KISEP Information Korean J Otolaryngol 2007;50:188-97 두경부암의 EGFR 표적치료 울산대학교의과대학이비인후과학교실 최승호 EGFR-targeted Therapy in Head and Neck Squamous Cell Carcinoma Seung-Ho Choi, MD, PhD Department of Otolaryngology, University of Ulsan College of Medicine, Seoul, Korea 서론 최근분자생물학적기법과지식이눈부시게발전하면서암치료에있어서도특정분자를표적으로하는치료, 이른바분자표적암치료 (molecular targeted cancer therapy) 에대한기대가높아지고있다. 그대표주자격인 epidermal growth factor receptor(egfr) 표적치료는이미두경부를포함한상당수의암에서효과가입증되고있으나임상적용에이르지는못하고있다. 두경부암은조기암이나국소진행암의경우치료성적에있어괄목할만한발전이있었다. 조기암은수술이나방사선치료만으로도완치에이르는경우가흔하며, 국소진행암은수술적절제후항암화학-방사선병합치료를통해높은국소제어율과생존율을얻을수있다. 1,2) 그러나재발하였거나원격전이를동반한두경부암은치료성적이과거에비해현저히개선되었다고말하기어렵다. Cisplatin, 5- flurouracil, methotrexate, taxane 등다양한항암제를병합투여하면단독투여에비해서종양반응률이높아지지만생존에있어서는유의한차이를보이지못하는것이다. 3-7) 이러한항암화학요법의한계와 field cancerization 8) 에의한 2차암발생은진행된두경부암에대한새로운치료법의필요성을절감하게하였고, EGFR 이종양의발생, 성장, 전이를증가시킨다는점과두경부암에서 EGFR 의과발현율이높다는점으로인해 EGFR 표적치료에대한기대가크다. EGFR 의구조와기능 ErbB1 또는 Her1 으로도알려진 EGFR 은 170 kda 의막횡단단백질 (transmembrane protein) 로서, N-말단부인세포외리간드결합영역 (extracellular ligand-binding domain), 막횡단영역 (transmembrane domain), 세포내단백질활성효소영역 (intracellular protein kinase domain), C-말단부에위치한 SH2 결합영역 (SH2-binding domain) 등으로구성되어있다. 9) EGFR은 ErbB2(Her2), ErbB3 (Her3), ErbB4(Her4) 와함께 receptor tyrosine kinase superfamily의 subclass I을구성하며이들 ErbB family 의세포내단백질활성효소영역은서로매우유사하고세포외영역과 C-말단영역은다양하게구성되어있다. 이들은리간드가결합하면 homodimer 또는 heterodimer 를형성하고이어세포내단백질활성효소영역의특정타이로신잔기 (tyrosine residue) 가인산화 (autophosphorylation) 됨으로써활성화된다는공통점을가지고있다. EGFR 유전자결손생쥐를이용한실험에서 ErbB family 는호흡기, 소화기, 피부, 심장등의발생에중요하다는사실이밝혀졌으며 10-12) 특히 EGFR 과 ErbB2 는다수의악성종양에서중요한역할을한다고알려져있다. EGFR의리간드로는 epidermal growth factor(egf), transforming growth factor α(tgf-α), amphiregulin, heparin binding EGF(HB-EGF), β-cellulin, epiregulin 의 6개단백질이알려져있다. 리간드결합에의해 EGFR 의타이로신잔기가인산화되면하류분자 (downstream molecules), 특히 SH2 영역을포함하고있는분자가결합하기쉬운조건이형성되어이들분자를인산화시키고다양한하류경로 (downstream pathway) 가활성된다. 악성종양에서중요한 EGFR 의하류신호경로로는 RASmitogen-activated protein kinase(mapk), 13,14) phosphotidylinosititol 3-kinase(PI3-K)-Akt, 15,16) phospholipase-cγ(plcγ)/protein kinase-c(pkc), 17,18) signal transducer and activator of transcription(stat) 19,20) 의네가지가대표적이다. 예를들어 EGFR 이 EGF 에의 188
최승호 해자극될경우 GRB2와의상호작용이일어나 SOS, Ras, Raf가동원 (recruitment) 되고이어 mitogen-activated protein kinase(mapk) 가활성화된다. 21) EGFR 의인산화는또한 phosphatidylinositol-3(pi-3) kinase를세포막으로동원시키고 PI-3 kinase 의 p85 subunit 과 EGFR SH2 영역과의결합을통해 PI-3 kinase 를활성화시키며, 활성화된 PI-3 kinase는 phosphatidylinositol-3,4,5- trisphosphate 의증가를통해 Akt 를활성화시켜결국세포자멸사를억제하고세포의성장과증식을촉진한다. 16) Signal transducer and activator of transcription 3 또는 5 (STAT3 또는 STAT5) 는 EGFR 의타이로신잔기 1086 과 1068 에상호작용하여활성화된후세포핵안으로이동하여특정 DNA promoter sequence에결합, 유전자발현을조절함으로써활성 EGFR 의신호를세포막으로부터핵으로전달하는데중요한역할을한다. 22) STAT3는일종의종양유전자로서작용하여세포형질전환을일으키며, 20) 두경부암의진행에서도중요한역할을함이밝혀졌다. 19) 비수용체성타이로신활성효소인 Src 역시 EGFR 세포질내 C- 말단부에결합함으로써활성화되며두경부암에서 EGFR- STAT 경로를매개하는역할을하기도한다. 23,24) Fig. 1에서 ErbB family 하류신호경로의개관을나타내었다. EGFR 은리간드결합에의해서뿐만아니라인접한타수용체로부터활성화되기도하는데 (transactivation) 에스트로겐에의해자극된 G-protein coupled receptor(gpcr) 가 EGFR 을활성화시키고그하류신호경로를통해유방암세포의성장과증식을촉진하는것이대표적인예이다. 25) 두경부암세포주에서도 G-related peptide 를투여하여 GPCR 을자극하면 TNF-α converting enzyme(tace) 가인산화되고 TACE 의작용에의해 EGFR 의리간드인 amphiregulin 이유리되어 EGFR 이활성화되는기전이보고된바있다. 26) 발암과정에서의 EGFR NIH3T3 세포에 EGFR 유전자전달감염 (transfection) 시키면세포의형질변환이이루어지고이세포를누드마우스에접종하면종양이발생하며, 27) 전암성병변에서 EGFR 과그리간드가과발현된다는사실은초기암발생에서 EGFR 이중요한역할을할가능성을보여준다. 정상구강점막에비해구강백반증조직은 EGFR 발현이더많으며, 28-30) 구강이외에폐, 자궁경부, 전립선의전암성병변에서도역시 EGFR 과발현이발견된다. 31-33) EGFR의과발현은 유방암, 폐암, 방광암, 난소암, 전립선암, 두경부암등다양한상피암에서도관찰이된다. 34,35) EGFR 발현은다양한기전을통하여조절될수있는데, 아교모세포종 (glioblastoma) 36) 를제외하면 EGFR 유전자증폭 (gene amplification) 은흔히관찰되지않고주로 epigenetic control 에의한 mrna 과잉생산이주요기전으로알려져있다. 37-40) EGFR 유전자의다형성역시 EGFR 의발현을변화시킬수있다. 한예로 EGFR 유전자 1번인트론의 CA-single sequence repeat(ca-ssr) 은 EGFR 유전자의전사효율을조절하여 EGFR 발현을조절하는데, 이대립유전자의길이가 21개이상으로반복되어있으면 EGFR 발현이감소하고 16개이하로짧게반복된세포에서는 EGFR 발현이증가한다. 41,42) 이러한 EGFR 유전자 1번인트론의다형성은인종간에차이가있어서긴대립유전자는동양인에게흔한반면짧은유전자는백인이나흑인에게더흔하다고하였다. 43) 또한 EGFR 유전자의 Sp1 recognition site의단일염기다형성 (single nucleotide polymorphism) 은 EGFR promotor 의활성을증가시켜암에서 EGFR 과발현의원인이되기도한다. 44) 바이러스도 EGFR 과발현의원인으로지목되는데예를들어 Ebstein-Barr 바이러스가비인강암을유발하는과정에는 latent membrane protein-1 (LMP-1) 의생산을통한 EGFR의과발현이기여하고, 45) B형간염바이러스는직접적으로 EGFR promotor 를자극함으로써간세포암종을유발한다. 46) EGFR 유전자의돌연변이로인해세포의 EGFR 활성도가증가될수있다. 가장널리알려진것은 EGFRvIII 인데 EGFR 세포외영역의 268 개아미노산으로이루어진부분을코딩하는 6번엑손의결손으로인해원래보다작은 145 kd의크기를가진다. 47) 리간드결합부가없으므로리간드와무관하게항상활성화상태를유지한다. 뇌, 폐, 유방, 전립선, 난소등의암에서의상태가기술된바있다. 정상세포에서는발견되지않고암세포에서만발견되므로, 이론적으로 EGFRvIII 를표적으로치료하면정상조직에대한독성을피할수있을것으로전망된다. 48) EGFR 과발현과함께 EGFR 리간드의과잉생산또한 EGFR 활성의상승을초래할수있다. EGFR 리간드중에서특히 TGF-α 의과발현은다수의암에서불량한예후와연관된다고알려졌으며, 49,50) 두경부암에서 EGFR 은 70 배, TGF-α mrna는 5배정도과발현되어있다고보고되었다. 51) 두경부암의대부분세포에서 EGFR 이강하게발현되며 52) 그이외에도방광암, 유방암, 대장암, 전립선암, 췌장암등에서높은비율로 EGFR 이과발현된다고보고되었 189
두경부암의 EGFR 표적치료 다 (Table 1). 53,54) EGFR 과 TGF-α 과발현의양상은서로차이가있어서 TGF-α 상승은초기발암단계인경도형성이상 (mild dysplasia) 에서나타나지만발암과정이진행되어도더이상상승하지않는반면, EGFR 은각단계의형성이상과암에이르기까지점차증가하는양상을보인다. 28,55) 일부연구에서는 EGFR 과발현과종양의임상적양상간에상관성이없다고하였지만, 56,57) 일반적으로 EGFR 과발현은두경부암의높은병기, 림프절전이, 낮은생존율, 방사선치료저항성과관계가있다고알려져있다. 34,35,51,58-61) Table 1. Tumors with EGFR overexpression Tumor type EGFR overexpression (% of tumors) Head and neck 80-100 Renal cell 50-090 Esophageal 43-089 Pancreatic 30-089 Non-small cell lung 40-080 Prostate 40-080 Breast 14-091 Colon 25-077 Ovarian 35-070 Glioma 40-063 EGFR Her2 Her3 Her4 EGF TGF-α Amphiregulin HB-EGF β-cellulin Epiregulin Heregulins/ Neuregulins NRG1 NRG1,2,3,4 Heregulins/ Neuregulins β-cellulin Epiregulin 이상과같이 EGFR 과그리간드가암의발생및진행에중요한역할을한다는증거가충분하고, 특히두경부암에서는 EGFR 의과발현율이높으므로 EGFR 은두경부암분자표적치료의좋은표적이될수있다. EGFR 표적치료의전략 EGFR 을표적으로하는전략으로는항체를이용하여세포외영역에서리간드결합을차단하는방법과저분자량타이로신활성효소억제제 (small molecule tyrosine kinase inhibitor) 를이용하여세포내영역의타이로신활성효소를억제하는방법이대표적이다. 그외에도 antisense oligonucleotide 를이용하여 EGFR 의생산을억제하는방법, 그리고 EGFR 신호경로를이용하지는않지만 EGFR 특이항체또는리간드에독소를붙여서 EGFR 발현세포를표적으로세포용해를시도하는방법이있다 (Fig. 2). 항 EGFR 단클론성항체 EGFR 의리간드결합영역에특이한항체는리간드보다결합력이강하여세포막표면에서리간드가수용체에결합하는것을차단한다. 또한 EGFR에항체가결합할경우 EGFR 이 dimerization 되기어려운구조가되면서 EGFR 의활성화가되지않으며, EGFR 의세포내이동과분 Monoclonal antibody/toxin conjugate Ligand-binding domain Tyrosine kinase domain Homo- or heterodimerization Small molecule tyrosine kinase inhibitor Ribosome-mRNA complex Gene Transcription Proliferation Survival Anti-apoptosis Cell cycle progression Antisense oligonucleotide Fig. 1. Ligands, downstream signaling pathways and cellular phenotypic effects of EGFR familiy. Fig. 2. EGFR-targeting strategies. 190 Korean J Otolaryngol 2007;50:188-97
최승호 Table 2. Anti-EGFR monoclonal antibodies in clinical trials Agent Type Generic/trade name C225 Chimeric IgG1 Cetuximab/Erbitux EMD 72000 Humanized IgG1 - h-r3 Humanized TheraCIM ABX-EGF Fully human IgG2 Panitumumab MDX-447 Humanized Humab-Mouse Mab 806 Anti-EGFRvIII - 해를촉진하여 EGFR 을 downmodulation 시킨다. 62) 많은종류의항 EGFR 단클론성항체가개발되어왔으며대부분정맥주사로투여된다. 최초의것은마우스와쥐에서생산되어 in vitro 실험에서나쥐를대상으로한실험에서는종양억제효과가뛰어났으나인체에서는이종단백질에대한면역반응으로인해직접사용하기어려웠다. 인간의면역글로불린서열을삽입하여인간-마우스키메라항체를만들어면역반응을회피함으로써비로소임상적으로효용가능하게되었고근래에는서열의대부분을인간의것으로만든 humanized antibody도만들어지고있다 (Table 2). Cetuximab(C225, Erbitux) 은가장먼저개발되어가장널리연구된대표적인항 EGFR IgG1 키메라항체이다. Cetuximab 은암세포또는암조직에대해다양한기전을통하여억제효과를나타낸다. 첫째, 세포주기정지. CDK2 를억제하는 p27kip1 의농도를증가시킴으로써 Rb 단백질의인산화를억제하여암세포의세포주기를 G1 주기에정지시킨다. 63) 둘째, 세포자멸사촉진. Anti-apoptotic protein 인 Bcl-2가감소하고 pro-apoptotic protein인 Bax가증가되며, 64) caspase 8이활성화되면서 65) 암세포의세포자멸사를촉진한다. 셋째, 혈관생성억제. 특이하게도 cetuximab은 in vitro 실험에서는 20~40% 의억제효과밖에보이지않지만, in vivo 실험에서는 75% 이상의억제효과를보이는데, 66) 그것은생체조직내에서 VEGF, IL-8, bfgf 등혈관신생성에관여하는요소들이억제되면서종양을공급하는혈관이감소하기때문으로해석된다. 67) 넷째, 종양세포침윤및전이억제. Cetuximab 은방광암마우스실험모델등에서폐전이를감소시키는효과가있다. 67) EGFR 을억제하면 matrix metalloproteinase(mmp) 9을비롯한 MMP의생산과활성이감소하며, 67) MMP 활성의감소는종양세포의 in vitro 침윤과 in vivo 성장및전이감소를초래한다. 68) MMP에대한억제효과는 cetuximab 이 in vitro보다 in vivo에서항암효과가더높은것을설명하는또하나의기전일수있다. 이상의 EGFR 억제기전은항 EGFR 항체뿐만아니라타이로신활성효소억제제에서도동일하다. 그러나타이로신활성효소억제제와달리 cetuximab 이결합한 EGFR 은세포안으로이동하여분해됨으로써결과적으로세포막에분포하는 EGFR 의양을감소시키며, 62) 생체내에서는 antibody-dependant cellular cytotoxicity(adcc) 반응을일으켜항암효과에기여할수있다. 69) 따라서타이로신활성효소억제제투여로 EGFR 의활성이최대한억제된상태에서도항 EGFR 항체를투여하면추가적인효과를얻을수있다. 70,71) Cetuximab 은두경부암, 대장암, 비소세포성폐암등의상피성종양을대상으로단독요법혹은항암제또는방사선치료와의병합요법으로임상시험이진행되어오고있다. 몇개의대단위임상시험결과를토대로 2006 년 3월, FDA 는국소또는경부진행된두경부편평상피암에서방사선과의병합요법에, 그리고항암치료에실패한재발또는전이성두경부편평상피암에서단독요법에 cetuximab 의사용을승인하였다. 치료경력이없으면서국소혹은경부진행된구인두, 하인두, 후두암환자를대상으로다국적으로시행된무작위 3상임상시험에서방사선-cetuximab 병합요법을시행한군 (n=211) 은방사선단독요법군 (n=213) 에비해국소조절기간 (24.4 개월대 14.9 개월, p=0.005) 과전반적인생존율 (49.0 개월대 29.3 개월, p=0.03) 이우수하였다. 72) 이연구에서나타난 cetuximab 의주된부작용은피부염과점막염이었고, grade 3/4의심한피부염은방사선-cetuximab 병합요법군에더많았으나 (34% 대 18%), 점막염의빈도는차이가없었다. 방사선-cetuximab 병합치료를하여도방사선단독치료에비해경부청소술후창상치유가저해되지는않으며, 73) 병합요법을통하여후두와하인두암환자에서후두보존율을높일수있다. 74) 재발성혹은전이성두경부암에서 cetuximab 으로화학요법의치료효과를높일수있을지에대해서도임상시험이진행되었다. 한다기관 2상시험에서는 platinum 계항암제치료에반응이없고국소치료에적합하지않은 96예의재발혹은전이성두경부암환자를대상으로하여 cetuximab 을투여하고이어 cisplatin 화학요법을시행하였다. 그결과, 반응률 10%, 질병조절률 ( 완전관해, 부분관해, 안정병변 ) 53%, 질병조절기간과전반적인생존기간의중앙값 85일과 183 일을얻었으며피부발진등견딜만한부작용만있어다른치료방법이없는말기두경부암환자에게 cetuximab 이도움이될수있다고하였다. 75) Eastern Cooperative Oncology Group(ECOG) 에의해시행된무작위 3상시험에서는재발성혹은전이성두경부암환자를 cisplatin과 cetuximab 을병합투여한실험군과 cisplatin 과위약을투여한대조군으로무작위배정하였다. 무진행생존기간 (progression-free survival) 의중앙값은실험군에 191
두경부암의 EGFR 표적치료 서 4.2 개월, 대조군에서 2.7 개월이었으며 (hazard ratio= 0.78), 전반적인생존율의중앙값은각각 9.2 개월과 8개월로유의한차이가없었으나반응률 ( 완전관해, 부분관해 ) 은실험군 26%, 대조군 10% 로차이가있었고 (p=0.03), EGFR 면역조직화학염색상전체세포의 80% 이하에서 EGFR 양성인경우 cetuximab 에의한증강효과가크다고하였다. 76) EGFR 발현이높은종양일수록 TKI 또는 cetuximab 의효과가좋을것으로예상되지만실험과임상시험에서는종종무관한것으로나타나는데그이유는아직밝혀지지않았으나몇가지가설로설명된다. 첫째, 종양에충분한농도의약제가도달하지못했거나, 둘째, EGFR 의발현및활성을측정하는방법상의오류, 셋째, 종양에서 EGFR 차단이불완전하였거나, 넷째, EGFR 의소멸과생성이빠른경우, 다섯째, EGFR 이암치료의적합한표적이아닐가능성등이다. 77) Cetuximab 이외에도 EMD 72000(martuzumab), 78,79) h-r3, 80) ABX-EGF(panitumumab) 81) 등 EGFR을표적으로하는항체들이개발되어전임상및임상시험중이다. 192 저분자량타이로신활성효소억제제 (Small Molecule Tyrosine Kinase Inhibitors, TKI) EGFR 이자극되어최종적으로작용을나타내기위해서는타이로신활성효소가활성화되어야한다. TKI 는 EGFR 세포내영역의 Mg-ATP 결합부에경쟁적으로결합함으로써 EGFR autophosphorylation을억제하는기능을한다. 과거 10여년간역가, EGFR 특이성, 작용의가역성, 생체이용률등에서차이가있는다양한종류의 EGFR 타이로신활성효소억제화합물이개발되어오고있다 (Table 3). 화학적으로 quinazoline 구조를골격으로하는화합물이대부분이지만 pyrrolo-pyrimidine 계 82,83) 나 pyridopyrimidine계 84) 화합물도있다. Gefitinib(Iressa, ZD1839) 는경구투여가가능한 quinazoline 계 TKI 로우리나라를비롯하여여러나라에서기 Table 3. EGFR tyrosine kinase inhibitors in clinical trials Agent Type Generic/trade name ZD1839 ErbB1 Gefitinib/Iressa OSI-774 ErbB1 Erlotinib/Tarceva CI-1033 Pan ErbB Canertinib EKB-569 ErbB1/2 - GW2016 ErbB1/2 - PKI-166 ErbB1/2 - 존의화학요법에반응하지않는비소세포성폐암에대해단독투여가가능하도록사용승인이되었다. 비교적 EGFR 에특이성을가지지만 EGFR 억제용량의 100 배정도의농도에서는 Her2 를비롯한타수용체의타이로신활성효소를억제할수있다. 85,86) 전임상실험결과, gefitinib 은 cetuximab 과유사한작용기전으로암세포의성장을억제하고세포자멸사를증가시며, 암세포의이동과침윤을억제하는한편, 종양의혈관생성을감소시키는효과가있다. 87,88) 두경부암세포주역시 in vitro실험과이종동물모델에서 gefitinib 에의해억제되는효과를보이는데성장억제효과는세포의 EGFR 발현정도에비례하며 89) Her2가과발현되어있는세포주도성장이억제되어 Her2 에대한작용을짐작하게한다. 90) Gefitinib 과항암제또는방사선을병합하였을때여러두경부암세포주의성장이단독치료에비해상승적또는부가적으로억제되는것이실험적으로증명되며, 91) cetuximab 과마찬가지로동물실험모델에서방사선치료에대한 gefitinib 의상승효과는암세포의성장억제뿐만아니라혈관생성억제효과에도기인한다. 92) Gefitinib 에대하여두경부암을포함한다양한암을대상으로임상시험이시행되었다. 두경부암을포함한고형암환자를대상으로한 1상시험에서대부분의부작용은경도또는중등도의피부발진과설사였으며대다수의환자는안정병변 (stable disease) 소견을보였다. 93,94) 두경부암환자 52예를대상으로한 2상시험에서는수용할만한부작용에 10.6% 의반응률을보였고, 53% 에서 gefitinib 투여가임상적으로환자에게유익한것으로판단되었다. 95) 이연구에서피부독성과항암효과는비례관계를보여피부독성이치료반응의예측인자로제시되었다. 약제감수성과피부독성이비례하는관계는항 EGFR 항체와 TKI 에게공통적인데 EGFR 이피부와점막에많이분포하는것을고려할때치료효과를거둘정도의약제가종양세포에도달하기위해서는피부와점막이약제에포화상태에이르러야하고따라서피부발진의부작용이심한것으로해석할수있다. 주목할만한것은 gefitinib 투여와관련하여비소세포성폐암환자에게투여하였을때급성간질성폐렴이발생하여사망하였다는보고인데일본에서만보고되었을뿐다른나라에서는보고가없어인종에따른차이가있을것으로예측되며사용에주의가요망된다고하였다. 96,97) Erlotinib(Tarceva, OSI-774) 은 gefitinib과마찬가지로 quinazoline 계 TKI 로서, FDA 는 2004 년화학요법에반응하지않는국소진행성또는전이성비소세포성폐암에사용승인한데이어 2005 년국소진행되었거나절제가불가능하거나전이성인췌장암환자에서 gemcitabine 과의병 Korean J Otolaryngol 2007;50:188-97
최승호 합요법을승인하였다. 두경부암을포함한여러암세포를대상으로광범위한전임상시험이시행되어, 실험적으로암세포의성장, 침윤, 전이에대한효과가입증되었다. 98) 이어시행된 1상시험에서나타난주요부작용은여드름모양의발진 (acneiform rash) 과설사였으며, 150~200 mg 이상을사용하면피부부작용이심하여일일허용량은 150 mg 으로정해졌다. 99) 이연구에포함된 3명의두경부암환자가운데 1명은 15개월간안정병변상태를유지하여임상효과에대해서도희망을갖게하였다. 115 예의두경부암환자를대상으로한다기관 2상시험연구에서 5예에서만부분관해를보여객관적반응률은 4.3% 였다. 안정병변을보인것은 38.3% 인 44예였고평균 16.1 주간안정상태를유지하였다. 무진행생존기간의중앙값은 9.6 개월이었으며전반적인생존기간의중앙값은 6개월이었다. 피부발진이 grade 2 이상으로심할경우유의하게치료에대해잘반응하여 gefitinib 과마찬가지로피부독성과치료결과와연관성을보였다. EGFR 양성인환자만선택한것은아니었지만대상환자의 76% 가 EGFR 면역조직화학염색에강양성이었고 EGFR 발현의정도는 erlotinib 치료반응, 피부독성, 생존과무관하였다. 비록반응률은화학요법에비해높지않았지만거의 40% 의환자가경미한부작용만으로안정병변을얻어고무적인결과라고할수있다. 100) 현재두경부암환자를대상으로 erlotinib 과방사선치료, cisplatin, taxotere 등의화학요법제, Cox-2 억제제, cetuximab, 항 VEGF 항체인 bevacizumab 등을다양하게조합한병합요법이임상시험되고있고 www.clinicaltrials. gov 웹사이트에서확인할수있다. EGFR Antisense 유전자치료 in vitro와누드마우스종양모델전임상실험에서 antisense oligonuleotide로종양세포에서 EGFR의발현이감소하고종양의성장이억제됨이확인되었으며, 101) 리포솜과함께 oligonucleotide를종양내주사하였을때주사부위의경한염증소견이외에는별다른독성이나타나지않았다. 102) 주사한유전자는 1개월이경과한후에도체내대부분의장기에존재함이 PCR 로확인되었다. 103) 독소결합체를이용한 EGFR 표적치료 종양세포에 EGFR 이과발현되는점을이용하여항 EGFR 항체나 EGFR 결합리간드에 Pseudomonas 또는 Diphtheria 독소를결합시켜투여하는방법이다. EGFR 하류경로를차 단하는것이아니라세포독소를이용하여종양세포의사멸을유도하기때문에다른 EGFR 표적치료와는작용기전이다르다. Pseudomonas exotoxin A 유전자를 EGFR 특이항체와 ErbB2 특이항체유전자에결합시켜재조합항체를생성하여두경부암세포주에투여한결과세포의성장이억제되었고, 이종이식종양모델에서는생성된종양이 50% 까지줄어드는결과가보고되었고, 104) Schmidt 등은같은독소를 TGF-α 에붙여투여하여 in vitro와 in vivo 에서종양억제효과를관찰하였다. 105) 독소를이용한 EGFR 표적치료는전신투여를하였을때피부와간등 EGFR 이높게발현되는조직에독성이나타나기때문에종양에직접국소주사로투여하여야한다는단점을가지고있다. 결 론 EGFR 을하향조절하였을때 in vitro 및 in vivo 전임상결과는암세포의성장과생존에필요한신호경로가억제되어세포사에이르게됨을보여주었고, 따라서두경부암을포함한상피성종양의새로운치료법으로서의가능성을강하게시사하였다. EGFR 을억제하는접근수단으로항 EGFR 항체, 저분자량타이로신활성효소억제제, EGFR DNA 또는 mrna에대한 anitisense oligonuleotide가시도되고있으며항 EGFR 항체인 cetuximab 과저분자량타이로신활성효소억제제인 gefitinib, erlotinib 이가장활발히연구되고있다. 이들약제의임상시험결과는심각한부작용없이비교적안전하게사용가능하나, 적어도현재까지단독으로는항암효과가그리뛰어나다고하기어렵다. 최근에보고된 cetuximab 과방사선의병합요법에대한임상시험결과는국소적으로진행된두경부암의치료에새로운선택을제시하였다. 72) Cetuximab에의한 EGFR 하류경로의억제는종양의방사선감수성을높여결과적으로환자의생존을증가시켰으나항암화학 -방사선병합치료에못미치는국소및경부조절은앞으로연구가필요한부분이다. 현재 EGFR 억제제와다양한항암제, 방사선치료, Cox-2 억제제, VEGF 억제제, 또는다른 EGFR 억제제와의병합요법이시도되고있어결과가주목된다. REFERENCES 1) Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19):1937-44. 2) Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N 193
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