| セッション情報 |
International Forum 2(Liver) 4.Treatment Strategy
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| タイトル |
IF2-4-III (Keynote lecture) Molecular Targeted Therapy for Hepatocellular Carcinoma
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| 演者 |
Melanie B.Thomas（The University of Texas MD Anderson Cancer CenterHoustonUSA） |
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| 抄録 |
Until recently there has been no published evidence that systemic chemotherapy improves overall sur-vival in any subset of HCC patients． HCC are clinically chemotherapy-resistance tumoursand this obser-vation is supported by low response rates across a wide variety of cytotoxic chemotherapy agents． Themost widely used agent has been adriamycin as a single agent or in combination． A pivotal Phase III trialof adriamycin versus combjnation chemotherapy （cisplatinuminterferonadriamycinand 5-fluorouracilPIAF） showed a statistically significant difference in response rate （RR） favouring PIAFbut no survivaldifferenceA majority of HCC （60% to 80%） arise in a background of chronic hepatitis and cirrhosis． Cir-rhosis can have a profound impact on anticancer drug therapy． Cirrhosis not only decreases drug metabo-lizing enzyme activitybut it also alters the absorptionplasma protein bindingdistributionand renal ex-cretion of drugs．In recent yearsseveral molecular “targets” including oncogenesoncoproteinsand cellular receptors havebeen identhied in a variety of cancers as being key elements in carcinogenic pathways． Consequently sev-eral agents have been developed thatby a variety of mechanismsinterfere with cell signaling and havedemonstrated anti-cancer activity． Several novel “targeted” or biologic agents are now being tested inHCC patients． Hepatocarcinogenesis is a complex multistepprocesswhich results in a large number ofheterogeneous molecular abnormalitiesand thus numerous potential targets for existing therapeuticagents． The molecular pathways that represent rational targets in HCC for novel therapies include ： theMAPK （mitogen-activated protein kinase） which is responsible for cellular proliferation and differentiation．Therapeutic agents that target this pathway include sorafenib （targets both raf and vascular endothelialgrowth factor receptor） and farnesyl transferase inhibitors （targeting ras）． A placebo-controlled interna-tional Phase III trial of sorafenib was conducted in HCC patients with Childs-Pugh A cirrhosis showed su-perior survival in the sorafenib arm compared to placebo （10．7 months vs． 7．9 monthsp ＝ 0.00058） ． Soraf-enib is now approved in the European Union and the United States for the HCC．The Pt3K／Akt／mTOR pathway （Phosphoinositide-3 kinase／Protein Kinase B／mammalian target of rapa-mycin） is responsible for cellular proliferation and apoptosisand is closely linked to cell cycle． PI3K is asso-ciated with cell surface growth factor receptorsand upon ligand binding can trigger formation of PIP3which in turn activates Akt and leads to a number of downstream events （mTOR being one of the tar-gets） ． This pathway is known to be up-regulated in a subset of HCC patients． Molecular targeted therapysuch as rapamycina naturally occurring mTOR inhibitorshowed promising results in HCC cell lines．Both the EGFR（epidermal growth factor receptor）and VEGFR（vascular endothelial growth factor recep-tor） families of growth factors are upregulated in HCC． EGFR／HER I expression was detected in 88％ ofthe patients in a phase II study of erlotinib in HCC． ln two phase II studies of this agentthe response rateswere was less than 10% but the disease control rate was more than 50%and median survival times were10．75 and13 monthsrespectively．HCCs are generally hypervascularand VEGF promotes HCC development and metastasis． Variousagents targeting the VEGF circulating ligand or transmembrane receptorincluding bevacizumab（Avastin(R)）sorafenib （Nexavar(R)）and TSU-68have been studied in patients with HCC． These studiesshowed a high disease control rate of over 80% and a median time te progression of more than 6 mQnths．TSU-68 is an oral anti-angiogenesis compound that blocks VEGFR-2 （vascular endothelial growth factorreceptor）PDGFR （platelet-derived growth factor receptor）and FGFR （fibroblast growth factor recep-tor） ； a phase I／II study has been conducted in Japan． |
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