118 Hanyang Medical Reviews Vol. 32, No. 2, 2012 http://dx.doi.org/10.7599/hmr.2012.32.2.118 간세포암의표적치료 Target Therapy for Hepatocellular Carcinoma 윤승규가톨릭의과대학서울성모병원소화기내과 Seung Kew Yoon, M.D., Ph.D. Division of Hepatology-Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea 책임저자주소 : 137-040, 서울시서초구반포대로 222 가톨릭대학교서울성모병원소화기내과 Tel: 02-2258-6018, Fax: 02-536-9559 E-mail: yoonsk@catholic.ac.kr identification of additional molecular targets in HCC and lead to treatments with enhanced efficacy and improved tolerability. Key Words: Carcinoma, Hepatocellular; Molecular Targeted Therapy; Sorafenib; Signal Transduction 서론 투고일자 : 2012 년 2 월 28 일심사일자 : 2012 년 3 월 13 일게재확정일자 : 2012 년 4 월 26 일 Abstract Hepatocellular carcinoma (HCC) is a highly malignant tumor that has limited treatment options in its advanced state. The efficacy of current anti-cancer chemotherapy in advanced HCC has not been satisfactory, and the management of HCC remains a major challenge for physicians. However, recent advancement in our understanding of the molecular mechanisms underlying carcinogenesis has provided novel targets in key signa ling pathways for tumor development. Recently, Sorafenib (Nexavar), a multi-kinase inhibitor targeting membrane receptors involved in angiogenic and mitogenic intra-cellular signaling including Raf, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptors (PDGFR), has been approved worldwide as a new target agent for HCC, and subsequent clinical trials of newly developed molecular target agents such as Brivanib and Everolimus are being conducted globally. In the near future, continued research will lead to the 간세포암은전세계적으로암발생률 6위, 암으로인한사망중 3위를차지하는악성종양으로, 환자의 70-90% 는간경변이나만성간질환을동반하고있고다른종양에비해암발생의주요원인인자들이비교적잘알려져있다. 그원인인자들로만성 B형간염바이러스 (hepatitis B virus, HBV) 감염, 만성 C형간염바이러스 (hepatitis C virus, HCV) 감염, 장기간의과음, 비만, 당뇨와연관된비알코올성지방간염 (non-alcoholic steatohepatitis, NASH) 이외에아플라톡신 B1 (aflatoxin B1, AFB1), 혈색소증, 유전질환등이보고되고있다 [1, 2]. 이들중국내의간세포암의가장흔한원인은만성 HBV 감염으로전체간세포암발병의약 70-80% 를차지하고있다. 이렇게간세포암의원인인자가잘알려져있음에도불구하고간세포암의발병기전은매우복잡한과정을거쳐일어나는데유전적인변이나후성적 (epi genetic) 변화와함께많은분자신호전달계가관여하여간세포의악성변화나질병의진행혹은전이를유도하게된다. 하지만이러한복잡한간세포암발병기전은아직도충분히이해되지않고있어아직도많은연구들이진행중이다. 최근간세포암에대한치료방법은다양하게발전하고있으나조기에간암을발견하지못할경우완치가어려워예후가매우불량하다. 현재간세포암의치료가이드라인은종양의크기, 간기능, 신체활력도를근간으로한 Barcelona Clinic Liver Clinic (BCLC) staging classification 을이용하고
Target Therapy for Hepatocellular Carcinoma 119 있는데이병기체계에서는간세포암을 0 (very early stage), A (early stage), B (intermediate stage), C (advanced stage), D (terminal stage) 의 5개병기로나누어각병기에따른치료전략을제시해주어현재세계적으로통용되고있다 [3]. 하지만현재까지진행된간세포암에서치료효과는극히제한적이라새로운치료제의개발이시급한실정에있다. 최근분자생명과학분야의발전으로다양한암종의발병기작에서새로운신호전달체계를규명하고이를표적으로하는표적치료제의개발이활발하게이루어지고있고, 이를이용하여전세계적으로많은분자표적치료제의임상연구가진행중이다. 간세포암에서는 multi-kinase inhibitor인 Sorafenib (Nexavar) 이진행성간세포암에서생존기간을증가시켰다는보고가나온이후 [4], 다양한표적치료제가연구되면서난치성간세포암치료에기대를모으고있다. 본종설에서는간세포암의발병기전과연관된신호전달체계에대해고찰해보고이들을표적하고있는표적치료제들에대한임상적의의를알아보고자한다. 본론 1. 간세포암의발병기전간세포암의주요원인인자로 HBV, HCV, alcohol, 자가면역성간염그리고최근에증가하고있는 NASH가있고, Histogenetic pathway Direct pathway HCV Alcohol HBV HCV AFB1 HBV NASH Direct carcinogenic P53 inactivation 이외에중국에서생산되는홍콩에서발현되는진균독소인 AFB1, 혈색소증, 알파-1-안티트립신결핍, 윌슨병등이보고되고있다 [5]. 일반적으로간세포암의발병기전은 2가지양식으로나눌수있는데, 병리조직학적으로여러가지원인에의해만성경과를거치면서간세포의염증과재생이반복되면서여기에유전적혹은후성적변화가동반되어간세포암으로진행되는기전이잘알려져왔지만, AFB1 이나 HBV의 HBx 유전자혹은 HCV core 유전자등이간세포내직접적인영향을미쳐만성염증이나재생과정을거치지않고도간암을일으킨다는보고가많은기초연구에서밝혀졌다 [6-8] (Fig. 1). 2. 간세포암의발병기전과연관된신호전달체계와표적치료제일반적으로간세포암의발병기작은세포표면의수용체 (receptor) 에성장인자 (growth factor) 가결합하여단백질- 인산화반응을활성화시키면증식성신호전달체계를활성화시켜이신호들을핵내로전달한다. 이러한신호전달계의핵심요소로표피성장인자수용체 (epidermal growth factor, EGFR), 변형성장인자 (transforming growth factor, TGF)-α/β, 인슐린양성장인자 (insulin-like growth factor, IGF), 혈관내피세포성장인자 (vascular endothelial growth factor, VEGF), 섬유아세포성장인자 (fibroblast growth factor, FGF), 혈소판유도성장인자 (platelet-derived growth factor, PDGF) 등이관여한다 (Fig. 2). 최근각종암에서이러한신호전달을표적으로하는암치료제개발이활발하게연구되고있다. 다음은간세포암에서성장인자관련신호전달체계를간단하게요약하였다. Chronic inflammation Cell proliferation & loss of growth control 1) 표피성장인자수용체 Regeneration Genetic/Epigenetic alteration Hepatcellular carcinoma Fig. 1. The etiologic factors and pathogenesis of hepatocellular carcinoma. HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; AFB1, aflatoxin B1; p53, tumor suppressor gene p53. 표피성장인자수용체는간세포의표면에발현되어세포의성장과분화, 생존에관여한다 [9]. 최근 Buckley 등은 [10] 간세포암조직중 66% 에서 EGFR이과발현된다고보고한바있고이외에간세포암을포함한여러고형암에서 EGFR의발현증가가보고되었다. EGFR은세포내에티로신키나아제 (tyrosine kinase) 부위가위치하고, 세포외에리간드가결합하는부위로구성되는데, 세포외부에서 TGF-
120 Hanyang Medical Reviews Vol. 32, No. 2, 2012 Fig. 2. Signaling pathways in hepatocarcinogenesis. Wnt/Hedgehog pathway, growth factor pathway, survival factor pathway, Akt/mTOR pathway, and Jak/stat pathway are involved in the hepatocarcinogenesis, and can be targeted for HCC therapy. DSH, Dishevelled; GBP,GSK3B binding protein; GSK3B, glycogen synthase kinase 3-beta; APC, adenomatous polyposis coli; PTCH1, PATCHED1 membrane protein; SMOH, Smoothened; SU, suppressor-of-fused; COS- 2, Drosophila Costal2; FU, Fused; PI3K, phosphoinositide 3-kinase; GLI, glioblastoma; RTK, receptor tyrosine kinase; SOS, son of sevenless homolog; Grb2, growth factor receptor-bound protein 2; MAP2K, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3 kinase; PKC, protein kinase C; AKT, v-akt murine thymoma viral oncogene homolog; PTEN, phosphatase and tensin homolog; Bcl XL, B-cell lymphoma extra large. α나 EGF와같은리간드가수용체에결합하면세포내의 Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of Rapamycin (mtor) 경로와 RAS/MAPK 신호전달경로가활성화되어간세포암의발생과증식이진행된다. EGFR 신호경로를차단하는표적치료는세포외리간드부착부위에결합하는중화단클론항체 (monoclonal antibody) 이용하거나티로신키나아제억제제를사용하여키나아제를통해이뤄지는신호전달경로를차단하는 2가지전략이이용된다. Erlotinib은 EGFR의티로신키나아제를억제하는소분자 (small molecule) 로써비소세포폐암의치료에주로사용되고있었는데, 최근간세포암에서 Philip 등 [11] 과 Thomas 등 [12] 이 Erlotinib 2상임상시험을통해각각 13 개월, 10.7개월의전체생존기간을보고하였고, VEGF의단클론항체인 Bevacizumab과병용치료를하였던 2상임상시험에서는 9.5개월, 15.7개월의전체생존기간을보였다 [13, 14]. 현재 Sorafenib 과 Erlotinib 병용치료와 Sorafenib 단 독치료를비교하는 3상임상시험 (Sorafenib and Erlotinib, A Randomized Trial Protocol for the Treatment of Patients with Hepatocellular Carcinoma, SEARCH) 이진행중이지만, Erlotinib의부작용 ( 피부발진, 피부건조, 위장관독성등 ) 이심해실제임상적용에문제가되는실정에있다. Lapatinib 은 EGFR과 HER-2/neu 의이중억제제로 MAPK, Akt, p70s6 키나아제를 downregulation 하여종양의성장을억제한다 [15]. Lapatinib 을이용한 2상임상연구에서는 5% 의반응률, 2.3개월의비진행생존 (progression free survival, PFS), 6.2개월의전생존기간 (overall survival, OS) 을보였다 [16]. Cetuximab 은 EGFR 억제단클론항체로써두경부암 [17] 과대장암 [18] 치료에미국 FDA의허가를받은약제인데, 30명의진행성간세포암환자를대상으로한 Cetuximab 의 2상임상시험에서 1.4개월의비진행생존 (PFS), 9.6개월의전생존기간 (OS) 을보였다 [19].
Target Therapy for Hepatocellular Carcinoma 121 2) 인슐린양성장인자수용체 (IGF) 인슐린양성장인자군은태아성장, 증식, 분화, 세포성장, 세포사멸등과같은많은역할을담당하면서여러악성종양의원인인자로작용한다 [20]. 최근연구에의하면간세포암에서 IGF-I 수용체의이상활성화가 20% 에서관찰되었고, IGF-II 의발현이 12-44% 에서증가되었으며, 이들수용체의기능이간세포암의병기, 전이및생존기간과관계가있다고보고하였다 [21, 22]. Cixutumumab (IMC-A12), BIIB022, AVE1642 등이 IGF를표적으로하는약제이며현재간세포암에서이들을이용한임상시험들이진행중이다. 3) PI3K/Akt/mTOR 신호전달경로 PI3K/Akt/mTOR 경로는암세포의증식, 분화, 생존, 이동및대사에관여하는단백의조절을담당하는데 [23], 세포표면에발현된다양한티로신키나아제수용체 (VEGFR-1, PDGFR-α, EGFR, c-met) 가활성화되면 PI3K의활성화가일어나고, 활성화된 PI3K는 Akt, mtor를순차적으로활성화시키며, RAS를간접적으로활성화시키기도한다. PI3K 는 phosphatase and tensin homologue (PTEN) 에의해억제되지만간세포암에서는 PTEN의기능손실이흔하다고보고되고있다 [24]. PI3K/Akt/mTOR 경로의활성화는간세포암에서나쁜예후와관련이있다고보고된바 [25], 특히세포분열의 G1기에서 S기로진행시세포성장및증식을조절하는 mtor는이경로의가장중요한매개체로표적치료의중요한목표가된다 [26]. mtor의억제제는현재간이식후면역억제제로흔히사용되고있으며, Sirolomus 와 Everolimus 가간세포암의표적치료제로연구되었는데 21명의간세포암환자에게 Sirolimus 를사용한연구에서부분반응 (partial response, PR) 1명 (4.8%), 안정질환 (stationary disease, SD) 이 5명 (23.8%) 이었으며 6.5개월의전체생존기간을보였다 [27]. Everolimus 는 in vitro 및 in vivo 내에서간세포암의성장을효과적으로억제하였고, 간세포암세포주에서 cisplatin 의세포독성을증가시켰다 [28, 29]. 현재 Sorafenib 을복용할수없는진행성간세포암환자에서 Everolimus 의효과를비교하는 3상임상시험 (Advanced Hepatocellular Carcinoma after Disease Progression or Intolerance to Sorafenib Everolimus for LiVer cancer Evaluation, EVOLVE-1) 과 Sorafenib 단독치 료와 Everolimus 와 Sorafenib 병합치료의효과를비교하는글로벌임상시험이진행중에있다. 4) RAS/RAF/ Mitogen-activated protein kinase (MAPK) 신호전달경로 MAPK 경로는 RAS, RAF, mitogen-activated protein extracellular kinase (MEK), extracellular signal-regulated kinase (ERK) 를포함하며, 세포의증식, 이동, 세포사멸의억제에관여한다 [30]. 간세포암에서 MAPK 경로의활성화는 EGFR, IGF와같은티로신키나아제수용체의자극을통해일어나며, RASSF1A, NORE1A 같은종양억제유전자가과메틸화로인해불활성화되면서 MAPK 경로가활성화되기도한다 [31]. 간세포암에서는 RAF와 RAS의돌연변이가다른고형암에비해드문편이지만, 야생형 RAF-1의과활성화가보고되고있다 [32-34]. Sorafenib은 RAF-1외에 B- RAF, VEGFR, PDGFR, FGFR1 등과같은티로신키나아제수용체, c-kit, Flt-3, RET와같은티로신키나아제를억제하여종양의성장에관여한다 [35]. 진행성간세포암환자에게 Sorafenib을투여한 3상임상시험에서전체생존기간의향상을보였고 [36], 이에따라국내에서적절한간기능 (Child- Pugh class A) 을가진진행성간세포암의표준치료로보험급여를인정받고있다. 5) Hepatocyte Growth Factor (HGF)/c-MET 신호전달경로간세포성장인자 (HGF) 는간세포의재생에중요한물질로간의성상세포에서분비된다 [37]. HGF는 c-met 수용체에결합하여중간엽세포의상피세포로의이행 (mesenchymal-epithelial transition) 을유도하고, 암세포의증식, 이동, 전이능력을증가시킨다 [38]. ARQ-197은 c-met 수용체티로신키나아제를억제하는약제로전신치료에실패한진행성간세포암환자에서위약과비교하는 2상임상시험이진행중이다. 6) Wnt-β catenin과 hedgehog 신호전달경로 Wnt 신호경로활성화는간세포암환자의약 1/3에서발
122 Hanyang Medical Reviews Vol. 32, No. 2, 2012 견된다. Wnt는세포외부의수용체 (Frizzled receptor, FZD) 에결합하여 β-catenin에신호가전달되면 E-cadherin에서 β-catenin이분리되어세포핵내로이동한다. 세포핵내에서 β-catenin은 c-myc, survivin, cyclin D와같은종양유전자를조절한다. Hedgehog (Hh) 신호는태아의간발달과재생, 줄기세포및세포분화에중요한역할을담당하는경로로써활성화되어간세포암의발생에관여한다. Wnt 경로와 Hedgehog 경로의조절이상은간세포암의발생에서흔히발견되지만효과적인치료약제는아직개발중이다. 7) 신생혈관억제신생혈관형성은간세포암을포함한악성종양의성장및전이에중요한요소로서, VEGF, FGF, angiopoietin 과같은혈관형성인자및 thrombospondin, angiostatin과같은혈관형성억제인자가관여하는복잡한과정으로이루어지고있다. 특히간세포암은신생혈관형성이활발한종양으로혈관형성의강도가암세포의혈관침범, 전이및예후와연관있다고알려져있다 [39, 40]. 혈관형성에관여하는여러인자중가장강력한인자는 VEGF로간세포암의예후인자로작용하게되는바. 따라서 VEGF 경로억제를통해신생혈관형성을막는표적치료에대한연구가많이이뤄지고있다 [41]. Bevacizumab 은 VEGF의이형질체를중화시키는단클론항체로현재대장암, 유방암, 비소세포폐암치료에미 FDA의허가를받은약제이다. 진행성간세포암에서이뤄진 2상임상시험에서 Bevacizumab은 13% 의반응률과 65% 의질병안정화를보여의미있는결과를보였고 [42], 현재는경동맥항암화학색전술 (transcatheter arterial chemoembolization) 과 Bevacizumab의병합요법, EGFR 티로신키나아제억제제인 Erlotinib과의병합요법에관한임상시험이진행중이다 [8]. 다만 Bevacizumab은고혈압 (15%), 출혈 (14%) 등의 grade 3-4의부작용이나타날수있어사용에주의가필요하다. Sunitinib은 Sorafenib 처럼다중키나아제억제제로 VEGFR, PDGFR, c-kit 등과같은티로신키나아제를억제하는약제이다. Sunitinib 은 IC 50 이 sorafenib 보다낮아더항암효과가클것으로예상했으나항암작용의이득보다골수억제, 피로, 수족구병 (Hand-Foot Skin reaction, HFER) 등과같은부작용이많아진행성간세포암에서 Sorafenib 과 Sunitinib을직접비교하는 3상임상시험은중도에중단되었다. Brivanib은 VEGFR과 FGFR을같이억제하는티로신키나아제억제제로진행성간세포암의초치료환자와신생혈관억제치료에실패한환자에서모두효과가있었다 [43, 44]. 현재는간세포암에서일차치료와이차치료약제로서 Brivanib의효과에대한 3상임상시험, Brivanib과 TACE 병합치료에대한임상시험이진행중이다. TSU-68은 VEGFR, PDGFR, FGFR을억제하는약제로일본에서진행성간세포암환자를대상으로한임상연구가이루어졌는데 [45], 항암효과는다른신생혈관형성억제제와비슷하였지만, aspartate aminotransferase (AST) 와 alanine aminotransferase (ALT) 의증가, 빈혈, 혈소판감소증, 복수, 복통등의부작용이나타나향후이약제의사용에대해신중해야할것으로생각된다. 3. 간세포암에서 Sorafenib 사용 Sorafenib은 RAF-1, B-RAF, VEGFR2, PDGFR, c-kit 수용체등의티로신키나아제및 serine threonine 키나아제를억제하는약제로써 [46] 간세포암에서표적치료제의시발점이되었다. 137명의진행성간세포암환자를대상으로한 2상임상시험에서 Sorafenib은 5% 미만의반응률을보였지만, 생존기간이 9.2개월로기대생존기간 (6개월 ) 보다높아효과가인정되었고 [4], 이어서진행된 3상임상시험 (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol, SHARP) 에서는, 602명의진행성간세포암환자를 Sorafenib 복용군과위약군으로나누어비교하였고, Sorafenib은전체생존기간을 10.7개월 ( 위약군 7.9개월 ), time to progression (TTP) 을 5.5개월 ( 위약군 2.8 개월 ) 로증가시켜주었다 [4]. SHARP 임상시험이 C형간염의유병률이높은지역에서시행된반면 B형간염의유병률이높은아시아-태평양지역에서도다른 3상임상시험이진행되었다 [36]. 아시아-태평양에서진행된임상시험에서는 SHARP 임상시험에포함된간세포암보다더진행된간세포암환자가많이포함되어생존기간이짧았지만위약군이 4.2개월의전체생존기간을보인반면 Sorafenib 복용군에서는 6.5개월로전체생존기간의증가를가져왔다. 위의두 3상임상시험에서보여준생존기간의증가정도는다른고
Target Therapy for Hepatocellular Carcinoma 123 형암에서표적치료제를사용하여얻은결과와비슷하였다 [47]. 이러한 3상임상시험들을바탕으로현재 Sorafenib은 BCLC 병기 C의진행성간세포암에서표준치료로인정받고있다. 현재에도 Sorafenib을이용한임상시험은 1상-4상에걸쳐 60개이상이등록되어이루어지고있다. 전학적변이에따라세분할수있을것이며이에따른환자의맞춤치료가가능한시대가도래할것으로기대된다. References 4. 표적치료제의현황과전망 Sorafenib의성공이후간세포암에서표적치료제에대한관심이증가되었고, 현재는 50개이상의표적치료제가 200 여개임상시험에이용되고있다. 표적치료제는 target에따라분류가가능하다. 요약하면다음과같다. 1) EGFR 억제제 : Erlotinib, Gefitinib, Lapatinib, Cetuximab 2) 신생혈관형성억제제 : Bevacizumab, Sorafenib, Suni - tinib, Vatalanib, Cediranib 3) mtor 억제제 : Everolimus, Termsirolimus 4) 기타약제 : c-met 억제제, IGFR1 억제제, Wnt 억제제이중가장많이연구되고있는약제는 Sorafenib이며 Bevacizumab, Erlotinib, Everolimus, Brivanib이그뒤를잇고있다. 또한 Sorafenib, Erlotinib, Brivanib, Linifanib, Everolimus 등은 3상임상시험이진행되고있다. 결론간세포암환자에서 Sorafenib의사용은간세포암치료에큰변화를가져왔다. Sorafenib 치료가진행성간세포암환자의생존기간증가를보이면서간세포암치료에서표적치료제의가능성을열어주었고, 이후간세포암의연구는분자수준의발병기전및신호전달경로에초점이맞춰지게되어, 그에따른수많은표적치료제개발이이루어지고있다. 하지만표적치료제가간세포암치료에중요한위치를차지하게되었으나치료의반응을예측할수있는생물표지자 (biomarker) 는아직잘알려지지않아이에대한연구가더욱필요한실정이다. 또한간세포암의발병기전은매우복잡해서하나의표적치료제만으로는최대효과를보기어렵기에표적치료제의병합요법, 또는기존치료와표적치료제의병합요법에대한연구가더욱필요할것으로생각된다. 이러한연구들을통해간세포암을분자유 1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76. 2. Poon D, Anderson BO, Chen LT, et al. Management of hepatocellular carcinoma in Asia: Consensus statement from the Asian Oncology Summit. 2009. Lancet Oncol 2009;10:1111-8. 3. Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010;30:61-74. 4. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. 5. Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist 2010;15 Suppl 4:14-22. 6. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6:674-87. 7. Wysocki PJ. Targeted therapy of hepatocellular cancer. Expert Opin Inv Drug 2010;19:265-74. 8. Kudo M. Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma. Dig dis 2011;29:289-302. 9. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. New Engl J Med 2008;358:1160-74. 10. Buckley AF, Burgart LJ, Sahai V, Kakar S. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am J Clin Pathol 2008;129:245-51. 11. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23: 6657-63. 12. Thomas MB, Chadha R, Glover K, Wang X, Morris J,
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