Clinical development of mTor inhibitors for renal cancer

References

• Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the international metastatic renal-cell carcinoma database consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141–148. PubMed PMID: 23312463; PubMed Central PMCID: PMC4144042.
   PubMed Web of Science ®Google Scholar
• Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol. 2016 Jul;70(1):93–105. PubMed PMID: 26935559.
   PubMed Web of Science ®Google Scholar
• Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016 Sep;17(9):1317–1324. PubMed PMID: 27498080.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473–1482. PubMed PMID: 26482279.
   PubMed Web of Science ®Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017 Mar 9;168(6):960–976. PubMed PMID: 28283069; PubMed Central PMCID: PMC5394987.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256–4265. PubMed PMID: 20549832.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814–1823. PubMed PMID: 26406150; PubMed Central PMCID: PMC5024539
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803–1813. PubMed PMID: 26406148
   PubMed Web of Science ®Google Scholar
• Molina AM, Hutson TE, Larkin J, et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014 Jan;73(1):181–189. PubMed PMID: 24190702; PubMed Central PMCID: PMC3889692.
   PubMed Web of Science ®Google Scholar
• Cai P, Tsao R, Ruppen ME. In vitro metabolic study of temsirolimus: preparation, isolation, and identification of the metabolites. Drug Metab Dispos. 2007 Sep;35(9):1554–1563. PubMed PMID: 17540708.
   PubMed Web of Science ®Google Scholar
• Houghton PJ. Everolimus. Clinical Cancer Res. 2010 Mar 1;16(5):1368–1372. PubMed PMID: 20179227; PubMed Central PMCID: PMC3003868.
   PubMed Web of Science ®Google Scholar
• Rini BI. Temsirolimus, an inhibitor of mammalian target of rapamycin. Clinical Cancer Res. 2008 Mar 1;14(5):1286–1290. PubMed PMID: 18316545.
   PubMed Web of Science ®Google Scholar
• Sehgal SN, Molnar-Kimber K, Ocain TD, et al. Rapamycin: a novel immunosuppressive macrolide. Med Res Rev. 1994 Jan;14(1):1–22. PubMed PMID: 8309312.
   PubMed Web of Science ®Google Scholar
• Klumpen HJ, Beijnen JH, Gurney H, et al. Inhibitors of mTOR. Oncologist. 2010;15(12):1262–1269. PubMed PMID: 21147869; PubMed Central PMCID: PMC3227930.
   PubMed Web of Science ®Google Scholar
• Benjamin D, Colombi M, Moroni C, et al. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Disc. 2011 Oct 31;10(11):868–880. PubMed PMID: 22037041
   PubMed Web of Science ®Google Scholar
• Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014 Mar;15(3):155–162. PubMed PMID: 24556838.
   PubMed Web of Science ®Google Scholar
• Le Tourneau C, Faivre S, Serova M, et al. mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? Br J Cancer. 2008 Oct 21;99(8):1197–1203. PubMed PMID: 18797463; PubMed Central PMCID: PMC2570519
   PubMed Web of Science ®Google Scholar
• O’Donnell A, Faivre S, Burris HA 3rd, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clini Oncol. 2008 Apr 1;26(10):1588–1595. PubMed PMID: 18332470
   PubMed Web of Science ®Google Scholar
• Boni JP, Hug B, Leister C, et al. Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations. Semin Oncol. 2009 Dec;36(Suppl 3):S18–S25. PubMed PMID: 19963096.
   PubMedGoogle Scholar
• Peralba JM, DeGraffenried L, Friedrichs W, et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clinical Cancer Res. 2003 Aug 1;9(8):2887–2892. PubMed PMID: 12912932
   PubMed Web of Science ®Google Scholar
• Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004 Jan 1;64(1):252–261. PubMed PMID: 14729632
   PubMed Web of Science ®Google Scholar
• Breuleux M, Klopfenstein M, Stephan C, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther. 2009 Apr;8(4):742–753. PubMed PMID: 19372546; PubMed Central PMCID: PMC3440776.
   PubMed Web of Science ®Google Scholar
• Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clini Oncol. 2009 May 1;27(13):2278–2287. PubMed PMID: 19332717; PubMed Central PMCID: PMC2738634.
   PubMed Web of Science ®Google Scholar
• Fiorini C, Massari F, Pedron S, et al. Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors. Am J Cancer Res. 2014;4(6):907–915. PubMed PMID: 25520878; PubMed Central PMCID: PMC4266722.
   PubMed Web of Science ®Google Scholar
• 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 Clini Oncol. 2008 Apr 1;26(10):1596–1602. PubMed PMID: 18332467
   PubMedGoogle Scholar
• 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 Clini Oncol. 2008 Apr 1;26(10):1603–1610. PubMed PMID: 18332469
   PubMed Web of Science ®Google Scholar
• 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 Aug 9;372(9637):449–456. PubMed PMID: 18653228
   PubMed Web of Science ®Google Scholar
• 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 Jan 22;5(1):e8. PubMed PMID: 18215105; PubMed Central PMCID: PMC2211560
   PubMed Web of Science ®Google Scholar
• O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006 Feb 1;66(3):1500–1508. PubMed PMID: 16452206; PubMed Central PMCID: PMC3193604
   PubMed Web of Science ®Google Scholar
• Arsham AM, Plas DR, Thompson CB, et al. Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res. 2004 May 15;64(10):3500–3507. PubMed PMID: 15150104
   PubMed Web of Science ®Google Scholar
• Chang SM, Kuhn J, Wen P, et al. Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs. 2004 Nov;22(4):427–435. PubMed PMID: 15292713.
   PubMed Web of Science ®Google Scholar
• Punt CJ, Boni J, Bruntsch U, et al. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncology. 2003 Jun;14(6):931–937. PubMed PMID: 12796032.
   PubMed Web of Science ®Google Scholar
• 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 Clini Oncol. 2004 Jun 15;22(12):2336–2347. PubMed PMID: 15136596
   PubMed Web of Science ®Google Scholar
• Lunardi G, Armirotti A, Nicodemo M, et al. Comparison of temsirolimus pharmacokinetics in patients with renal cell carcinoma not receiving dialysis and those receiving hemodialysis: a case series. Clin Ther. 2009 Aug;31(8):1812–1819. PubMed PMID: 19808140.
   PubMed Web of Science ®Google Scholar
• 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 Clini Oncol. 2004 Mar 1;22(5):909–918. PubMed PMID: 14990647
   PubMed Web of Science ®Google Scholar
• Jacobsen W, Serkova N, Hausen B, et al. Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc. 2001 Feb–Mar;33(1–2):514–515. PubMed PMID: 11266932.
   PubMed Web of Science ®Google Scholar
• Taylor PJ, Franklin ME, Graham KS, et al. A HPLC-mass spectrometric method suitable for the therapeutic drug monitoring of everolimus. J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Apr 1;848(2):208–214. PubMed PMID: 17084681
   PubMed Web of Science ®Google Scholar
• Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinetics. 2004;43(2):83–95. PubMed PMID: 14748618.
   PubMed Web of Science ®Google Scholar
• Kovarik JM, Hartmann S, Figueiredo J, et al. Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplants. Pharmacotherapy. 2002 Feb;22(2):154–159. PubMed PMID: 11837553.
   PubMed Web of Science ®Google Scholar
• Bitting RL, Healy P, Creel PA, et al. A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2014 Aug;12(4):241–250. PubMed PMID: 24685058; PubMed Central PMCID: PMC4623321.
   PubMed Web of Science ®Google Scholar
• Campbell MT, Millikan RE, Altinmakas E, et al. Phase I trial of sunitinib and temsirolimus in metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015 Jun;13(3):218–224. PubMed PMID: 25465491; PubMed Central PMCID: PMC4991027.
   PubMed Web of Science ®Google Scholar
• Fishman MN, Srinivas S, Hauke RJ, et al. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. Eur J Cancer. 2013 Sep;49(13):2841–2850. PubMed PMID: 23726267; PubMed Central PMCID: PMC4666006.
   PubMed Web of Science ®Google Scholar
• Hainsworth JD, Waterhouse DM, Penley WC, et al. Sorafenib and everolimus in advanced clear cell renal carcinoma: a phase I/II trial of the SCRI Oncology Research Consortium. Cancer Invest. 2013 Jun;31(5):323–329. PubMed PMID: 23614653.
   PubMed Web of Science ®Google Scholar
• Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2012 Apr 1;118(7):1868–1876. PubMed PMID: 21898375; PubMed Central PMCID: PMC3609026.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hudes GR, Curti BD, et al. Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma. J Clini Oncol. 2007 Sep 1;25(25):3958–3964. PubMed PMID: 17761980
   PubMed Web of Science ®Google Scholar
• Plimack ER, Tan T, Wong YN, et al. A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma. Oncologist. 2014 Apr;19(4):354–355. PubMed PMID: 24674872; PubMed Central PMCID: PMC3983829.
   PubMed Web of Science ®Google Scholar
• Powles T, Foreshew SJ, Shamash J, et al. A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. Eur J Cancer. 2014 Aug;50(12):2057–2064. PubMed PMID: 24908540.
   PubMed Web of Science ®Google Scholar
• Carlo MI, Molina AM, Lakhman Y, et al. A phase Ib study of BEZ235, a dual inhibitor of phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in patients with advanced renal cell carcinoma. Oncologist. 2016 Jul;21(7):787–788. PubMed PMID: 27286790; PubMed Central PMCID: PMC4943396.
   PubMed Web of Science ®Google Scholar
• Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378–388. PubMed PMID: 26794930.
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Manola JB, Pins M, et al. BEST: a randomized phase ii study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma–a trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clini Oncol. 2015 Jul 20;33(21):2384–2391. PubMed PMID: 26077237; PubMed Central PMCID: PMC4500832
   PubMed Web of Science ®Google Scholar
• Hainsworth JD, Spigel DR, Burris HA,3, et al. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clini Oncol. 2010 May 1;28(13):2131–2136. PubMed PMID: 20368560
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clini Oncol. 2014 Sep 1;32(25):2765–2772. PubMed PMID: 25049330
   PubMed Web of Science ®Google Scholar
• Negrier S, Gravis G, Perol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011 Jul;12(7):673–680. PubMed PMID: 21664867.
   PubMed Web of Science ®Google Scholar
• Powles T, Wheater M, Din O, et al. A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol. 2016 Mar;69(3):450–456. PubMed PMID: 26364551.
   PubMed Web of Science ®Google Scholar
• Ravaud A, Barrios CH, Alekseev B, et al. RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon alpha-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncology. 2015 Jul;26(7):1378–1384. PubMed PMID: 25851632.
   PubMed Web of Science ®Google Scholar
• Ryan CW, Vuky J, Chan JS, et al. A phase II study of everolimus in combination with imatinib for previously treated advanced renal carcinoma. Invest New Drugs. 2011 Apr;29(2):374–379. PubMed PMID: 20012337.
   PubMed Web of Science ®Google Scholar
• Davis ID, Long A, Yip S, et al. EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma. Ann Oncology. 2015 Jun;26(6):1118–1123. PubMed PMID: 25701452.
   PubMed Web of Science ®Google Scholar
• Merchan JR, Qin R, Pitot H, et al. Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study. Cancer Chemother Pharmacol. 2015 Mar;75(3):485–493. PubMed PMID: 25556030; PubMed Central PMCID: PMC4348698.
   PubMed Web of Science ®Google Scholar
• Pal S, Azad A, Bhatia S, et al. A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma. Clinical Cancer Res. 2015 Aug 1;21(15):3420–3427. PubMed PMID: 25788492; PubMed Central PMCID: PMC4526387
   PubMed Web of Science ®Google Scholar
• Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist. 2012;17(1):135–144. PubMed PMID: 22207567; PubMed Central PMCID: PMC3267813.
   PubMed Web of Science ®Google Scholar
• Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 2017 May;18(5):654–662. PubMed PMID: 28314691.
   PubMed Web of Science ®Google Scholar
• Funakoshi T, Latif A, Galsky MD. Risk of hematologic toxicities in patients with solid tumors treated with everolimus: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2013 Oct;88(1):30–41. PubMed PMID: 23830806.
   PubMed Web of Science ®Google Scholar
• Xu J, Tian D. Hematologic toxicities associated with mTOR inhibitors temsirolimus and everolimus in cancer patients: a systematic review and meta-analysis. Curr Med Res Opin. 2014 Jan;30(1):67–74. PubMed PMID: 24028709.
   PubMed Web of Science ®Google Scholar
• Coinu A, Petrelli F, Barni S. Optimal treatment of poor-risk renal cell carcinoma patients with mTOR inhibitors and anti-VEGFR agents. Expert Rev Anticancer Ther. 2016;16(1):33–43. PubMed PMID: 26535485.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017 Feb 20;35(6):591–597.
   PubMed Web of Science ®Google Scholar
• Procopio G, Bellmunt J, Dutcher J, et al. Sorafenib tolerability in elderly patients with advanced renal cell carcinoma: results from a large pooled analysis. Br J Cancer. 2013 Feb 5;108(2):311–318. PubMed PMID: 23322192; PubMed Central PMCID: PMC3566810
   PubMed Web of Science ®Google Scholar
• Bracarda S, Sisani M, Marrocolo F, et al. GOAL: an inverse toxicity-related algorithm for daily clinical practice decision making in advanced kidney cancer. Crit Rev Oncol Hematol. 2014 Mar;89(3):386–393. PubMed PMID: 24309065.
   PubMed Web of Science ®Google Scholar
• National Center for Biotechnology Information. PubChem Compound Database; CID=70798655. (cited 2017 Sep 31. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/70798655
   Google Scholar