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1 소라페닙이후의간세포암표적치료제 HCC: New targeted agents beyond sorafenib 김강모 울산대학교의과대학서울아산병원간센터내과 Sorafenib is the only approved systemic molecular targeted agent (MTA) for advanced stage hepatocellular carcinoma (HCC). However, because of the modest efficacy of sorafenib on HCC, there has been huge need for more efficacious MTAs in the treatment of HCC. Increasing knowledge of molecular hepatocarcinogenesis becomes the basis for the search of novel therapeutic targets in HCC and this includes genetic and epigenetic alteration, growth/angiogenic factors and signaling pathways, immunologic changes, and arginine metabolism in HCC. A lot of new MTAs have been and are being studied in clinical trials, and these MTAs are categorized to multikinase inhibitors, MET inhibitors, antiangiogenic agents and mtor inhibitors. Several combination regimens of two MTAs and immunologic modulator is an another new attempt in HCC clinical trials. This review will summarize the result and the current status of various novel MTAs in the treatment of HCC. Keywords: hepatocellular carcinoma, molecular targeted agent, multikinase inhibitor, MET inhibitor, mtor inhibitor 1. 서론 국소치료가불가능하거나실패한간세포암환자를대상으로한연구에서소라페닙은위약군에비해유의하게 overall survival의향상을보인최초의표적치료제로서 1,2 대한간암학회와국립의료원이 2014년발표한간세포암종진료가이드라인에서간외전이가있거나간혈관침범이있는경우, 그리고다른치료에반응하지않고진행하는경우일차적으로사용하는치료법으로권고되고있다 ( 가이드라인.pdf). 하지만실지임상에서는소라페닙투여를결정하는것이이처럼단순하지가않은데, 간문맥분지침범의경우와같이 transarterial chemoembolization (TACE) 이나방사선치료와같은다른국소치료법을시도할수있는경우에도소라페닙단독치료를고집해야하는가에대한논의가있고다른국소치료법과의병합치료가단독치료에비해과연효과적인가에대한결론도나와있지가않아서진행성간세 52 대한간학회 The Korean Association for study of the Liver

2 김강모 소라페닙이후의간세포암표적치료제 포암을대상으로하는전향적연구가현재진행중이다. 이와더불어소라페닙에의한항종양반응은그대부분이간세포암의성장을억제하는것으로실지종양을괴사시키는경우는많지않고손발피부반응, 설사, 식욕부진등의부작용이드물지않으며그비용도만만치않아서보다좋은치료제대한요구가매우높은실정이다. 본연제에서는소라페닙연구의성공이후진행되었거나진행되고있는간세포암에대한표적치료제들의연구를정리하고향후개발가능한전략을소개해보고자한다. 2. Hepatocarcinogenesis 간세포암의표적치료제를개발하는데있어첫번째단계는간세포암의발생과증식및진행에있어서원인이되는분자생물학적변화를알아보는것일것이다. 간세포암의발생및증식은하나의주도적인분자생물학적기전으로설명되지않고복잡한 multistep process에의할것으로생각되며암발생에관여하는거의대부분의 pathway 가관련되어있어서표적치료제의개발이더욱어려운이유가된다. 3 1) Molecular pathogenesis of hepatocellular carcinoma (HCC) (1) Genome wide alteration Hepatocarcinogenesis와관련이있을것으로생각되는 gene과그 gene의 chromosome상위치는다음과같다 ; c-myc (8q), cyclin A2 (4q), cyclind1 (11q), Rb1 (13q), AXIN1 (16p), p53 (17p), IGFRII/M6PR (6q), p16 (9p), E-cadherin (16q), SOCS (16p), PTEN (10q). 거의대부분의간세포암세포에서염색체의 amplification이나 deletion이발견되는데흔히발견되는 amplification의위치는 1q (58% 78%), 6p, 8q, 17q, 20q이며 deletion은 4q, 8p, 13q, 16q, 17p에서많이나타난다. 11q13 (cyclind) 와 6p21 (VEGFA) 의 amplification에대한보고가있다. 4,5 (2) Somatic mutations 간세포암에서 somatic mutation 에대한보고는다른암에비해많지않으며 mutation 의유병률도연구마다다양한결과를보인다. Tumor suppressor gene인 TP53 mutation 이간세포암의 27% (0-67%) 에서보고되어있고 beta-catenin mutation이 17% 에서나타난다고보고되어있다. 이외에 AXIN1, phosphoinositol 3- kinase A (PI3KA), K-Ras mutation 에대한보고는있으나 epidermal growth factor receptor (EGFR), Her2/neu, phosphatase and tensin homolog (PTEN), H-Ras mutation에대한보고는아직부족하다. 6 (3) Gene instability and epigenetic alteration 간세포암에서 gene instability는 telomere shortening, aberrant methylation, mismatch repair gene의이상에 53

3 2014 대한간학회추계 Single Topic Symposium 의해나타나며간세포암의 90% 에서 telomerase activity가증가되어있다는보고가있다. 이외에간세포암의일부 gene promotor region의 CpG island에 abnormal methylation이일어나서 epigenetic silencing이일어나는데 tumor suppressor gene인 p16ink4a, E-cadherin, NORE1A, RASSF1, IGFR-II/MP6, BRCA1 등이그대상이다. 6 2) Growth/angiogenic factors and signaling pathways in HCC 간세포암은유전적으로 heterogeneous하지만일부 signal pathway 가간세포암의증식에중요한역할을한다고잘알려져있으며이에대한억제제가활발히개발되고있는데그 pathway 는 Ras/Raf/MEK/ERK (MAPK) pathway, phosphoinositol 3-kinase (PI3k)/Akt/mammalian target of rapamycin (mtor) pathway, Wnt/beta catenin pathway 이다. 5,6 이들은 growth/angiogenic factor와그수용체를통해활성화되는데여기에는 vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) 와그수용체들이관여한다. 이분야는간세포암표적치료제연구에서가장활발히개발되었던분야로 Raf kinase, VEGFR, PDGFR inhibitor인 sorafenib이대표적이고 EGFR inhibitor인 cetuximab, erlotinib, gefitinib, lapatinib, VEGFR inhibitor인 ramucirumab, cabozantinib, sunitinib, linifanib (sunitinib, linifanib 은 PDGFR inhibition 도함 ), mtor inhibitor인 everolimus, temsirolimus 등이포함된다. VEGF는혈관내피세포에존재하는 VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/Kdr), VEGFR-3 (Flt-4) 를통해 angiogenesis, 간세포암의증식등에관여하는데 VEGF inhibitor 로는 bevacizumab, brivanib 등이있다. 이외에도간세포암의증식에관여할것으로생각되어연구되는 pathway로는 c-mesenchymal-epithelial transition factor (MET)/HGF signaling, basic fibroblast growth factor (bfgf) pathway, insulin-like growth factor signaling, nuclear factor- B, extrinsic/intrinsic apoptotic pathways 등이있는데 c-mek inhibitor인 cabozantinib, tivantinib이현재연구되고있는약물이고 FGFR inhibitor로는 brivanib이있다. 3) Molecular immunologic target Tumor specific effector T cell의침착이있는간세포암에서간이식후간세포암의재발이적었다는보고와 7 anti-cd3 와 IL-2에의해증식을촉진한 autologous T lymphocyte 주입이간세포암의수술후재발을줄였다는보고는 8 T cell immunotherapy의가능성을시사한다. 간세포암에특이적인 CD8+ T cell 반응을일으키기위해서는간세포암에특이적인 tumor-associated antigen (TAA) 의 processing과 presentation이일어나야하는데이 TAA로는 alpha-fetoprotein (AFP), glypican-3 (GPC3), NY-ESO-1, SSX-2, melanoma antigen gene-a (MAGE-A), telomerase reverse transcriptase (TERT) 등이있다 (1) Regulatory T cell (Treg) 은여러연구에서 immunosuppressive cytokine IL-10을분비하여 CD4+ 와 54 대한간학회 The Korean Association for study of the Liver

4 김강모 소라페닙이후의간세포암표적치료제 표 1. 간세포암에서소라페닙의연구결과 SHARP trial1 Asia Pacific trial2 sorafenib placebo HR (95% CI) sorafenib placebo HR (95% CI) Patients OS, months TTP, months DCR, % HR, Hazard ratio; OS, overall survival; TTP, time to radiological progression; DCR, disease control rate, defined as the proportion of patients who had the best response rating of complete response, partial response, or stable disease, which was maintained 4 weeks from the first manifestation of that rating CD8+ T cell 모두를억제하는데향후간세포암의 tumor specific T cell response를높이기위한연구의타깃이될수있다. 14 (2) Myeloid-derived suppressor cells (MDSCs) 는 monocytes/macrophages, granulocytes, dendritic cells (DCs) 이혼재되어있으며최근 arginase activity를변화시켜 CD4+ T cell에서 Foxp3와 IL-10을분비하도록하는것으로알려졌는데역시향후연구에서이에대한억제제가시도될수있다. 15 (3) Impairment of TAA processing and presentation and lack of CD4+ T cell response 간세포암조직에서 HLA class I과 B7 costimulatory molecule이감소되어있다는보고와 16 circulating myeloid DCs이억제되어있다는보고는간세포암에서 TAA processing과 presentation이억제되어있을수있음을시사한다. 또한간세포암초기병기와다르게진행할수록 AFP-specific CD4+ T cell의반응이떨어져있다는보고는 17 CD4+ helper T cell의부재가 CD8+ T cell exhaustion 을일으킬수있음을시사하며이러한기전이향후간세포암면역치료연구의타깃이될수있다. (4) Programmed cell death-1 (PD-1)/programmed cell death-ligand1 (PD-L1) pathway 많은암세포와일부 MDSC는그표면에 PD-L1을발현하는것으로보고되는데이는 CD8+ T cell에서과발현되는 PD-1과결합하여 T cell을억제함으로써암세포의면역회피기전으로작용하는것으로알려져있다. 18 이러한기전을억제하는것이향후간세포암의면역치료법으로개발될수있다. 19,20 4) Arginine deprivation and argininosuccinate synthetase (ASS1) expression Arginine은 semi-essential amino acid로서세포의생존과대사에반드시필요한아미노산이다. 정상세포에서는 citruline과 aspartate에서합성이가능하지만간세포암, malignant melanoma, malignant pleural mesothelioma, prostate cancer, 신장암등에서는 epigenetic silencing에의해 rate limiting enzyme인 argininosuccinate synthetase (ASS1) 가억제되어있어합성이어렵고그생존을위해 arginine의외부유입이반드시필요하게된다 (arginine auxotrophy, 아르기닌영양요구성 ). 이러한암종에서혈중 arginine을 depletion 시키는경우해당암세포의 apoptosis를유발하게되어치료에이용할수있는데 pegylated arginine deiminase 55

5 2014 대한간학회추계 Single Topic Symposium 표 2. 현재임상연구중인표적치료제들 Molecular targeted agents for HCC Development status Multikinase inhibitors Sorafenib Approved Sunitinib Linifanib Brivanib Lenvatinib Phase 3, 1st line, serafenib controlled Axitinib Phase 2, 2nd line, single arm Regorafenib MET inhibitors Tivantinib Cabozatinib Antiangiogenic agents Bevacizumab (+erlotinib) Phase 2, 1st line, sorafenib controlled Ramucirumab mtor inhibitors Everolimus Temsirolimus (+bevacizumab) Temsirolimus (+sorafenib) Phase 2, 2nd line, single arm Combination treatment of MTA Sorafenib + Erlotinib Sorafenib + Vorinostat Phase 1 Other MTAs ADI PEG20 PEG BCT 100 Phase 2, 2nd line, single arm Nivolumab Phase 1 HCC, hepatocellular carcinoma; MTA, molecular targeted agent (ADI-PEG20) 이현재간세포암에서임상연구중에있다. 이와반대로 ovarian cancer, 위암, 대장암등에서 는 ASS1이과발현되어있어이러한 arginine auxotrophy를보이지않으며 platinum 치료에민감성을나타내게된다 소라페닙이후의표적치료제연구 ( 표 2) (source: ClinicalTrials.gov) PDGFR-α/β, VEGFR-1-3, Raf kinase, c-kit, Flt-3, RET 등을억제하는 multikinase inhibitor인 sorafenib이진행된간세포암에서위약군에비해유의한효과를보인후많은새로운표적치료제의연구가있어왔으나현재까지 sorafenib 단독치료보다우월한성적을보고하는약제는없었다. 다음은이전에진행되었거나현재진행중인표적치료제를소개하고지한다. 56 대한간학회 The Korean Association for study of the Liver

6 김강모 소라페닙이후의간세포암표적치료제 1) Multikinase inhibitors VEGFR-1/2, PDGFR-α/β, Raf kinase, c-kit, Flt-3, RET을억제하는것으로알려진 sunitinib 은 3상 1 st line, sorafenib과 head to head 연구에서심각한출혈의부작용과열등한효능으로인해연구가중단되었다. VEGFR과 PDGFR을억제하는 linifanib은최근 3상 1 st line, sorafenib과 head to head 연구에서 median time to progression (TTP) 은우월하였으나 (linifanib vs sorafenib, 5.4개월 vs 4.0개월, HR: , p=0.001) overall survival (OS) 은차이가없었다 (linifanib vs sorafenib, 9.1개월 vs 9.8개월, HR: 1.046, 95% CI: 0.896, 1.221). FGFR과 VEGFR을동시에억제하는약제로기대를모았던 brivanib 은 1 st line 3상연구와 (brivanib vs sorafenib, 9.5개월 vs 9.9개월, p=0.3116) 2 nd line 3상연구에서 (brivanib vs placebo, 9.4개월 vs 8.2개월, p=0.3307) 각각 sorafenib 및 placebo와비교하여 OS에차이가없었다. 현재간세포암에서임상진행중인 multikinase inhibitor로는 lenvatinib, axitinib, regorafenib이있다. Lenvatinib 은 VEGFR-1-3, FGFR-1-4, RET, PDGFR-β, c-kit 등을억제하는데현재 sorafenib과 head to head, 3상 1 st line 연구중이며결과가기대된다. Axitinib은 VEGFR-1-3, PDGFR-β, c-kit 등을억제하는데현재 2상 2 nd line, single arm 연구중이며, egorafenib은 sorafenib의구조를약간만바꾸어서그효능을높이고부작용을줄인약제로서현재 3상 2 nd line, placebo 대조군연구가진행중이다. 2) MET inhibitors MET/HGF signaling pathway 는최근에각광받고있는 pathway 로결합할경우 MAPK pathway 와 PI3k/Akt/mTOR pathway를활성화시킨다. Tivantinib은 MET inhibitor로서간세포암을대상으로한 2상 placebo 대조군연구에서유의한결과를보이지않았으나 high MET expression subgroup에서비교적좋은결과를보여현재 3상 2 nd line, placebo 대조군연구가진행중이다. Cabozatinib은 MET/VEGFR2 dual inhibitor로서역시 3상 2 nd line, placebo 대조군연구가진행중인데이연구들에서는치료반응을예측하는 biomarker로간세포암에서의 MET expression 활성화여부가사용될수있을것이다. 3) Antiangiogenic agents Bevacizumab 은 VEGF와결합하여 VEGFR pathway를억제하는 recombinant, humanized monoclonal antibody로서간세포암에서시행된여러 2상연구에서 개월의 median PFS와 의 median OS을보고하고있으나 22 단독치료로서의 3상연구결과는아직없다. 2상 single arm 연구에서도 bevacizumab + erlotinib 병합치료가대부분을차지하고있으며현재는간세포암을대상으로 2상 1 st line, sorafenib 대조군연구가진행중이다. VEGFR2를특이적으로억제하는 monoclonal antibody 인 ramucirumab은간세포암 2상 1 st line 연구에서 50% 의 disease control rate (DCR) 와 4.3개월의 median PFS를보여현재 3상 2 nd line, pla- 57

7 2014 대한간학회추계 Single Topic Symposium cebo 대조군연구가진행중이며곧결과가발표될것으로기대된다. 4) mtor inhibitors 대표적인 mtor inhibitor 인 everolimus는최근 3상 2 nd line, placebo 대조군연구에서 median OS과 (everolimus vs placebo, 7.56개월 vs 7.33개월, HR: 1.05, p=0.675) median TTP에서유의한차이가없었다 (everolimus vs placebo, 2.96개월 vs 2.60개월, HR: 0.93, CI: 0.75, 1.15). 또다른 mtor inhibitor인 temsirolimus는 VEGF inhibitor 인 bevacizumab이나 sorafenib과의병합치료로 2상연구가진행되었다. Temsirolimus + bevacizumab 병합치료연구는 2상 2 nd line, single arm 연구이었는데 response rate나 progression free survival (PFS) 이미리정해둔목표 (6 month PR >2 patients or PFS 6 months >18 out of 25) 를만족하지않아서연구가중단되었다. Temsirolimus + sorafenib 병합치료연구는 2상 2 nd line, single arm 연구로현재진행중이다. 5) 표적치료제의병합연구 1 st line, sorafenib + erlotinib vs sorafenib + placebo 3상연구는 median OS에서유의한차이를보이지못하여실패하였다 (sorafenib + erlotinib vs sorafenib + placebo, 9.5개월 vs 8.5개월, HR: 0.929, p=0.204). Vorinostat은 histone deacetylase (HDAC) inhibitor로서 epigenetic activity에의해여러작용을한다고알려져있는데 sorafenib + vorinostat 병합치료로간세포암에서현재 1상연구중이다. 6) 다른표적치료제들간세포암의 arginine auxotrophy를이용하여혈중 arginine을 depletion 시키는치료제로 ADI-PEG20과 PEG-BCT-100이있다. ADI-PEG20 은미생물에서유래한 arginine deaminase를 pegylation 시킨것으로현재간세포암을대상으로 3상 2 nd line, placebo 대조군연구가진행중이고 PEG-BCT-100은 recombinant human arginase를 pegylation 시킨것으로현재 2상 2 nd line, single arm 연구가진행중이다. Nivolumab은 T cell 표면의 PD-1을막는 fully human IgG4 monoclonal antibody 로서 immune modulator 로간세포암에작용할것으로기대되는약제로현재 1상연구중이다. 4. 결론 간세포암의표적치료제로소라페닙이성공한이후새로운표적치료제가곧뒤따라개발될것으로기 대하였으나이후의연구결과는실망스럽기까지하다. 간세포암의발생과증식과정이하나의분자생물학 58 대한간학회 The Korean Association for study of the Liver

8 김강모 소라페닙이후의간세포암표적치료제 적기전에의하지않고여러다양한복잡한기전에의하기때문에어쩌면특정 target을억제하는표적치료제단독요법으로좋은결과를얻기가어려운것이당연한결과가아닌가하는생각조차든다. 현재도 multikinase inhibitor를비롯하여 c-met, VEGF pathway, mtor pathway 억제제등다양한약제들이개발되고있으므로그임상연구결과들을잘지켜보아야하겠다. 그리고향후에는서로다른표적치료제간의병합요법, anti PD-1 이나 HDAC 억제제, ADI-PEG20 등새로운접근의치료법들의결과를지켜보아야하겠고이러한새로운치료법의다국적임상연구에도적극적으로참여하여야하겠다. 참고문헌 1. 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: Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double blind, placebo controlled trial. Lancet Oncol 2009;10: Bertino G, Demma S, Ardiri A, Proiti M, Gruttadauria S, Toro A, et al. Hepatocellular carcinoma: novel molecular targets in carcinogenesis for future therapies. Biomed Res Int 2014;2014: Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008;68: Tanaka S, Arii S. Molecular targeted therapies in hepatocellular carcinoma. Semin Oncol 2012;39: Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007;27: Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler SL, et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol 2006;45: Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356: Thimme R, Neagu M, Boettler T, Neumann Haefelin C, Kersting N, Geissler M, et al. Comprehensive analysis of the alphafetoprotein specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology 2008;48: Komori H, Nakatsura T, Senju S, Yoshitake Y, Motomura Y, Ikuta Y, et al. Identification of HLA A2 or HLA A24 restricted CTL epitopes possibly useful for glypican 3 specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res 2006;12: Shang XY, Chen HS, Zhang HG, Pang XW, Qiao H, Peng JR, et al. The spontaneous CD8+ T cell response to HLA A2 restricted NY ESO 1b peptide in hepatocellular carcinoma patients. Clin Cancer Res 2004;10: Bricard G, Bouzourene H, Martinet O, Rimoldi D, Halkic N, Gillet M, et al. Naturally acquired MAGE A10 and SSX 2 specific CD8+ T cell responses in patients with hepatocellular carcinoma. J Immunol 2005;174: Mizukoshi E, Nakamoto Y, Marukawa Y, Arai K, Yamashita T, Tsuji H, et al. Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma. Hepatology 2006;43: Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T regulatory cells. Hepatology 2005;41: Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, et al. A new population of myeloid derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008;135:

9 2014 대한간학회추계 Single Topic Symposium 16. Fujiwara K, Higashi T, Nouso K, Nakatsukasa H, Kobayashi Y, Uemura M, et al. Decreased expression of B7 costimulatory molecules and major histocompatibility complex class I in human hepatocellular carcinoma. J Gastroenterol Hepatol 2004;19: Behboudi S, Alisa A, Boswell S, Anastassiou J, Pathan AA, Williams R. Expansion of anti AFP Th1 and Tc1 responses in hepatocellular carcinoma occur in different stages of disease. Br J Cancer 2010;102: Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, et al. PD 1 and PD L1 upregulation promotes CD8(+) T cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011;128: Breous E, Thimme R. Potential of immunotherapy for hepatocellular carcinoma. J Hepatol 2011;54: Teramoto K, Ohshio Y, Fujita T, Hanaoka J, Kontani K. Simultaneous activation of T helper function can augment the potency of dendritic cell based cancer immunotherapy. J Cancer Res Clin Oncol 2013;139: Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T, et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer 2010;126: Fang P, Hu JH, Cheng ZG, Liu ZF, Wang JL, Jiao SC. Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carcinoma: a systematic review of phase II trials. PLoS One 2012;7:e 대한간학회 The Korean Association for study of the Liver

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<B0E6C8F1B4EBB3BBB0FA20C0D3BBF3B0ADC1C E687770> 2012 개원의와함께하는임상강좌 경희대학교의과대학종양혈액내과학교실 백선경 한국인사망원인 평균수명까지생존시암발생확률 길라잡이 : 개정된가이드라인을중심으로 History of anti-cancer chemotherapy Chabner BA & Roberts TG Jr. Nat Rev 2005 Use standard therapies 2012 개원의와함께하는임상강좌