臨床泌尿器科66巻1号

2012年01月発行

特集 進行性腎癌に対する分子標的治療薬・薬剤選択ガイド

Non-clear cell RCCに対する分子標的治療；発癌機構から導かれる個別化医療

著者： 岸田健¹

所属機関： ¹神奈川県立がんセンター泌尿器科

ページ範囲：P.59 - P.67

要旨　腎細胞癌に対する分子標的薬はclear cell RCCの発癌メカニズムの研究から発展したものであり，異なる発症機序を持つ各種non-clear cell RCCに対しては異なる治療が適応されるべきと考えられる。ところがnon-clear cell RCCの発癌シグナルはclear cell RCCのシグナルと細胞内でリンクしていることが解明され，さらに実際の臨床においてもclear cell RCCを対象にした分子標的薬がnon-clear cell RCCに対しても有効であるというデータが報告されつつある。従来のサイトカイン療法はclear cell RCCに対してのみ有効でありnon-clear cell RCCでの有効性は極めて低かったため，分子標的薬はnon-clear cell RCCにおいてより大きい恩恵をもたらすといえる。腎細胞癌に対する組織型別の個別化医療を可能にし得る分子標的薬治療について最近の知見を基に解説する。

参考文献

1）Kovacs G, Akhtar M, Beckwith BJ, et al：The Heidelberg classification of renal cell tumours. J Pathol 183：131-133, 1997

2）Latif F, Tory K, Gnarra J, et al：Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 28；260（5112）：1317-1320, 1993

3）Kondo K, Yao M, Yoshida M, et al：Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma：relationship to clinicopathological parameters. Genes Chromosomes Cancer 34：58-68, 2002

4）Kishida T, Stackhouse TM, Zbar B, et al：Cellular proteins that bind the von Hippel-Lindau disease gene product：mapping of binding domains and the effect of missense mutations. Cancer Res 55：4544-4548, 1995

5）Maxwell PH, Wiesener MS, Chang GW, et al：The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399：271-275, 1999

6）Schmidt L, Duh FM, Chen F, et al：Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16：68-73, 1997

7）Nakaigawa N, Yao M, Baba M, et al：Inactivation of von Hippel-Lindau gene induces constitutive phosphorylation of MET protein in clear cell renal carcinoma. Cancer Res 66：3699-3705, 2006

8）Jeffers M, Schmidt L, Nakaigawa N, et al：Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA 94：11445-11450, 1997

9）Toro JR, Nickerson ML, Wei MH, et al：Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73：95-106, 2003

10）Isaacs JS, Jung YJ, Mole DR, et al：HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer：novel role of fumarate in regulation of HIF stability. Cancer Cell 8：143-153, 2005

11）Pavlovich CP, Walther MM, Eyler RA, et al：Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26：1542-1552, 2002

12）Nickerson ML, Warren MB, Toro JR, et al：Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2：157-164, 2002

13）Baba M, Hong SB, Sharma N, et al：Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA 103：15552-15557, 2006

14）Weterman MA, Wilbrink M and Geurts van Kessel A：Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t（X；1）（p11；q21）-positive papillary renal cell carcinomas. Proc Natl Acad Sci USA 93：15294-15298, 1996

15）Tsuda M, Davis IJ, Argani P, et al：TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition, Cancer Res 67：919-929, 2007

16）Linehan WM, Pinto PA, Srinivasan R, et al：Identification of the genes for kidney cancer：opportunity for disease-specific targeted therapeutics. Clin Cancer Res 13：671s-679s, 2007

17）Hudes G, Carducci M, Tomczak P, et al：Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356：2271-2281, 2007

18）Dutcher JP, de Souza P, McDermott D, et al：Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 26：202-209, 2009

19）Gore ME, Szczylik C, Porta C, et al：Safety and efficacy of sunitinib for metastatic renal-cell carcinoma：an expanded-access trial. Lancet Oncol 10：757-763, 2009

20）Stadler WM, Figlin RA, McDermott DF, et al：Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer 116：1272-1280, 2010

21）Choueiri TK, Plantade A, Elson P, et al：Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 26：127-131, 2008

22）Plimack ER, Jonasch E, Bekele BN, et al：Sunitinib in papillary renal cell carcinoma（pRCC）：results from a single-arm phase Ⅱ study. ASCO-2010 Genitourinary Cancers Symposium

23）Lee J, Ahn J, Lim H, et al：Multicenter prospective phase Ⅱ study of sunitinib in non-clear cell cell type renal cell carcinoma. 2011 Genitourinary Cancers Symposium. J Clin Oncol 29：2011

24）Gordon MS, Hussey M and Nagle RB：Phase Ⅱ study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer：SWOG S0317. J Clin Oncol 27：5788-5793, 2009

25）Srinivasan R, Linehan WM, Vaishampayan U, et al：A phase Ⅱ study of two dosing rejimens of GSK 1363089（GSK089）, a dual MET/VEGFR2 inhibitor, in patients with papillary renal cartinoma. J Clin Oncol. 2009 ASCO Annual Meeting Proceedings, vol 27, No15S, 2009：5103

26）Schöffski P, Garcia JA, Stadler WM, et al：A phase Ⅱ study of the efficacy and safety of AMG 102 in patients with metastatic renal cell carcinoma. BJU Int 108：679-686, 2011

27）Malouf GG, Camparo P, Oudard S, et al：Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma（RCC）：a report from the Juvenile RCC. Ann Oncol 21：1834-1838, 2010

28）Choueiri TK, Lim ZD, Hirsch MS, et al：Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma. Cancer 116：5219-5225, 2010

29）Golshayan AR, George S, Heng DY, et al：Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. J Clin Oncol 27：235-241, 2009