Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

被引：157

作者：

Dabora, Sandra L. ^{[1
]}

Franz, David Neal ^{[4
]}

Ashwal, Stephen ^{[5
]}

Sagalowsky, Arthur ^{[6
]}

DiMario, Francis J., Jr. ^{[7
]}

Miles, Daniel ^{[8
]}

Cutler, Drew ^{[5
]}

Krueger, Darcy ^{[4
]}

Uppot, Raul N. ^{[2
]}

Rabenou, Rahmin ^{[8
]}

Camposano, Susana ^{[2
]}

Paolini, Jan ^{[2
]}

Fennessy, Fiona ^{[3
]}

Lee, Nancy ^{[9
]}

Woodrum, Chelsey ^{[9
]}

Manola, Judith ^{[3
]}

Garber, Judy ^{[3
]}

Thiele, Elizabeth A. ^{[2
]}

机构：

[1] Biogen Idec Hemophilia, Weston, MA USA

[2] Massachusetts Gen Hosp, Boston, MA 02114 USA

[3] Dana Farber Canc Inst, Boston, MA 02115 USA

[4] Univ Cincinnati, Cincinnati, OH USA

[5] Loma Linda Univ, Loma Linda, CA 92350 USA

[6] Univ Texas SW, Dallas, TX USA

[7] Univ Connecticut, Hartford, CT 06112 USA

[8] NYU, New York, NY USA

[9] Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

PLOS ONE | 2011年 / 6卷 / 09期

关键词：

RENAL-CELL CARCINOMA; GROWTH FACTOR-D; RAPAMYCIN ANALOG CCI-779; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; MUTATIONAL ANALYSIS; IMPROVED SURVIVAL; MAMMALIAN TARGET; LUNG-FUNCTION; MOUSE MODEL; COMPLEX;

D O I：

10.1371/journal.pone.0023379

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Conclusions: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.

引用

页数：16

共 56 条

[1] Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States [J].