FOCUSED ISSUE OF THIS MONTH pissn 1975-8456 / eissn 2093-5951 http://dx.doi.org/10.5124/jkma.2016.59.3.189 난소암치료이행성연구의최신동향 주웅 1,2 이화여자대학교의학전문대학원 1 산부인과학교실, 2 의과학연구소 Current trend in translational research for treatment of ovarian cancer Woong Ju, MD 1,2 Department of Obstetrics and Gynecology, 1 Medical Research Institute, 2 Ewha Womans University College of Medicine, Seoul, Korea Ovarian cancer is the most lethal gynecologic cancer. Countless efforts have been made to improve the survival of ovarian cancer patients by clinicians as well as basic researchers so far. As a result of those extensive translational researches some of promising molecular targets and its proper therapies are introduced into practice for treating intractable ovarian cancer, which includes anti-angiogenic therapy, tyrosine kinase inhibitor, and other modulators of cancer-related signaling pathways. Current trend of translational researches in ovarian cancer treatment are mainly focused on discovering companion diagnostics which can categorize the subgroup of patient having specific biomarker that may serve as a target of new treatment because the consequent outcome of new therapy varies depending on the molecular profile of each patient. It is important for clinician to consider each ovarian cancer patients to have a possible therapeutic target and to examine the tissue biopsies with available companion diagnostics. In addition more interest and endeavor should be given to the clinical trials to apply the result of up-to-date translational researches. Key Words: Ovarian neoplasms; Translational medical research; Companion diagnostics 서론 상피성난소암은부인암중치사율이가장높은암으로발 생률은세계적으로연간 200,000 만건이며사망률은연간 125,000 건에이른다 [1]. 최근몇십년간최초의종양감축술 술기의발전과새로운항암제제, 복강내투여법및항암제 조합의개발로단기적진행은다소개선이있으나일차치료 후의재발, 항암제내성은아직완전히극복되지못하고있 Received: February 11, 2016 Accepted: February 28, 2016 Corresponding author: Woong Ju E-mail: goodmorning@ewha.ac.kr Korean Medical Association 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. 어장기생존율은답보상태에있는실정이다. 다른암종과마찬가지로난소암연구에도최신분자생물학적기술들이도입되면서게놈차원의분석들이진행되어 DNA 복제수변이, 메틸화, 돌연변이등에대한정보들이축적되고있다. 이러한최신기술을이용한이행성연구를통해난소암의암화과정을밝히고환자마다의예후의차이를설명하고종국적으로이를치료표적으로발굴하고자하는노력들이지속적으로행해지고있다. 그결과몇몇표적치료제들은실제임상에도입되어사용되고있으며무병생존율을개선시키고특정환자군에서전체생존율의향상까지도보이고있다. 최근의난소암의이행성연구는주로표적치료에이용되는표적을발굴하고검증하는단계로이어지는경향을보이고있는데, 검증이완료되어치료가능한환자군을선별할수있는진단은동반진단이라고명명할수있게된다. 여기서는상 난소암치료이행성연구의최신동향 189
피성난소암의치료효과및생존율개선을위한이행성연구와이를검증하는임상시험의최신동향을살펴보고자한다. Low-grade Serous Ovarian Carcinoma 현재까지의난소암이행성연구는대부분고등급장액성난소암 (high-grade serous carcinoma, HGSC) 을대상으로한것들이었다. HGSC의발생률이높고임상양상이급격하여최우선의연구과제가되었던것인데, 최근에는저등급장액성난소암 (low-grade serous carcinoma, LGSC) 에대한이해성연구도활발히이루어지고있다. LGSC는양성낭선종에서시작하여경계성종양단계를거쳐난소암으로발전하는과정을거치는데진행속도가비교적느린반면항암제에대한반응이우수하지않은것으로알려져있다 [2]. 또한 LGSC는 HGSC에서 p53의돌연변이가자주발견되는것에비해 MARK 경로의돌연변이가더자주발견된다 [3]. 이러한 LGSC 환자군에서 MEK 저해제에대한연구들이진행되고있다. MEK 저해제인 selumetinib에대한 Gynecologic Oncology Group 제2상임상시험에의하면 52명의재발성 LGSC 환자중 15% 가반응성을보였고 65% 의환자가종양유지상태를보였다 [4]. 재발성혹은지속성 LGSC 환자를대상으로하는 MEK 저해제제3상임상시험인 MILO 시험 (MEK Inhibitor in Low-grade Serous Ovarian Cancer) 이현재진행중에있다 (NCT01849874). MEK 경로를통한내성이 PI3K/AKT 경로를통한다는점에착안하여이두가지경로를모두차단하는제제를이용한전임상연구결과들이상당한효과를보이고있어이를이용한시험도장차시행될것으로기대된다 [5]. 이밖에도 nutlin-2와같은물질을이용하여 p53의분해과정을막는방법으로세포사멸을유도하는연구들이진행되고있다 [6]. Cancer-related Inflammation 다양한사이토카인및염증세포들이종양증식, 전이, 세 포사멸회피, 신생혈과합성등의과정에서중요한역할을한다는사실들은상피성난소암에서도지속적으로밝혀져왔는데, 최근의이행성연구결과들은이러한염증반응중일부가치료표적이될수있음을보여주고있다. 종양괴사인자 α (tumor necrosis factor α, TNF-α) 와이로인해유도되는 interleukin (IL)-6가난소암의암화과정에관여한다는점을바탕으로 Madhusudan 등 [7] 은 TNF-α의길항제인 etanercept를이용한제2상임상시험을시행하였는데, 저자들은 30명의진행성난소암환자중여섯명이종양안정화상태를보이고 17명중 11명이 IL-6의유의한감소를보였다고보고하였다. Brown 등 [8] 은항-TNF 항체인 infliximab을이용한제 1상임상시험을시행하였는데, 여덟명의난소암환자를포함한 41명의진행성암환자가참여하였다. 혈장 IL-6는항체투여후 24시간및 48시간에유의하게감소하였고여덟명의난소암환자중한명은종양안정화상태를보였다. 이결과를토대로 Coward 등 [9] 은상피성난소암환자를대상으로 siltuximab을이용한항-il-6 치료제2상임상시험을진행하였다. 참여한 18명의환자중한명은부분반응을보였고일곱명은종양안정화상태를보였다. 심각한이상반응은없었으며 siltuximab은잘견딜수있는치료로평가되었다. Aflibercept 혈관내피성장인자 (vascular endothelial growth factor, VEGF) 수용체단클론항체인 bevacizumab이상피성난소암치료에이미도입되어사용되면서 VEGF등의신호전달경로저해제에대한연구가지속되었고보다효율적인제제를개발하려는노력에서 VEGF-trap이라고도불리는 aflibercept에대한연구와임상시험이진행되고있다. Aflibercept은 VEGF 수용체 1의세도메인과면역글로블린 G의 Fc 부위가결합된단백질로서 VEGF 리간드에대한친화력이매우뛰어나암세주실험에서우수한항암효과를보였다. 그러나양전하를띤성질상생체내반감기가 190 대한의사협회지
Ju W Translational research in ovarian cancer treatment 매우짧다는단점이있었다. 이를개선하기위해면역글로블린 G의 Fc 부위에 VEGF 수용체 1의두도메인과 VEGF 수용체 2의세도메인을결합시키는시도를했고이결과 VEGF 리간드친화력은유지한채생체내반감기가길어지게되었다. 이후 aflibercept에대한 2상임상시험들이재발성난소암환자를대상으로진행되었다. Coleman 등 [10] 은 46명의재발성난소암환자들에게 aflibercept (6 mg/kg iv) 와 docetaxel (75 mg/m 2 iv) 를 3주간격으로병용투여하고 54% 의반응률을보고하였는데, 이중 10명의환자는완전관해를보였고무병생존기간은 6.2개월 ( 중앙값 ), 전체생존기간은 24.3개월 ( 중앙값 ) 이었다. Gotlieb 등 [11] 은 55명의환자를대상으로이중맹검무작위배정임상시험을실시하였는데 aflibercept (4 mg/kg iv) 을매 2주마다투여한군에서복수천자횟수가유의하게감소함을보고하였으나전체생존율에는차이가없었던반면위장관계이상반응등 3도이상의독성이 aflibercept군에서더많이나타났다. 이밖에도 alflibercept의복강내투여가전체생존율개선에도움이되는지에대한임상시험도진행중이다. Nintedanib Nintedanib (BIBF 1120) 은경구투여가가능하고세가지혈관형성경로를표적으로하는물질로서 VEGF 수용체, 섬유모세포성장인자수용체및혈소판기원성장인자수용체를표적으로한다. 83명의재발성난소암환자를대상으로위약대조제2상임상시험을진행한결과 nintedanib (250 mg twice daily) 을투여받은군에서무병생존율의개선을보였다. 이후시행된이중맹검제3상임상시험은 1,366명의난소암환자의수술후일차항암치료로 carboplatin/ paclitaxel 조합에 nintedanib 또는위약을추가하는것이었는데위약군에비해 nintedanib군에서무병생존기간이유의하게개선된결과를보였다 (18.3 vs. 16.6 months; hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.98; P=0.0239). Trebananib (AMG 386) 안지오텐신 1 (angiopoietin-1, Ang1) 과안지오텐신 2 (angiopoietin-2, Ang2) 는혈관내피세포의 Tie2 수용체에작용하여 VEGF와는다른경로를통해혈관리모델링을중재한다. Trebananib (AMG 386) 은 Ang1과 Ang2에 Fc를결합하여만든단백으로이들이 Tie2 수용체에작용하는것을차단한다 [12]. Trebananib은전임상동물모델에서혈관형성억제효과를보였으며재발성난소암환자를대상으로한제1상연구에서도단일제제로서투여되어효과를보였으며, 재발성난소암환자를대상으로한무작위배정제2상연구에서도무병생존기간을연장시켰다. 혈관형성억제라는작용은동일하나 trebananib은기존의 VEGF 경로저해제와는달리가장유의한독성으로부종이나타났다. TRINOVA-1 제3상임상시험에서는 32개국 919명의재발성상피성난소암환자를 paclitaxel/trebananib 혹은 paclitaxel/ 위약군으로무작위배정하여치료하였는데그결과 trebananib 포함군의무병생존기간이유의하게길었다 (7.2 vs. 5.4 months; hazard ratio, 0.66; 95% confidence interval, 0.57 to 0.77; P<0.001) [13]. 이어진 TRINOVA-2 임상시험은 223명의재발성상피성난소암환자를무작위배정하여 pegylated liposomal doxorubicin/trebananib군과 pegylated liposomal doxorubicin/ placebo군을비교하고 (Clinicaltrials.gov identifier NCT01281254) TRINOVA-3 임상시험은 2,000명의상피성난소암환자의일차치료에 carboplatin/paclitaxel과함께 trebananib 혹은위약을투여하여그결과를비교하고있다 (NCT01493505). HER family 표피성장인자 (epidermal growth factor receptor, EGFR or ERBB1) 는난소암의 25 50% 에서발견되며일부연구에서예후인자로보고되고있다 [14]. 그러나 EGFR 단클론항체인 cetuximab이나 EGFR tyrosine kinase 저해제인 gefitinib을이용한제2상연구에의하면 EGFR 경로차단은 난소암치료이행성연구의최신동향 191
난소암환자에서는제한적인효과만을보이고있음을알수있다 [14,15]. 이와유사하게 erlotinib 역시일차항암치료를마친고위험군난소암환자를대상으로한제3상임상시험에서유의한이득을증명하지못했다 [16]. Bookman 등 [17] 은 HER2 차단제인 trastuzumab을이용하여재발성혹은지속성난소암환자 837명을대상으로제 2상임상시험을진행하였는데, 7.3% 의반응률과 2개월의무병생존기간을보였는데이는동일한방법으로시행한유방암환자들의반응에비해현저히낮은결과였다. 또한같은연구에서 HER2의종양내과발현이 11.4% 에불과하다는점과예후와는유의한상관관계가없음을보고하였다. 유사한결과가 Gynecologic Oncology Group의다른이행성연구에서도보고되었는데 FISH (fluorescence in situ hybridization) 를이용하여검출한결과난소암에서 HER2 유전자의증폭은단 7% 에서만발견되었으며예후를예측하지못했다 [18]. 한편, 최근의이행성연구결과는난소암에서 HER3와 HER4의과발현을보고하고있다. 202명의난소암환자의조직 array를용한분석에서 HER3의활성은 79% 에서, 간세포성장인자의활성은 56% 에서발현되는것으로나타났다 [19]. HER3는 PI3K 신호경로를활성화시키는것으로알려져있으며난소암의불량한예후와연관이있음이보고되었다 [20]. 이러한연구를바탕으로지속된연구에서 HER3 의단클론항체인 MM-121은세포주실험과이종이식동물모델에서종양의성장을유의하게저해하는것으로밝혀졌고 [21], MM-121을이용한무작위배정제2상임상시험이진행중이다 (NCT01447706). 결론 난소암치료를위한이행성연구동향은표적발굴과검증및표적치료로이어지는과정이라고요약할수있다. 이과정에서치료표적을가지고있는적절한환자군을선별하는것이중요하기때문에동반진단연구가점차자리잡고있다. 동반진단은치료반응을높이고부작용을최소화하는개인맞춤형치료를가능케할것이므로향후이러한연구경향 은바뀌지않을것으로예상된다. 난소암은종양자체의조직학적구성과악성도, 분화도가 매우이질적일수있으며환자개개인마다조직학적아형이 다르고유전자발현프로파일이나 DNA 복제수가달라동일 한치료에다양한반응과상이한예후를보일수있다. 따라 서이행성연구결과를치료에적정하게적용하기위해서는 최초진단및수술과정, 이후재발및추적과정에서환자의 검체를이용한정확하고포괄적인동반진단이이루어질수 있도록해야하는데이부분은임상의의관심과노력이없이 는성취되기어렵다. 또한최근의이행성연구들은표적발굴후검증, 임상시험 까지의일정이매우빨라지고있으므로연구자, 임상의, 인 허가기관, 환자 / 보호자단체등관련된모든이해당사자들 이이행성연구의특징과전개에대해잘이해하고, 연구결 과를안전하게적용하려는노력이한층더필요하다. 찾아보기말 : 난소암 ; 이행성연구 ; 동반진단 ORCID Woong Ju, http://orcid.org/0000-0002-0013-8304 REFERENCES 1. Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol 2006;20:207-225. 2. Gershenson DM, Sun CC, Bodurka D, Coleman RL, Lu KH, Sood AK, Deavers M, Malpica AL, Kavanagh JJ. Recurrent lowgrade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol 2009;114:48-52. 3. Li J, Fadare O, Xiang L, Kong B, Zheng W. Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis. J Hematol Oncol 2012;5:8. 4. Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, Mannel R, Yamada SD, Mutch D, Rodgers WH, Birrer M, Gershenson DM. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013;14:134-140. 5. Gershenson DM. The life and times of low-grade serous carcinoma of the ovary. Am Soc Clin Oncol Educ Book 2013 [Epub]. http://dx.di.org/10.1200/edbook_am.2013.33.e195. 6. Kojima K, Konopleva M, McQueen T, OʼBrien S, Plunkett W, Andreeff M. Mdm2 inhibitor Nutlin-3a induces p53-mediated 192 대한의사협회지
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Peer Reviewers Commentary 본논문은난소암분야에서최근시행되고있는이행성연구를 종합적으로분석하여현재의연구흐름을제시한자료이다. 현재 진행중인다양한표적치료제들의연구현황에대한설명으로바 탕으로이러한새로운표적치료제가효과를보일수있는특정 환자군을선별하는진단적 tool 을개발하는과정이현재의 trend 임을체계적으로기술하고있다. 이는난소암을연구하는임상의 사및기초과학자들에향후의연구진행방향에대한방향제시를 해주고있다는점에서의의가있는논문이라여겨진다. 정책과제를제안하여발전을위한방향제시를했다는점에서의 의가있는논문이라판단된다. [ 정리 : 편집위원회 ] 난소암치료이행성연구의최신동향 193