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Korean J Gastroenterol Vol. 61 No. 3, 147-154 http://dx.doi.org/10.4166/kjg.2013.61.3.147 pissn 1598-9992 eissn 2233-6869 REVIEW ARTICLE 췌장암분자표적치료의최신지견 조재희 관동대학교의과대학내과학교실, 명지병원소화기내과 Recent Update of Molecular Targeted Therapy in Pancreatic Cancer Jae Hee Cho Division of Gastroenterology, Myongji Hospital, Department of Internal Medicine, Kwandong University College of Medicine, Goyang, Korea Pancreatic ductal adenocarcinoma is one of the most dreaded malignancies and the 5th leading cause of cancer-related death in Korea. Late diagnosis and unfavorable response to both chemotherapy and radiotherapy result in exceptionally poor prognosis. Recently, the rapid advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis, and there are many attempts to modulate signal pathway using specific targeted agent. However, the most of them have so far failed to improve survival significantly except erlotinib. The real challenge is now how these impressive advances of molecular biology could be successfully integrated into better clinical implications. Herein, we summarize the latest insights into the carcinogenesis, and their repercussions for novel targeted agents for pancreatic cancer, and provide a review of recent clinical trials using molecular targeted therapy. (Korean J Gastroenterol 2013;61:147-154) Key Words: Pancreatic neoplasms; Molecular targeted therapy 서론 2012년에발표된대한민국국가암등록 2010년통계자료에따르면췌장암 ( 췌장선암 ; pancreatic ductal adenocarcinoma) 은 9번째호발암으로, 5년생존율이 8.0% 로보고되며, 암연관사망의 5번째원인 (6%) 을차지하는불량한예후를보이는질병이다. 특히 2년생존율이 10% 내외에불과하고, 내원당시약 80-90% 에서국소진행성또는원격전이가진단되며, 설혹조기에발견되어근치적수술을시행한경우에도약 70-80% 정도에서암이재발하기때문에다양한항암화학요법, 방사선요법및분자표적치료등이필요하다. 그러나, 이러한다양한췌장암치료에도불구하고, 90년대중반과최근 5 년동안 (2006-2010년) 의생존율비교에서전체암생존율향상 (22.9%) 과달리췌장암은오히려 1.4% 의 5년생존율감소 가확인되어, 보다효과적인분자표적치료및개인맞춤치료법의도입이필요하다. 1-3 췌장암치료제는 1997년 gemcitabine과 5-fluorouracil (5-FU) 비교연구를통해전이성췌장암에서 gemcitabine이증상개선과생존기간을연장시킬수있다고공인된이후, 4 약 15년이지난현재까지도동일한치료가근간이되고있다. 치료효과의개선을위해다양한병용약물요법이시도되었으나, gemcitabine과분자표적치료제 erlotinib 병합요법에서 23% 무진행생존기간연장, 18% 사망위험감소, 그리고 0.3개월의생존기간연장이보고된이외에는대규모 3상연구를통한효과가입증되지않았다. 5 최근 5-FU, oxaliplatin, leucovorin, irrinotecan 병합요법 (FOLFIRINOX) 을 1차항암요법으로사용한 PRODIGE 4/ACCORD-11 trial 연구에서기존 gemcitabine 단독사용과비교해약 5개월정도의미있 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 조재희, 412-270, 고양시덕양구화정동 697-24, 관동대학교의과대학내과학교실, 명지병원소화기내과 Correspondence to: Jae Hee Cho, Division of Gastroenterology, Myongji Hospital, Department of Internal Medicine, Kwandong University College of Medicine, 697-24 Hwajeong-dong, Deogyang-gu, Goyang 412-270, Korea. Tel: +82-31-810-5431, Fax: +82-31-810-7002, E-mail: jhcho932@kd.ac.kr Financial support: This work was supported (Jae Hee Cho) by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0013944). Conflict of interest: None. Korean J Gastroenterol, Vol. 61 No. 3, March 2013 www.kjg.or.kr

148 조재희. 췌장암분자표적치료의최신지견 는생존기간의연장이확인되어새로운치료방법으로각광받고있으나, 6 연구대상선정의문제점과다양한합병증의발생으로사용에제한이있고, 특히국내의경우는보험적용문제로실제사용에어려움이많다. 이번논고에서는췌장암과정상세포의분자생물학적발암기전의차이를이용한다양한표적치료제의임상적유용성에대해살펴보고자한다. 본론 췌장암은다양한분자생물학적발생기전을가지고있다. 포괄적유전체분석 (comprehensive genetic analysis) 을통해췌장암은평균 63개의유전자변이 (exomic alteration) 와 12개의핵심적신호전달체계의이상이있음이알려졌으나, 7 이러한변이발현여부는개개의경우에따라서다양한이질성 (heterogeneity) 이있어, 특정부위에대한치료로췌장암전체의치료효과의상승을기대하기는어렵다. 최근다양한표적치료제들이개발되어연구되고있으나현재까지는단독요법보다는기존항암화합요법또는방사선치료와병합하여치료효과를극대화고자하고있다 (Table 1). 본장에서는다음과같이세포생존 (cell survival) 및신생혈관형성 (angiogenesis) 관련신호전달체계, 발생 (development) 관련신호전달체계, 기질 (stromal) 반응, 면역 (immune) 반응, 후생성변화 (epigenetic change), 암줄기세포 (cancer stem cell) 의 6개의범주에대한다양한치료적접근을알아보고자한다. 8,9 1. 세포생존및신생혈관형성관련신호전달체계 1) Epidermal growth factor receptor (EGFR) EGFR은세포막당단백질 (glycoprotein) 수용체로 tyrosine kinase 수용체이다. Epidermal growth factor (EGF), transforming growth factor (TGF)-α 등의리간드 (ligand) 가 EGFR 과결합하여세포질내 (intracellular) 수용체의 tyrosine residue의인산화를유도하고하방의 mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), serine/threonine kinase AKT 및 signal transduction and transcription (STAT) 등의신호전달체계가활성화하여세포의증식및사멸억제등을유발한다. 췌장암의 90% 에서 EGFR의과발현이나타나며, 10 현재임상에서유일하게효과가인정된 erlotinib 표적치료제가이에해당하는약물이다. Erlotinib은 EGFR의 ATP binding site에 ATP와경쟁적으로결합하여 tyrosine kinase의활성을억제하는경구용약제로 gemcitabine과병용해서사용한경우 gemcitabine 단독사용과비교하여유의한생존기간의연장효과를보였다 (6.24 vs. 5.91개월 ). 5 사실비용효과적인측면에서경미한생존기간의연장은 erlotinib 치료의중대한한계점이나, grade 2 이상의피부발진이생긴환자의경우중앙생존기간이 10.5개월로최근발표된 FOLFIRINOX 3상연구결과와유사하여선택적인대상환자를구분하여사용할경우충분한효과를기대할수있다. Cetuximab은 EGFR 세포외 (extracellular) 영역의리간드와경쟁적으로작용하는마우스단클론항체 (monoclonal antibody) 와인체 IgG1을혼합한키메라항체 (chimeric monoclonal antibody) 로 EGFR에리간드가결합하는것을막아서하부신호전달체계를억제한다. 이를통해 Bcl-2와같은 anti-apoptotic 단백질의발현이감소되고, vascular endothelial growth factor (VEGF) 및 fibroblast growth factor (FGF) 의분비를감소시켜, 종양미세환경을조절하고암세포성장억제및세포사멸을일으킨다. 그러나 gemcita- Table 1. Results of Phase III Trials of Molecular Targeted Agents in Advanced/Metastatic Pancreatic Cancer Target Series Regimen Number Median survival (month) p-value MMP Bramhall et al. (2002) 49 Marimastat+ FT Van Cutsem et al. (2004) 25 Tipifarnib+ EGFR Moore et al. (2007) 5 Erlotinib+ EGFR, VEGF Van Cutsem et al. (2009) 16 Bevacizumab+erlotinib+ Erlotinib+ VEGF Kindler et al. (2010) 15 Bevacizumab+ EGFR Philip et al. (2010) 11 Cetuximab+ VEGF Kindler et al. (2011) 17 Axitinib+ VEGF, B-Raf, PDGFR-B Gonçalves et al. (2012) 18 Sorafenib+ 120 119 341 347 285 284 306 301 302 300 362 357 314 316 52 52 5.4 5.4 5.9 6.3 6.2 5.9 7.1 6.0 5.8 5.9 6.3 5.9 8.5 8.3 8.0 9.2 0.99 0.75 0.03 0.21 0.95 0.23 0.54 0.23 MMP, matrix metalloproteinase; FT, farnesyl transferase; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; PDGFR-B, platelet derived growth factor receptor-b;, gemcitabine. The Korean Journal of Gastroenterology

Cho JH. Recent Update of Molecular Targeted Therapy in Pancreatic Cancer 149 bine과 cetuximab을병용한연구에서생존기간의연장은확인되지않았다. 11 Panitumab은 EGFR에대한인간형단클론항체로췌장암에서 2상연구가진행되었으나, 3도이상의부작용빈도가증가하였고생존기간의연장이관찰되지않았다. 12 그외 human epidermal growth factor receptor 2 (HER2) 를대상으로하는단클론항체 trastzumab과 EGFR/ HER2의 tyrosine kinase ATP 결합에경쟁적인억제작용을하는경구약제 lapatinib도모두실망스러운결과를보였다. 8 EGFR 표적치료는신호전달체계하방의 K-Ras mutation이췌장암에서약 90% 에서관찰되기때문에제한적인효과를보일수밖에없다고생각할수있으나, 기존연구에서 EGFR과 K-Ras를이용한 erlotinib의치료반응예측이실패하였기때문에추가적인연구를통해예측인자를확인하여야 EGFR 표적치료의효과증대를기대할수있을것이다. 2) VEGF 신생혈관형성 (angiogenesis) 은악성종양의성장과전이에필수적이며, 이과정을억제하여암의성장을억제할수있다. VEGF는전이성대장암에서활발히사용되고있는표적치료대상으로, 췌장암의경우도 vascular endothelial growth factor receptor (VEGFR) 의과발현 (overexpression) 과예후와의연관성이확인되어효과가기대되었다. 13 Bevacizumab은 tyrosine kinase인 VEGFR1과 VEGFR2에결합하는재조합 (recombinant) 단클론항체이다. citabine과병합한긍정적인 2상연구결과를토대로 3상연구를진행하였으나생존기간의연장은관찰되지않았으며, 14,15 gemcitabine/erlotinib 치료에 bevacizumab을추가한 AVITA 3상연구에서도생존기간의연장은관찰되지않아췌장암에서효과를확인할수없었다. 16 Axitinib은 VEGFR tyrosine kinase의 ATP binding site에경쟁적결합을하여작용하는경구약제로, VEGFR1, 2, 3 뿐만아니라혈소판유래성장인자수용체 (platelet derived growth factor receptor, PDGFR), c-kit을억제하는다중 (multiple) tyrosine kinase 억제제이다. Axitinib과 gemcitabine을병합치료한 3상연구가진행되었으나, 중간분석에서치료효과가확인되지않아서조기중단되었다. 17 Sorafenib도유사하게 VEGFR2, B-Raf, PDGFR-B를억제하는다중 tyrosine kinase 억제제이나, gemcitabine과병용투여한 3상연구에서효과적이지못했다. 18 Aflibercept (VEGF-Trap) 은 VEGFR1,2의세포외도메인을 IgG의 Fc domain과융합하여제작한 VEGF 및 placental growth factor를중화시키는약제이나마찬가지로효과적이지못했다. 19 이러한다양한 VEGF 표적치료제들이다른암과비교해췌장암에서유독효과적이지못한이유는아마도췌장암주변기질의저혈관성 (hypovascular) 이중요원인으로추정되고있으며, 이러한제한점을극복하기위해기존항암화학요법에추가하여다양한기질 (stromal) 반응을조절하는분자표적치료제를병용하는연구가필요하다. 3) Insulin-like growth factor-1 receptor (IGF-1R) EGFR과 VEGF 표적치료제의불충분한치료효과로인해 tyrosine kinase의다른아형인 IGF-1R에대한관심이증가되고있다. IGF-1R은세포표면에서발현되며인산화과정을 Fig. 1. Schematic overview of major survival and proliferation signal pathways and molecular targeted agents currently evaluated in pancreatic cancer. RTK, receptor tyrosine kinase; Grb2, growth factor receptor bound protein 2; SOS, sons of sevenless homolog; MEK, mitogen activated protein/extracellular signal regulated kinase kinase; ERK, extracellular signal regulated kinase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue; mtor, mammalian target of rapamycin; S6K1, S6 kinase 1; 4EBP, 4E binding protein; IGF-1R, insulin-like growth factor-1 receptor; VEGF, vascular endothelial growth factor; HIF, hypoxia inducible factor. Vol. 61 No. 3, March 2013

150 조재희. 췌장암분자표적치료의최신지견 거쳐 Ras-Raf-mitogen activated protein/extracellular signal regulated kinase kinase (MEK)-extracellular signal regulated kinase (ERK) 하방의신호전달체계와그외독립적인 PI3K/Akt 신호전달체계모두를활성화한다 (Fig. 1). K-Ras mutation이동반된췌장암에서도 IGF-1R의억제는 K-Ras를거치지않는다른신호전달체계를억제할수있기때문에세포사멸및항암제저항성극복에효과적인대상이될수있다. 20,21 IGF-1R 단클론항체인 cixutumumab (IMC-A12) 은 gemcitabine/erlotinib과함께사용한 2상연구에서중앙생존기간및무진행생존기간의차이가없어실망스러운결과를보였으나, 22 다른형태의단클론항체인 AMG-479는현재임상시험이진행되고있으며효과가주목되고있다 (Clinicaltrials.gov: NCT01231347). 4) K-Ras/Raf/MEK/ERK K-Ras는세포증식과사멸을억제하는대표적인단백질로세포막과결합되어있는 GTPase이다. K-Ras 유전자돌연변이는췌장암의 90% 이상에서발견되며, 암발생 (carcinogenesis) 초기단계인췌장상피내종양 (pancreatic intraductal neoplasia, PanIN) 에서부터발현되고, 암발생과유지 (maintenance) 모두에관계되는것으로알려져있다. 23 K-Ras 단백질의 post-translational modification 과정에서 farnesyltransferase (FT) 를차단하여 K-Ras 하방신호전달체계를억제할수있는 tipifarnib 약물이개발되었으나, 24 gemcitabine과병용치료한 3상연구에서중앙생존기간의연장이관찰되지않았다. 25 기존의 tipifarnib의 FT 억제효과에추가하여 geranylgeranyltransferase를동시에억제할수있는 L-778123이개발되었으나, 심각한심독성으로연구가중단되었다. 26 K-Ras의경우암발생과유지에모두관여하지만, 만성췌장염등의양성질환에서도발현되기때문에, 표적치료의대상으로활용할수있는지는추가적인연구가필요하다. 흥미로운점은최근 K-Ras 백신을췌장암수술후투여한코호트연구에서장기생존자의경우 T세포의 K-Ras 면역기억반응이확인되어수술후보조치료로활용가능성이제시되었다. 27 K-Ras 의존신호전달체계하방의 MEK/ERK 신호전달체계억제를위한연구가진행되고있으며, 경구 MEK 억제제인 CI-1040을 15명의췌장암에서사용한 2상연구가시도되었으나효과적이지못하였다. 28 그외다른 MEK 억제제인 GSK1120212, MSC1936369B와 gemcitabine 병용연구가진행되고있으며, AZD6244의경우는 gemcitabine 저항성췌장암환자에서 erlotinib과병용하여사용하는연구가진행되고있다 (Clinicaltrials.gov: NCT01231581, NCT01016483, NCT01222689) (Fig. 1). 5) Phosphoinositide 3-kinase (PI3K)/Serine-threonine kinase (Akt)/mammalian target of rapamycin (mtor) 과 phosphatase and tensin hologue (PTEN) PI3K/Akt 신호전달체계는췌장암을포함한악성종양에서흔히증가되어있으며불량한예후인자로작용한다. 29 수용체의 tyrosine kinase가활성화되면 PI3K/Akt 신호전달체계를거쳐하방의 mammalian target of rapamycin (mtor) 및 NFκB가활성화되어암세포의증식을촉진하고사멸을억제한다 (Fig. 1). 그외 Akt 활성을조절하는 PTEN은정상세포에서 Akt를비활성화시키지만, 췌장암에서발현이소실되어 Akt 하방 mtor 등을발현을증가시킬수도있다. 30 Akt antisense oligonucleotide RX-0201은 1/2상연구가진행되고있으며 (Clinicaltrials.gov: NCT01028495), PI3K 억제제인 BKM120, PI3K/mTOR 억제제 BEZ235도 MEK 억제제와병용한 1상연구가진행되고있다 (Clinicaltrials.gov: NCT01571024, NCT01337765). MEK 억제제와병용한연구들은 Ras/Raf/ MEK/ERK 신호전달체계와 PI3K/Akt 신호전달체계를동시에억제하는방법이기때문에단독신호전달체계를억제하는경우와비교해추가적인우월한효과가기대된다. mtor는 serine/threonine kinase로유전자전사과정및세포사멸과관계있는것으로알려져있다. mtor 억제제는 rapamycin, everolimus (RAD001) 및 sirolimus가있으며, 경구 mtor 억제제인 everolimus를 gemcitabine 저항성 (refractory) 췌장암환자에서단독투여한 2상연구가진행되었으나충분한효과가확인되지않았고, 31 현재항암화학요법및 erlotinib등과병용한연구가진행되고있다 (Clinicaltrials.gov: NCT00560963, NCT01077986). 6) Poly (ADP-ribose) polymerase (PARP) PARP는 DNA 복구 (repair) 및세포사멸을조절하는단백질로, 활성화를통해유방암세포의 DNA 복구를억제하는것으로알려져있다. 가족성췌장암과같은일부의췌장암에서는 BRCA2 돌연변이가동반되어 DNA 복구체계의결함이관찰되고있기때문에, 32 PARP 억제를통한치료효과를기대할수있다. PARP-1 억제제인 iniparib은 BRCA2 mutation 췌장암에서의미있는효과가증례보고로발표되었으며, 33 항암화학요법과병행하여 olraparib 또는 veliparib 과같은 PARP 억제제병용투여가현재연구되고있다 (Clinicaltrials.gov: NCT01296763, NCT01489868, NCT01585805). 7) Src Src family kinases는암유발 (protooncogenic) 비수용체 tyrosine kinase이며, 췌장암에서과발현되어있다. 34 AZD0530 은 Src family kinases를억제하는약물로, gemcitabine 저항성환자를대상으로 2상연구를진행하고있으며, gemcitabine 과병용하여 1/2상연구를진행하고있다 (Clinicaltrials.gov: The Korean Journal of Gastroenterology

Cho JH. Recent Update of Molecular Targeted Therapy in Pancreatic Cancer 151 NCT00735917). 8) Rearranged during transfection (RET) RET은 glial-derived neurotrophic factor family (GDNF) 수용체 tyrosine kinase 일종으로, 췌장암세포의증식과침윤과연관있다. RET은췌장암의 65% 에서발현되며, GDNF 리간드인 neuturin과 artemin은 65%, 75% 에서발현되는것으로알려져있다. 35,36 RET 억제제인 vandetanib은 EGFR과 VEGFR 모두에서도억제효과를갖는약물로갑상선수질암 (medullary cancer) 을대상으로한 3상연구에서생존율향상을보였으며, 췌장암에서도 gemcitabine과병용하여연구가진행되고있다 (Clinicaltrials.gov: NCT01601808). 37 2. 발생관련신호전달체계 Hedgehog, notch, and Wnt β-catenin 등의발생관련신호전달체계는췌장암에서재활성화되어발견되며, 항암화학요법에대한저항성증가및췌장암진행과연관된것으로알려져있다. 7,38,39 Notch 신호전달체계는발생기에세포운명 (cell fate) 을결정하는신호전달체계로췌장암에서는발생시기와아형 (subtype) 에따라종양발생, 유지, 진행및억제과정모두와연관있는것으로알려져있다. 40-42 γ-secretase는세포내 Notch를활성화하여핵내에서전사과정을조절하게하는효소로이를표적으로억제하는 RO4929097과 MK0752 는현재전이성췌장암에서임상연구가진행되고있어효과가기대된다 (Clinicaltrials.gov: NCT01232829, NCT01098344). Hedgehog 신호전달체계도발생과정과관여하는신호전달체계로, 췌장암에서발현이증가되어있다. 최근연구결과에서는췌장암세포가 hedgehog 리간드를분비하여, 주위간질세포의 Hedgehog 신호전달체계를활성화하며이를통해간질조직의 desmoplastic 반응을일으키는것으로발표되었으며, 이를표적으로하는치료방법이시도되고있다. 43 3. 면역반응암세포에대한국소적또는전신적면역반응을이용한치료가새로운접근방법으로제시되고있다. 분자표적치료는암세포의특정한신호전달체계에억제작용을하지만, 숙주 (host) 면역반응은전체적인암세포에대한조절및파괴를일으킨다. T세포면역반응은다양한활성 / 억제신호를통해서조절되며, 특정암항원에대한 T세포면역관용은암세포면역반응의중추적인역할을한다. 9,44 Ipilimumab과같은 cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) 에대한인간항체는 CTLA-4를차단함으로암세포에대한지속적인면역반응을일으키고암세포파괴를유도할수있다. Iplimumab과또다른 CTLA-4항체인 tremelimumab은현재연구가진행중이다 (Clinicaltrials.gov: NCT01473940, NCT00556023). 또한 tumor necrosis factor (TNF) receptor superfamily member로 T세포의존항암면역반응의중요인자로알려진 CD40을이용한치료가시도되고있다. CD40 agonist 항체인 CP870, 893과 gemcitabine을병용한 1상연구에서종양크기감소, CD40-activated tumoricidal 대식세포 (macrophage) 의종양내침윤및기질 (stroma) 소실이확인되어, 절제가능췌장암에서수술전후요법으로 CP870, 893를이용한임상시험이진행되고있다 (Clinicaltrials.gov: NCT01456585). 45 상기기술한전신면역반응이외에도, 국소종양에대한선택적인항암사이토카인 (cytokine) 면역반응연구도진행되고있다. Fibronectin extradomin B (ED-B) 는신생혈관생성과암세포성장과연관되는암항원으로 ED-B에대한항체 L19와항암 cytokine인 IL-2를결합시킨 L19-IL2의경우, 암세포와국소적인결합을통해전신적인독성을줄이고국소적인 IL-2의효과를증진할수있기때문에 1/2상연구가진행되고있다 (Clinicaltrials.gov: NCT01198522). 4. 기질 (Stromal) 반응췌장암은심한섬유화를동반하며, 세포외간질 (extracellular matrix) 은다양한염증세포, 성상 (stellate) 세포및활성 fibroblast로구성된다. 최근까지도췌장암의치료는암세포중심으로접근하였지만, 세포외간질의중요기능이알려지면서효율적인항암화학약물의전달을위한기질반응이관심을끌고있다. 상기기술한발생관련신호전달체계중 sonichedgehog 신호전달체계는기질반응을조절하는중요한신호전달체계이다. 46 Hedgehog 수용체는 PTCH1 및 SMO로구성되며, SMO 억제제인 IPI926이개발되어췌장암에서연구되었다. IPI926은암세포주위실질의감소를유발하고, 동물실험에서암세포내 gemcitabine의농도를높이고생존기간을연장하여효과가기대되었으나, 47 진행성췌장암에서 gemcitabine과 IPI926를병용한임상연구는 IPI926 치료군이오히려생존기간이감소하여조기종료되었다. 그러나다른 hedgehog 억제제인 GDC-0449와 LDE225는 gemcitabine과 FOLFIRINOX 항암화학요법과병용하여연구가진행되고있다 (Clinicaltrials.gov: NCT01195415, NCT01485744). TGF-β 는간질생성, 침윤, 전이, 신생혈관형성과암세포면역회피와관련있으며, 48 TGF-β1 수용체의선택적결합을방해하는 LY2157299는진행성또는전이성췌장암에서 1/2상연구가진행되고있다. 그러나세포외간질조직의정상적인생리적현상과형태적재구성에중요한효소인 matrix metalloproteinase의경구억제제 marimastat을이용한 gemcitabine 병용진행성췌장암연구는실망스런결과가관찰되었다. 49 Hedgehog 또는 TGF-β와같은신호전달체계가아닌무세포간질조직에대한표적치료방법이최근시도되고있다. Vol. 61 No. 3, March 2013

152 조재희. 췌장암분자표적치료의최신지견 Non-sulphated glycosaminoglycan인 hyaluronan은세포외간질에풍부하게분포하는물질이다. PEGylated human recombinant PH20 hyaluronidase (PEGPH20) 는 hyalouronan을분해하는효소로, 세포외간질내혈류공급을증가시켜종양내 gemcitabine의농도를증가시키고생존기간의연장을기대할수있다. 50,51 PEGPH20과 gemcitabine을병용한연구가현재전이성췌장암에서진행되고있다 (Clinicaltrials.gov: NCT01453153). 그리고표적치료의개념은아니지만, 기질반응에대한관심이증가되면서다양한방법을통한효율적항암약물전달을위한노력이진행되고있다. Nanoparticle albumin-bound (nab)-paclitaxel은 paclitaxel과 albumin을결합한 nanoparticle 제형으로부작용을줄이고암세포내약물농도를높일수있는방법으로, 1/2상연구에서 48% 의반응률과 12.2개월의중앙생존기간이확인 되어 52 추가적인 3 상연구가진행되고있으며 (Clinicaltrials.gov: NCT01161186, NCT01470417, NCT01010945), 그외 liposomal phospholipid vesicle (EndoTAG-1) 과같은새로운제형의 paclitaxel, liposomal 제형의 irrinotecan인 PEP02 등이개발되어연구가진행되고있다. 53,54 5. 후생성변화 (epigenetic change) 유전적변화와달리후생성변화는 DNA의변화를동반하지않는가역적인변화이지만표적치료의대상이된다. 췌장암에서 DNA 메틸화 (methylation) 와히스톤 (histone) acetylation은암발생기전과관련이있으며, 이를대상으로한표적치료제가개발되었다. Histone acetylation은크로마틴 (chromatin) 구조를느슨하게하여 DNA의전사를활발하게한다. Histone deacetylase (HDAC) 는다양한유전자특히암억제유전자의전사를줄일수있는효소이며, 췌장암에서는 HDAC2 및 HDAC6가과발현되어세포사멸저항성과관련있는것으로연구되었다. 55,56 HDAC를억제하는 vorinostat은항암화학요법과방사선치료를병행하는국소진행성췌장암에서병용연구가진행되고있다 (Clinicaltrials.gov: NCT00948688). DNA 메틸화는유전자 silencing과관계되는후생성변화이다. 특히암억제유전자의과메틸화 (hypermethylation) 는암억제유전자의발현을억제하여암발생과관련있다. 5-azacitidine은 DNA methyltransferase를억제하는약제로진행성췌장암에서 1상연구가진행되고있으나 (Clinicaltrials.gov: NCT01167816), 이러한약제는췌장암발생기전과관계되지않은정상세포의다른유전자에도영향을끼치기때문에결과를조심스럽게해석하여야한다. 6. 암줄기세포 (cancer stem cells) 암줄기세포는정상적인줄기세포가생체내에지속적으로 존재하면서끊임없는분열과분화과정을거치는것과마찬가지로, 암의발생에도이를조절하는줄기세포가존재하며이러한세포자체의유전자변이또는특정분화단계세포의유전자변이가다양한표현형의암세포증식을초래하고암이발생한다는이론으로, 여러연구를통해암의발생, 성장, 전이및항암제저항성과관련있는것으로알려져있다. 2,57,58 췌장암줄기세포는 CD24+/CD44+/ESA+ 혹은 CD133+/ CXCR4+ 표지자를가지며, 이러한암세포를 nude 또는 NOD/SCID mouse에주입할경우매우적은세포수로암을발생시킬수있다. 또한 gemcitabine 저항성세포주형성을위해저농도의항암제를지속적으로처리하였을경우췌장암세포가항암제저항성을획득하면서 epithelial to mesenchymal transition (EMT) 암세포형태로전환되며, c-met 인산화및 CD24+/CD44+/ESA+의발현증가를보여, 췌장암줄기세포가항암제저항성세포주에서증가하는경우를확인할수있다. 59 Li 등 60 의동물연구에서는 c-met이췌장암줄기세포의성장, 전이능력과연관되며, 표적치료의대상으로적용가능성이있다고발표하였다. 그러나최근까지도암줄기세포에대한분자생물학적연구및표적치료제개발은초기단계로, 추후항암제저항성극복및궁극적인암정복을위해서는암줄기세포를대상으로표적치료제의개발및적용이필요하다. 결론 췌장암에서기대를모았던다양한항암화학요법및방사선치료가일관된치료효과를제시하지못했기때문에분자생물학적관점에서발암과정및신호전달체계에대한다양한표적치료제가개발되었으나, 현재까지도췌장암의치료성적향상에큰도움이되지못하고있다. 사실췌장암세포내부의신호전달체계는매우복잡하고중복되어있으며, 다양한이질성을갖고있기때문에특정신호전달체계한부위에대한단독표적치료는효과적이지못할가능성이높다. 이러한한계점을극복하기위해두종류이상의다양한표적치료제조합또는기존항암화학요법등과병용하여치료하는연구가진행되고있다. 표적치료제사용에있어또다른중요한점은개인별맞춤치료의필요성증가이다. 췌장암과관계되어있는다양한표적물질은개인별로변이및발현정도가차이가나기때문에, 치료전다양성에근거한맞춤치료및치료효과예측방법이필요하다. 일례로췌장암수술조직에서 gemcitabine 약물수송체 (transporter) 인 human equilibrative nucleoside transporter 1 (hent1) 과활성화효소인 deoxycytidine kinase (dck) 의과발현은수술후 gemcitabine 보조요법의좋은치료효과를예측할수있는인자임이발표되 The Korean Journal of Gastroenterology

Cho JH. Recent Update of Molecular Targeted Therapy in Pancreatic Cancer 153 었다. 61 이러한항암화학요법의치료반응예측을위한노력과함께표적치료의효과를예측할수있는표지인자에대한추가연구가필요하다. 국내의경우건강보험심사평가원에서항암치료약제사용을제한하기때문에새로운복합항암화학요법의도입및표적치료제의보험급여는용이치않으며, 새로운표적치료신약개발이다국적제약회사위주로진행되기때문에췌장암치료에있어선도적인위치를점하기는어렵다. 그러나췌장암에대한치료전략의재정립과성적의극대화를위해서는췌장암에대한다양한기초및임상연구가필요하고, 추후예후예측인자발견을통해적절한환자군을선택하여다양한치료방법을조합한혁신적인치료기법을적용한다면췌장암의극복에한걸음더다가갈수있을것이다. 추후이러한노력의결과로국내실정에맞는규격화된췌장암치료지침의제정을기대한다. REFERENCES 1. Woo SM. Pancreatic cancer. Korean J Gastroenterol 2012;59(3 Suppl):181-187. 2. Song SY. Etiology and carcinogenesis of pancreatic ductal adenocarcinoma. Korean J Gastroenterol 2008;51:71-83. 3. Kim YT. Chemotherapy for pancreatic cancer. Korean J Gastroenterol 2008;51:111-118. 4. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-2413. 5. 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