Multicenter phase 2 trial of sirolimus for tuberous sclerosis: Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease

PLoS ONE

Volumn 6, Issue 9, 2011, Pages

  Dabora, Sandra L ^a   Franz, David Neal ^d   Ashwal, Stephen ^e   Sagalowsky, Arthur ^f   DiMario Jr , Francis J ^g   Miles, Daniel ^h   Cutler, Drew ^e   Krueger, Darcy ^d   Uppot, Raul N ^b   Rabenou, Rahmin ^h   Camposano, Susana ^b   Paolini, Jan ^b   Fennessy, Fiona ^c   Lee, Nancy ⁱ   Woodrum, Chelsey ⁱ   Manola, Judith ^c   Garber, Judy ^c   Thiele, Elizabeth A ^b  

^a BIOGEN   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c DANA FARBER CANCER INSTITUTE   (United States)

^d UNIVERSITY OF CINCINNATI   (United States)

^e LOMA LINDA UNIVERSITY   (United States)

^f UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^g UNIVERSITY OF CONNECTICUT   (United States)

^h NEW YORK UNIVERSITY   (United States)

ⁱ BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

RAPAMYCIN; VASCULOTROPIN D; ANTIINFECTIVE AGENT;

ACNE; ADULT; ANEMIA; ANGIOMYOLIPOMA; ARTHRALGIA; ARTICLE; BONE MARROW SUPPRESSION; BRAIN TUMOR; CLINICAL ARTICLE; CONTROLLED STUDY; DIARRHEA; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG ERUPTION; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EPISTAXIS; FACE TUMOR; FEMALE; HEMANGIOFIBROMA; HEMATOLOGIC DISEASE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTRIGLYCERIDEMIA; KIDNEY HEMANGIOMYOLIPOMA; KIDNEY TUMOR; LEUKOCYTE; LEUKOPENIA; LIVER ANGIOMYOLIPOMA; LIVER TUMOR; LOADING DRUG DOSE; LOW DRUG DOSE; LUNG FUNCTION; LYMPHANGIOLEIOMYOMATOSIS; LYMPHOCYTOPENIA; MALE; MENSTRUATION DISORDER; METABOLISM; MULTICENTER STUDY; NECROSIS; NEUTROPENIA; NEUTROPHIL; PHASE 2 CLINICAL TRIAL; PROTEIN BLOOD LEVEL; PROTEINURIA; SIDE EFFECT; SKIN; STOMATITIS; TREATMENT DURATION; TUBEROUS SCLEROSIS; TUMOR RECURRENCE; TUMOR REGRESSION; TUMOR VOLUME; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; WEIGHT GAIN; ADOLESCENT; AGED; CHEMICALLY INDUCED DISORDER; CLINICAL TRIAL; MIDDLE AGED;

ADOLESCENT; ADULT; AGED; ANGIOMYOLIPOMA; ANTI-BACTERIAL AGENTS; FEMALE; HUMANS; KIDNEY NEOPLASMS; LIVER NEOPLASMS; MALE; MIDDLE AGED; SIROLIMUS; TUBEROUS SCLEROSIS; VASCULAR ENDOTHELIAL GROWTH FACTOR D; YOUNG ADULT;

EID: 80052472675     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0023379     Document Type: Article

References (57)

1. Crino PB, Nathanson KL, Henske EP, (2006) The tuberous sclerosis complex. N Engl J Med 355: 1345-1356.
2. Roach ES, Gomez MR, Northrup H, (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13: 624-628.
3. Henske EP, Wessner LL, Golden J, Scheithauer BW, Vortmeyer AO, et al. (1997) Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol 151: 1639-1647.
4. Nie D, Di Nardo A, Han JM, Baharanyi H, Kramvis I, et al. (2010) Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 13: 163-172.
5. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, et al. (2008) Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 14: 843-848.
6. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, et al. (2001) Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared with TSC1, Disease in Multiple Organs. Am J Hum Genet 68: 64-80.
7. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, et al. (2001) Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 164: 661-668.
8. Gomez M, Sampson J, Whittemore V, eds. (1999) The tuberous sclerosis complex. Third Ed. ed Oxford, England Oxford University Press.
9. Gao X, Pan D, (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15: 1383-1392.
10. Inoki K, Corradetti MN, Guan KL, (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: 19-24.
11. Potter CJ, Huang H, Xu T, (2001) Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105: 357-368.
12. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356: 2271-2281.
13. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, et al. (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372: 449-456.
14. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, et al. (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364: 514-523.
15. Lee L, Sudentas P, Donohue B, Asrican K, Worku A, et al. (2005) Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 42: 213-227.
16. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, et al. (2008) Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 28: 5422-5432.
17. Woodrum C, Nobil A, Dabora SL, (2010) Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors. Journal of Translational Medicine 8: 14.
18. Zeng LH, Xu L, Gutmann DH, Wong M, (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63: 444-453.
19. Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, et al. (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 63: 1236-1242.
20. El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ, (2003) Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 361: 1348-1349.
21. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, et al. (2002) Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 277: 30958-30967.
22. Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES, (1998) Renal lesion growth in children with tuberous sclerosis complex. J Urol 160: 141-145.
23. Shepherd CW, Gomez MR, Lie JT, Crowson CS, (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66: 792-796.
24. Casper KA, Donnelly LF, Chen B, Bissler JJ, (2002) Tuberous sclerosis complex: renal imaging findings. Radiology 225: 451-456.
25. Sooriakumaran P, Gibbs P, Coughlin G, Attard V, Elmslie F, et al. (2009) Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated. BJU Int 105: 101-106.
26. Simon R, (1989) Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 10: 1-10.
27. Therasse P, (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205-216.
28. Mahalati K, Kahan BD, (2001) Clinical pharmacokinetics of sirolimus. Clinical Pharmacokinetics 40: 573-585.
29. Schubert M, Venkataramanan R, Holt DW, Shaw LM, McGhee W, et al. (2004) Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients. Am J Transplant 4: 767-773.
30. Motulsky H, (2003) Fitting Models to Biological Data using Linear and Nonlinear Regression San Diego, CA GraphPad Software, Inc.
31. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, et al. (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358: 140-151.
32. Rodriguez-Moreno A, Ridao N, Garcia-Ledesma P, Calvo N, Perez-Flores I, et al. (2009) Sirolimus and everolimus induced pneumonitis in adult renal allograft recipients: experience in a center. Transplant Proc 41: 2163-2165.
33. Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, et al. (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet 13: 731-741.
34. Costello LC, Hartman TE, Ryu JH, (2000) High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 75: 591-594.
35. Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, et al. (2001) Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 164: 669-671.
36. Lohela M, Bry M, Tammela T, Alitalo K, (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21: 154-165.
37. Lohela M, Saaristo A, Veikkola T, Alitalo K, (2003) Lymphangiogenic growth factors, receptors and therapies. Thromb Haemost 90: 167-184.
38. Carsillo T, Astrinidis A, Henske EP, (2000) Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A 97: 6085-6090.
39. Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J, (2009) Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest 135: 1293-1300.
40. Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, et al. (2006) Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol 4: 143-152.
41. Young LR, Inoue Y, McCormack FX, (2008) Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med 358: 199-200.
42. Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, et al. (2010) Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 138: 674-681.
43. Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, et al. (2011) Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 trial. Clin Cancer Res.
44. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, et al. (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New England Journal of Medicine 363: 1801-1811.
45. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, et al. (2002) Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 277: 30958-30967.
46. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, et al. (2011) Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis. N Engl J Med.
47. White DA, Camus P, Endo M, Escudier B, Calvo E, et al. (2010) Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 182: 396-403.
48. Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, et al. (2007) Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med 9: 88-100.
49. Peces R, Peces C, Cuesta-Lopez E, Perez-Duenas V, Vega-Cabrera C, et al. (2010) Low-dose rapamycin reduces kidney volume angiomyolipomas and prevents the loss of renal function in a patient with tuberous sclerosis complex. Nephrol Dial Transplant.
50. Haemel AK, O'Brian AL, Teng JM, (2010) Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 146: 715-718.
51. Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, et al. (2008) The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol 159: 473-475.
52. Rauktys A, Lee N, Lee L, Dabora SL, (2008) Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatol 8: 1.
53. Lee L, Sudentas P, Dabora SL, (2006) Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex. Genes Chromosomes Cancer 45: 933-944.
54. Lee N, Woodrum C, Nobil A, Rauktys A, Messina MP, et al. (2009) Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models. BMC Pharmacol 9: 8.
55. Watson MS, Epstein C, Howell RR, Jones MC, Korf BR, et al. (2008) Developing a national collaborative study system for rare genetic diseases. Genet Med 10: 325-329.
56. Johnson SR, Tattersfield AE, (1999) Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 160: 628-633.
57. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J, (2004) Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest 126: 1867-1874.