jassem J., et al. Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2006, 100(Suppl. 1):S286. [Abstract 6091].
50. Bourgier C, Ray-Coquard I, Provencal J, et al. Exploratory subgroup analysis of the TAMRAD phase 2 GINECO trial evaluating tamoxifen (TAM) plus everolimus (RAD) vs TAM alone in patients with hormone-receptor-positive, HER2-negative metastatic breast cancer (mBC) with prior exposure to aromatase inhibitors (AIs): implication for research strategies. Presented at: The European Multidisciplinary Cancer Congress, September 23-27, 2011, Stockholm, Sweden [Abstract 5005].
51. Bachelot T, Ferrero J-M, Cropet C, et al. Translational studies within the TAMRAD randomized GINECO trial: evidence for TORC1 activation marker as a predictive factor for everolimus efficacy in metastatic breast cancer. Presented at: 4th IMPAKT Breast Cancer Conference, May 3-5, 2012, Brussels, Belgium [Abstract 13O_PR].
52. Baselga J., Campone M., Piccart M., et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012, 366:520-529.
53. Piccart-Gebhart MJ, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase III trial. Presented at: 48th Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL [Abstract 559].
54. Campone M, Noguchi S, Pritchard KI, et al. Efficacy and safety of everolimus in postmenopausal women with advanced breast cancer (BOLERO-2): effect of visceral metastases. Presented at: 2012 ESMO Congress, September 28-October 2, 2012, Vienna, Austria [Abstract 324PD].
55. Tabernero J., Rojo F., Calvo E., et al. Dose- and 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, 26:1603-1610.
56. Buckner J.C., Forouzesh B., Erlichman C., et al. Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer. Invest New Drugs 2010, 28:334-342.
57. Ross J.S., Slodkowska E.A., Symmans W.F., Pusztai L., Ravdin P.M., Hortobagyi G.N. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009, 14:320-368.
58. Slamon D.J., Leyland-Jones B., Shak S., et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001, 344:783-792.
59. Cameron D., Casey M., Press M., et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008, 112:533-543.
60. Meric-Bernstam F., Hung M.C. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res 2006, 12:6326-6330.
61. von Minckwitz G., du Bois A., Schmidt M., et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 2009, 27:1999-2006.
62. Blackwell K.L., Burstein H.J., Storniolo A.M., et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010, 28:1124-1130.
63. Berns K., Horlings H.M., Hennessy B.T., et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007, 12:395-402.
64. Jerusalem G., Fasolo A., Dieras V., et al. Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2011, 125:447-455.
65. Andre F., Campone M., O'Regan R., et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 2010, 28:5110-5115.
66. Dalenc F, Campone M, Hupperets P, et al. Everolimus in combination with weekly paclitaxel and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab and taxanes: a multicenter phase II clinical trial. Presented at: 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL [Abstract 1013].
67. Morrow P.K., Wulf G.M., Ensor J., et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 2011, 29:3126-3132.
68. U.S. National Institutes of Health. Daily everolimus in combination with trastuzumab and vinorelbine in HER2/neu positive women with locally advanced or metastatic breast cancer (BOLERO-3). 2012 [accessed 09.08.12]. http://clinicaltrials.gov/ct2/show/NCT01007942.
69. +), locally advanced or metastatic breast cancer (BC). J Clin Oncol 2012, 30(Suppl.). [Abstract TPS648].
70. U.S. National Institutes of Health. Trastuzumab with or without everolimus in treating women with breast cancer that can be removed by surgery. 2012 [accessed 09.08.12]. http://www.clinicaltrials.gov/ct2/show/NCT00674414?term=NCT00674414&rank=1.
71. Don A.S., Zheng X.F. Recent clinical trials of mTOR-targeted cancer therapies. Rev Recent Clin Trials 2011, 6:24-35.
72. Shor B., Gibbons J.J., Abraham R.T., Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 2009, 8:3831-3837.
73. Zheng X.F., Florentino D., Chen J., Crabtree G.R., Schreiber S.L. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 1995, 82:121-130.
74. Cybulski N., Hall M.N. TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 2009, 34:620-627.
75. Sun S.Y., Rosenberg L.M., Wang X., et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2005, 65:7052-7058.
76. Wan X., Harkavy B., Shen N., Grohar P., Helman L.J. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007, 26:1932-1940.
77. Dancey J. MTOR signaling and drug development in cancer. Nat Rev Clin Oncol 2010, 7:209-219.
78. Rodrik-Outmezguine V.S., Chandarlapaty S., Pagano N.C., et al. MTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov 2011, 1:248-259.
79. Holt S.V., Logie A., Davies B.R., et al. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). Cancer Res 2012, 72:1804-1813.
80. Maira S.M., 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, 7:1851-1863.
81. Chiarini F., Grimaldi C., Ricci F., et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res 2010, 70:8097-8107.
82. Manara M.C., Nicoletti G., Zambelli D., et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res 2010, 16:530-540.
83. Papadopoulos K.P., Markman B., Tabernero J., et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors. J Clin Oncol 2008, 26(Suppl.). [Abstract 3510].
84. Molckovsky A., Siu L.L. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology meeting. J Hematol Oncol 2008, 1:20.
85. Wagner A.J., Burris HA, de Bono J.S., et al. Pharmacokinetics and pharmacodynamic biomarkers for the dual PI3K/mTOR inhibitor GDC-0980: initial phase I evaluation. Mol Cancer Ther 2009, 8(Suppl.). [Abstract B137].
86. Dolly S., Wagner A.J., Bendell J.C., et al. A first-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 Oncol 2010, 28(Suppl.). [Abstract 3079].
87. Garlich J.R., De P., Dey N., et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 2008, 68:206-215.
88. Schwertschlag U.S., Chiorean E.G., Anthony S.P., et al. Phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of SF1126 a vascular targeted pan phosphoinositide 3-kinase (PI3K) inhibitor in patients with solid tumors. J Clin Oncol 2008, 26(Suppl.). [Abstract 14532].
89. Chiorean E.G., Mahadevan D., Harris W.B., 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(Suppl.). [Abstract 2558].
90. Jessen K., Wang S., Kessler L., et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral antitumor activity. Mol Cancer Ther 2009, 8(Suppl.). [Abstract B148].
91. Chresta C.M., Davies B.R., 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, 70:288-298.
92. Houghton P.J., Maris J.M., Courtright J., et al. Pediatric Preclinical Testing Program (PPTP) stage 1 evaluation of AZD8055 an inhibitor of mTOR kinase. Mol Cancer Ther 2009, 8(Suppl.). [Abstract C57].
93. Carayol N., Vakana E., Sassano A., et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A 2010, 107:12469-12474.
94. Tan D.S., 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. J Clin Oncol 2010, 28(Suppl.). [Abstract 3006].
95. Janes M.R., Limon J.J., So L., et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010, 16:205-213.
96. Janes M.R., Fruman D.A. Targeting TOR dependence in cancer. Oncotarget 2010, 1:69-76.
97. Johnston S.R. BOLERO-2 - will this change practice in advanced breast cancer?. Breast Cancer Res 2012, 14:311.
98. Chavez-MacGregor M, Barlow WE, Gonzalez-Angulo AM, et al. S1207: phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor-positive and HER2-neu negative breast cancer: NCT01674140. Presented at: CTRC-AACR San Antonio Breast Cancer Symposium, December 4-8, 2012, San Antonio, TX [Abstract OT2-2-04].
99. Gerlinger M., Rowan A.J., Horswell S., et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012, 366:883-892.
100. Longo D.L. Tumor heterogeneity and personalized medicine. N Engl J Med 2012, 366:956-957.