Portal de Periódicos da CAPES

Antitumoral Activity of Rapamycin in Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex

2006; Elsevier BV; Volume: 48; Issue: 3 Linguagem: Inglês

10.1053/j.ajkd.2006.05.018

1523-6838

Ralf Wienecke, Ingrid Fackler, Ulrich Linsenmaier, Karin Mayer, Thomas Licht, Matthias Kretzler,

Tuberous Sclerosis Complex Research

A 19-year old patient with tuberous sclerosis presented with a renal angiomyolipoma. Because animal trials of tuberous sclerosis showed an effect of rapamycin on renal tumors, our patient was administered rapamycin for 6 months. During this time, the renal angiomyolipoma shrank significantly, regrew during an 8-month period, and decreased in size again after readministration of rapamycin. A 19-year old patient with tuberous sclerosis presented with a renal angiomyolipoma. Because animal trials of tuberous sclerosis showed an effect of rapamycin on renal tumors, our patient was administered rapamycin for 6 months. During this time, the renal angiomyolipoma shrank significantly, regrew during an 8-month period, and decreased in size again after readministration of rapamycin. PATIENTS WITH TUBEROUS sclerosis complex (TSC) experience multiple hamartomas that may lead to epilepsy, mental retardation, heart failure, and renal insufficiency.1Roach E.S. Gomez M.R. Northrup H. Tuberous sclerosis complex consensus conference Revised clinical diagnostic criteria.J Child Neurol. 1998; 13: 624-628Crossref PubMed Scopus (919) Google Scholar In most patients, renal angiomyolipomas develop that may cause bleeding, hypertension, and progressive renal insufficiency. Treatment options for patients with renal angiomyolipomas currently include only invasive strategies, eg, embolization or surgery.2Dickinson M. Ruckle H. Beaghler M. Hadley H.R. Renal angiomyolipoma Optimal treatment based on size and symptoms.Clin Nephrol. 1998; 49: 281-286PubMed Google Scholar, 3Kessler O.J. Gillon G. Neuman M. Engelstein D. Winkler H. Baniel J. Management of renal angiomyolipoma Analysis of 15 cases.Eur Urol. 1998; 33: 572-575Crossref PubMed Scopus (69) Google Scholar, 4Williams J.M. Racadio J.M. Johnson N.D. Donnelly L.F. Bissler J.J. Embolization of renal angiomyolipomata in patients with tuberous sclerosis complex.Am J Kidney Dis. 2006; 47: 95-106Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar No pharmacological treatment options for patients with tuberous sclerosis are available. In patients with renal angiomyolipoma, there is a mutation in TSC2 and activation of the mammalian target of rapamycin signaling pathway.5El-Hashemite N. Zhang H. Henske E.P. Kwiatkowski D.J. Mutation in TSC2 and activation of mammalian target of rapamycin signaling pathway in renal angiomyolipoma.Lancet. 2003; 361: 1348-1349Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 6Ma L. Chen Z. Erdjument-Bromage H. et al.Phosphorylation and functional inactivation of TSC2 by Erk Implications for tuberous sclerosis and cancer pathogenesis.Cell. 2005; 121: 179-193Abstract Full Text Full Text PDF PubMed Scopus (1039) Google Scholar This study provides the rationale for a molecular target–driven intervention of the TSC through pharmacological blockade of mammalian target of rapamycin. It was hypothesized that rapamycin (sirolimus) may be useful in targeting angiomyolipoma growth in patients with tuberous sclerosis. Rapamycin induces regression of renal cell carcinomas of the Eker rat strain, a naturally occurring rat strain that carries a heterozygous TSC2 mutation.7Kenerson H.L. Aicher L.D. True L.D. Yeung R.S. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors.Cancer Res. 2002; 62: 5645-5650PubMed Google Scholar, 8Kenerson H. Dundon T.A. Yeung R.S. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex.Pediatr Res. 2005; 57: 67-75Crossref PubMed Scopus (130) Google Scholar In light of this preclinical evidence, we started a clinical trial using rapamycin for the treatment of patients with tuberous sclerosis. Rapamycin showed antitumoral activity against a renal angiomyolipoma in a 19-year-old man with tuberous sclerosis caused by a mutation in TSC2 (4943delG). Pretreatment imaging showed 2 renal angiomyolipomas; 1 was located in the right kidney with documented growth in serial magnetic resonance imaging (MRI) during 4 years (from 1999 to 2003). The pretrial abdominal MRI (Fig 1A) showed tumor volume of 134 mL (tumor size, 5.2 × 6.8 × 7.3 cm). The tumor in the other kidney had been constant in size (1.6 mL; left side) during 4 years. In addition, the patient had multiple cerebral tubers and subependymal nodules. Beginning in August 2003, rapamycin was administered orally, starting with 1 mg every other day in increasing dosage to reach target serum levels of 4 to 5 ng/mL and then continued at this dosage (2 mg/d) until February 2004. There were no side effects, except for a mild acneiform skin rash. The first follow-up MRI was performed after 4 months in December 2003 and showed a significant decrease in tumor volume to 39 mL (−71%; tumor size, 4.8 × 3.1 × 5.0 cm). In February 2004, a second MRI showed an additional decrease to 23 mL (−83%; tumor size, 4.0 × 2.5 × 4.5 cm; Fig 1B). According to the study protocol, rapamycin therapy was terminated. Until October 2004, the angiomyolipoma regrew to a volume of 116 mL (+ 517%; tumor size, 6.6 × 4.7 × 7.2 cm), and rapamycin therapy was reinstituted. Under continuous rapamycin treatment again, a rapid decrease in volume (45 mL; −61%) was achieved in December 2004, which was reconfirmed in February 2005 and in April 2006 (Fig 2). The contralateral angiomyolipoma and cerebral manifestations did not change during the treatment. To our best knowledge, this is the first clinical evidence that rapamycin shows activity against renal tumors arising in patients with tuberous sclerosis. Significant shrinkage of a renal angiomyolipoma was observed. It should be noted that the contralateral angiomyolipoma, which had not grown before, remained unchanged during the entire treatment course, suggesting that only proliferating TSC2-deficient cells may be sensitive to this therapy. Another limitation is that rapamycin cannot cross the blood-brain barrier. Expectedly, cerebral manifestations were unaffected by the treatment. Our observation that only the progressive angiomyolipoma responded to treatment suggests that rapamycin affects growing lesions with proliferating tumor cells. Rapamycin has been used in transplantation medicine for some years. Inclusion of rapamycin in posttransplantation regimens is associated with a decreased number of skin cancers.9Mathew T. Kreis H. Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients Results from five multicenter studies.Clin Transplant. 2004; 18: 446-449Crossref PubMed Scopus (270) Google Scholar The serum level achieved in our patient is similar to those used in transplantation medicine. In tumor models, inactivation of the target of rapamycin by rapamycin may induce apoptosis or a decrease in cell size or necrosis caused by tumor thrombosis through the induction of tissue factor or an antianigogenic effect caused by inhibition of vascular endothelial growth factor.8Kenerson H. Dundon T.A. Yeung R.S. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex.Pediatr Res. 2005; 57: 67-75Crossref PubMed Scopus (130) Google Scholar, 10Boulay 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: 5319-5328Crossref PubMed Scopus (320) Google Scholar, 11Guba M. Yezhelvev M. Eichhorn M.E. et al.Rapamycin induces tumor-specific thrombosis via tissue factor in the present of VEGF.Blood. 2005; 105: 4463-4469Crossref PubMed Scopus (116) Google Scholar, 12Guba M. von Breitenbuch P. Steinbauer M. et al.Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis Involvement of vascular endothelial growth factor.Nat Med. 2002; 8: 128-135Crossref PubMed Scopus (1576) Google Scholar Which mechanism is the most effective has to be determined. The continuing trial will show the response rate to rapamycin in a larger number of patients. In addition, rapamycin increases the susceptibility of cells to apoptosis, and there is the possibility of successful combination therapies, such as rapamycin and interferon γ or cisplatin.13El-Hashemite N. Zhang H. Walker V. et al.Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models Synergistic effects of rapamycin-IFN-gamma treatment.Cancer Res. 2004; 64: 3436-3443Crossref PubMed Scopus (52) Google Scholar, 14Beuvink I. Boulay A. Fumagalli S. et al.The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation.Cell. 2005; 120: 747-759Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar The authors thank Tuberous Sclerosis Germany for funding.