mTOR-blocking agents in advanced renal cancer: An emerging therapeutic option

Expert Opinion on Investigational Drugs

Volumn 18, Issue 2, 2009, Pages 175-187

  Dasanu, Constantin A ^a   Clark III, Bernard A ^b   Alexandrescu, Doru T ^c  

^a SAINT FRANCIS HOSPITAL AND MEDICAL CENTER   (United States)

^b UNIVERSITY OF CONNECTICUT SCHOOL OF MEDICINE   (United States)

^c GEORGETOWN UNIVERSITY   (United States)

Author keywords

Everolimus; Hypophosphatemia; Mammalian target of rapamycin; Renal cell carcinoma; Temsirolimus

Indexed keywords

ALPHA INTERFERON; ANTILIPEMIC AGENT; AXITINIB; BEVACIZUMAB; DEFOROLIMUS; DIPHENHYDRAMINE; EVEROLIMUS; HYDROXYZINE; INSULIN; LIDOCAINE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; OCTREOTIDE; ORAL ANTIDIABETIC AGENT; PAZOPANIB; RAPAMYCIN; RECOMBINANT INTERFERON; RECOMBINANT INTERLEUKIN 2; SORAFENIB; SUNITINIB; TEMSIROLIMUS; ANTINEOPLASTIC AGENT; ANTINEOPLASTIC ANTIBIOTIC; DRUG DERIVATIVE; MAMMALIAN TARGET OF RAPAMYCIN; PROTEIN KINASE;

ACNE; ACUTE KIDNEY FAILURE; ADVANCED CANCER; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; APHTHOUS ULCER; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; BIPOLAR DISORDER; BLADDER CANCER; BONE MARROW SUPPRESSION; BREAST ADENOCARCINOMA; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; CANCER SURVIVAL; CARCINOGENESIS; CHEMOTHERAPY INDUCED EMESIS; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; CREATININE BLOOD LEVEL; DIABETES MELLITUS; DIARRHEA; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ERUPTION; DRUG HALF LIFE; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; DRUG SYNTHESIS; DRUG TARGETING; DRUG WITHDRAWAL; DRY SKIN; EDEMA; ENZYME INHIBITION; FATIGUE; FIBROSING ALVEOLITIS; GRAFT REJECTION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; HYPOCALCEMIA; HYPOPHOSPHATEMIA; IMMUNOSUPPRESSIVE TREATMENT; INFECTION; INSULIN RESISTANCE; INTERSTITIAL LUNG DISEASE; INTESTINE PERFORATION; KIDNEY CANCER; KIDNEY CARCINOMA; KIDNEY DYSFUNCTION; LEUKOPENIA; LYMPHOCYTOPENIA; LYMPHOMA; MACULOPAPULAR RASH; MONOTHERAPY; MOUTH ULCER; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUROENDOCRINE TUMOR; NEUTROPENIA; OPTIMAL DRUG DOSE; OSTEOSARCOMA; OVERALL SURVIVAL; PNEUMONIA; PROSTATE CANCER; PROTEIN FUNCTION; PRURITUS; RASH; RECOMMENDED DRUG DOSE; REVIEW; SIDE EFFECT; SINGLE DRUG DOSE; SOFT TISSUE SARCOMA; STOMATITIS; THROMBOCYTOPENIA; ANIMAL; CHEMICALLY INDUCED DISORDER; DRUG EFFECT; KIDNEY TUMOR; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PHASE 3 CLINICAL TRIAL; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ANTIBIOTICS, ANTINEOPLASTIC; ANTINEOPLASTIC AGENTS; CARCINOMA, RENAL CELL; CLINICAL TRIALS, PHASE I AS TOPIC; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; HUMANS; HYPOPHOSPHATEMIA; KIDNEY NEOPLASMS; PROTEIN KINASES; SIGNAL TRANSDUCTION; SIROLIMUS;

EID: 65549102093     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543780902721229     Document Type: Review

References (47)

1. Alexandrescu DT, Dasanu CA. Kidney cancer therapy: new perspectives and avenues. Expert Opin Pharmacother 2006;7(18):2481-2489 •• A comprehensive review of various emerging molecularly targeted therapies in advanced RCC. (Pubitemid 44932453)
2. Radulovic S, Bjelogrlic SK. Sunitinib, sorafenib and mTOR inhibitors in renal cancer. J BUON 2007;12(Suppl 1):S151-62 (Pubitemid 350213827)
3. Hutson TE, Figlin RA. Evolving role of novel targeted agents in renal cell carcinoma. Oncology (Williston Park) 2007;21(10):1175-1180 (Pubitemid 47463373)
4. Smith SM. Clinical development of mTOR inhibitors: a focus on lymphoma. Rev Recent Clin Trials 2007;2(2):103-110 (Pubitemid 46773877)
5. Garcia JA, Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 2008;7(6):1347-1354
6. Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs 2006;17(5):487-494 (Pubitemid 44309964)
7. Turner KJ, Moore JW, Jones A, et al. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res 2002;62:2957-2961
8. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther 2007;82(4):381-388 (Pubitemid 47414349)
9. Rao RD, Buckner JC, Sarkaria JN. Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug Targets 2004;4(8):621-635 • An important review of the mechanism of action of rapamycin as an anti-neoplastic and immunosuppressive agent. (Pubitemid 40013570)
10. Reddy GK, Mughal TI, Rini BI. Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma. Clin Genitourin Cancer 2006;5(2):110-113
11. Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 2002;3(2):295-304 (Pubitemid 34456089)
12. Shor B, Zhang WG, Toral-Barza L, et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 2008;68(8):2934-2943 • An important preclinical study delineating the antiproliferative activity of temsirolimus at micromolar concentrations.
13. Seeliger H, Guba M, Kleespies A, et al. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev 2007;26(3-4):611-621 • A paper showing potent antiangiogenic properties of rapamycin and its analogs.
14. Metcalf CA III, Bohacek R, Rozamus LW, et al. Structure-based design of AP23573, a phosphorus-containing analog of rapamycin for antitumor therapy. Proc Am Assoc Cancer Res 2004;45:2476
15. US National Institutes of Health database of clinical trials. Available from: www.clinicaltrials.gov
16. 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(12):2336-2347 • A study establishing the first evidence of antitumor activity of CCI-779 in RCC. (Pubitemid 41115390)
17. 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 • A Phase II study showing an important antitumor activity of temsirolimus in previously treated patients with advanced RCC. (Pubitemid 41103603)
18. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289 (Pubitemid 34032623)
19. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271 •• A paper establishing a new first-line therapeutic option for patients with advanced RCC with poor prognostic features. (Pubitemid 46849157)
20. Wood L, Bukowski RM, Dreicer R, et al. Temsirolimus in metastatic renal cell carcinoma (mRCC): Safety and efficacy in patients previously treated with VEGF-targeted therapy [abstract 16067]. J Clin Oncol 2008;26
21. Bellmunt J, Szczylik C, Feingold J, et al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 2008;19(8):1387-1392
22. UpToDate, Inc. Temsirolimus drug information. Available from: www.uptodate.com
23. Négrier S. Temsirolimus in metastatic renal cell carcinoma. Ann Oncol 2008;19(8):1369-1370
24. Simpson D, Curran MP. Temsirolimus: in advanced renal cell carcinoma. Drugs 2008;68(5):631-638
25. 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 Clin Oncol 2008;26(10):1588-1595
26. Jac J, Amato RJ, Glessinger S, et al. A phase II study of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic renal cell carcinoma [abstract 5113]. J Clin Oncol 2008;26
27. Motzer RJ, Escudier BJ, Oudard S, et al. RAD001 plus best supportive care (BSC) vs BSC plus placebo in patients with metastatic renal cell carcinoma (RCC) that has progressed on VEGFr-TKI therapy: results from a randomized, double-blind, multicenter phase III study (ASCO 2008 Abstract). J Clin Oncol 2008;26:256s
28. 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):449-456 •• A study showing efficacy of everolimus in patients with metastatic clear-cell RCC who have failed anti-VEGF TK inhibitors.
29. Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008;26(3):361-367 (Pubitemid 351171685)
30. Mita MM, Britten CD, Poplin E, et al. Deforolimus trial 106: a phase I trial evaluating 7 regimens of oral deforolimus (AP23573, MK-8669) [abstract 3509]. J Clin Oncol 2008;26
31. Malizzia LJ, Hsu A. Temsirolimus, an mTOR inhibitor for treatment of patients with advanced renal cell carcinoma. Clin J Oncol Nurs 2008;12(4):639-646
32. Kalaitzidis R, Tsimihodimos V, Bairaktari E, et al. Disturbances of phosphate metabolism: another feature of metabolic syndrome. Am J Kidney Dis 2005;45(5):851-858 (Pubitemid 43181044)
33. Baker SB, Worthley LI. The essentials of calcium, magnesium and phosphate metabolism: part II. Disorders. Crit Care Resusc 2002;4(4):307-315
34. Bugg NC, Jones JA. Hypophosphataemia: pathophysiology, effects and management on the intensive care unit. Anaesthesia 1998;53(9):895-902 (Pubitemid 28431598)
35. Davis SV, Olichwier KK, Chakko SC. Reversible depression of myocardial performance in hypophosphatemia. Am J Med Sci 1988;295(3):183-187 • A study linking severe hypophophatemia and reversible depression of myocardial performance. (Pubitemid 18098188)
36. Venditti FJ, Marotta C, Panezai FR, et al. Hypophosphatemia and cardiac arrhythmias. Miner Electrolyte Metab 1987;13(1):19-25 • A study showing hypophosphatemia to be associated with significant ventricular ectopic activity.
37. Dwyer K, Barone JE, Rogers JF. Severe hypophosphatemia in postoperative patients. Nutr Clin Pract 1992;7(6):279-283
38. Fischer P, Patel P, Carducci MA, et al. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma [abstract 16020]. J Clin Oncol 2008;26
39. Whorf RC, Hainsworth JD, Spigel DR, et al. Phase II study of bevacizumab and everolimus (RAD001) in the treatment of advanced renal cell carcinoma (RCC) [abstract 5010]. J Clin Oncol 2008;26
40. Ansell SM, Inwards DJ, Rowland KM Jr, et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008;113(3):508-514
41. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23(23):5314-5322 (Pubitemid 46206985)
42. Pandya KJ, Dahlberg S, Hidalgo M, et al. A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol 2007;2(11):1036-1041 (Pubitemid 350059580)
43. Margolin K, Longmate J, Baratta T, et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 2005;104(5):1045-1048
44. Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 2005;23(4):357-361
45. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26(26):4311-4318
46. Chawla SP, Tolcher AW, Staddon AP, et al. Survival results with AP23573, a novel mTOR inhibitor, in patients with advanced soft tissue or bone sarcomas: update of phase II trial [abstract 10076]. J Clin Oncol 2007;25
47. Rizzieri DA, Feldman E, Dipersio JF, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008;14(9):2756-2762