成果報告書詳細
管理番号20110000001466
タイトル*平成22年度中間年報 基礎研究から臨床研究への橋渡し促進技術開発/橋渡し促進技術開発/がん細胞に発現する必須アミノ酸トランスポーター(LATI)を分子標的とする新規抗がん療法の研究開発 
公開日2011/11/23
報告書年度2010 - 2010
委託先名国立大学法人群馬大学 ジェイファーマ株式会社 学校法人北里研究所北里大学東病院
プロジェクト番号P07022
部署名バイオテクノロジー・医療技術部
和文要約
英文要約Title: Anti-cancer translational research and development: Targeting cancer-expressing essential amino acid transporter LAT1 (FY2010-FY2012) FY2010 Annual Report

The following six itemized projects have been performed: 1. We have established companion diagnosis and developed a new method to evaluate therapeutic effectiveness via strategy of combining therapy with diagnosis. Using an anti-LAT1 monoclonal antibody, gastric cancer specimens were immuno-histochemically stained resulting in high LAT1 expression in gastric cancer. Stronger staining was obtained in non-scirrhrous cancer than observed via scirrhous cancer specimens. 2. The bulk chemical synthesis of JPH203, an LAT1-specific inhibitor and the development of suitable formulations were conducted. A kilogram scale-up synthesis of JPH203 has been completed. As an intravenous applicable formulation, a new JPH203:cyclodextrin complex has been established and evaluated to be highly soluble in water. Furthermore, JPH203:CD is as efficacious as JPH203 hydrochloride salt. 3. We have conducted molecular interaction studies between LAT1 and JPH203. Since no information on tertiary structure of LAT mammalian membrane transporter proteins are available, a simulation analysis of LAT1 was made using bacterial crystal structures. As a functional approach, two cell lines established from human gastric and pancreatic cancers, 44As3-11 and MIAPaCa-2 were used and confirmed strong inhibitory effects of JPH203 on amino acid uptake and cell growth. 4. We have conducted in vitro (metabolism and drug-drug interaction studies) and in vivo (rat PK) experiments. JPH203 is metabolically stable in mouse, rat, dog, monkey, and human liver microsomal incubations. JPH203 is metabolized to N-Acetyl-JPH203 in rat, monkey and human S9 liver incubates; a trace amount of NAc-JPH203 formed in mouse incubates while no formation was observed in dog incubates. We have developed robust LC/MS-MS BAPK (Bioanalytical Pharmacokinetic) methodology. The pharmacokinetics of JPH203 administered intravenously to male Sprague-Dawley rats displays a very fast initial distribution followed by a very long elimination phase of both JPH203 and NAc-JPH203. Authentic NAc-JPH203 has been prepared and demonstrated to be an active metabolite. Oral PK and determination of other ADME properties (i.e. protein binding studies) are warranted. 5. Clinically optimal dose estimation using LAT1-specific PET probe, FMT. Conducting experiments with oocytes expressing hLAT1 and hLAT2, we confirmed that both α-methyl-tyrosine (MT) and α-methyl-(3-fluoro)-tyrosine (FMT) are substrates of hLAT1, not hLAT2. As a radio-labeled FMT with a longer half life than ¹⁸F-FMT for animal model experiments, chemical synthesis of ³H-MT has been achieved and initial ³H-FMT attempted. An established cell line from non-small cell lung cancer, H1395 has been treated with BCH and together with anti-EGRF tyrosine-kinase inhibitor, gefitinib resulting in an additive effect. 6. Investigative clinical study: To obtain basal control values of longevity in best supportive care patients, a protocol for retrospective studies has been designed using medical records in malignant gastric and pancreatic cancers via Kitasato University East Hospital. Evaluation of safety assessment has been decided to follow the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
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