The Study of Connective Tissue Growth Factor C-Terminal Domain as Small Molecule Drug for Treatment of Peritoneal Metastasis in Gastric Cancer

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Project title/計畫英文名

Project Number/計畫編號

MOST104-2314-B002-054-MY2

Translated Name/計畫中文名

利用結締組織生長因子C 端為小分子藥物來治療胃癌腹膜轉移之研究

Project Principal Investigator/計畫主持人

CHIUNG-NIEN CHEN

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

李心予

Start date/計畫起

01-08-2015

Expected Completion/計畫迄

12-07-2016

摘要：胃癌腹膜轉移在胃癌的治療中是個⾮非常棘⼿手且致命的疾病. 結締組織⽣生⾧長因⼦子在正常在正常的⽣生理現象與疾病中都扮演著重要的⾓角⾊色. 本團隊先前的研究顯⽰示結締組織⽣生⾧長因⼦子的的C 端(Connectivetissue growth factor C-terminal) 會透過與癌細胞表⾯面上所表現的整合素alpha3beta1 (integrinalpha3beta1)結合來達到抑制癌細胞與腹膜之間的結合. 我們希望透過利⽤用刪減突變法(deletionmutation)將整合素alpha3 的部分做突變來更徹底的研究結締組織⽣生⾧長因⼦子C 端與整合素alpha3beta1之間的結合, 並找出雙⽅方特定的結合點. 透過合成⼩小分⼦子的C 端的序列來研究此⼩小分⼦子是否具有更好的療效. 同時我們將在⼩小⿏鼠腹膜轉移模式中驗證此⼩小分⼦子對於腹膜轉移的療效. 在此同時, 我們也希望利⽤用cDNA 點陣(cDNA microarray)來尋找更多與腹膜轉移相關的差異性表現基因, 讓我們可以更深⼊入了解胃癌腹膜轉移的分⼦子機制, 期望可以找到更多可以治療此疾病的標地. 另外, 在胃癌的治療中有許多臨床常⽤用的治療藥物, 例如5-FU, cisplatin, 以及近年發展的標靶藥物avastin. 這些藥物透過同時與本團隊所發現的重組結締組織⽣生⾧長因⼦子C 端是否可達到更佳的療效, 也是本團隊在此研究計畫中想要探討的主題.此計劃預計分為三年執⾏行：第⼀一年：1. 以刪減突變法來產⽣生各式具有整合素alpha3 的突變株基因來進⼀一步確認胃癌細胞是透過整合素alpha3beta1 來進⾏行轉移的過程並利⽤用合成的結締組織⽣生⾧長因⼦子C 端⼩小分⼦子來作為抑制沾黏的抑制劑並以沾黏分析法來觀察在細胞實驗中是否有療效.第⼆二年：1. 利⽤用結締組織⽣生⾧長因⼦子C 端以及其合成⼩小分⼦子來探討在⼩小⿏鼠腹膜轉移模式中是否具有療效並利⽤用其合成⼩小分⼦子合併5-FU, cisplatin 或avastin 在⼩小⿏鼠腹膜轉移模式中是否具有更好的療效.第三年：以cDNA microarray 來尋找更多與腹膜轉移相關的差異性表現基因, 並在病⼈人組織檢體驗證這些基因表現量, 以利尋找更多可以治療腹膜轉移的標地.
Abstract: Gastric cancer peritoneal metastasis is an aggressive and lethal disease that implies a poor prognosis forpatients with gastric cancer. Connective tissue growth factor (CTGF) plays important roles in normalphysiology as well as pathology, and our previous study have identified its C-terminal domain as an effectiveadhesion blocker for cancer cells to peritoneal through binding with integrin alpha3beta1 that is expressed oncancer cell surface. We wish to further confirm the binding site of CTGF C-terminal with integrinalpha3beta1 by generating deletion mutations of integrin alpha3 subunit as well as synthesize smallerfragments of CTGF C-terminal to determine the therapeutic potential in preventing gastric cancer peritonealmetastasis. We also wish to discover more differentially expressed genes in gastric cancer peritonealmetastasis using cDNA microarray and attempt to identify more targets that may be able to assist in themanagement of gastric cancer. Currently, there are a few chemotherapeutic drugs or targeted therapy drugsthat are frequently used in the treatment of gastric cancer, such as 5-FU, cisplatin and avastin. We wish todetermine if CTGF C-terminal or synthetic fragments of CTGF C-terminal combined with these frequentlyused cancer treatment drugs would have higher efficiency in treatment of gastric cancer.We wish to carry out our study in three years:Year 1:To generate deletion mutations of integrin alpha3 and using adhesion assay to further confirm the role ofintegrin alpha3beta1 in gastric cancer peritoneal metastasis as well as to synthesize small fragments of CTGFC-terminal domain as anti-adhesion agent to determine the therapeutic potential in vitro.Year 2:To study the therapeutic potential of synthetic small fragment of CTGF C-terminal domain in the treatmentof gastric cancer in vivo and to study the their effects of combination therapy with 5-FU, cisplatin or avastinin vivo.Year 3:Using cDNA microarray to identify differentially expressed genes in peritoneal metastasis and confirm geneexpression in gastric cancer patient tumor specimens.

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The Study of Connective Tissue Growth Factor C-Terminal Domain as Small Molecule Drug for Treatment of Peritoneal Metastasis in Gastric Cancer

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