煉丹四年 Si2C首顆新藥將亮相 2015-02-02 經濟日報 記者黃文奇／台北報導
生技整合育成中心抗肝癌藥SC-43 最快本季發表 今年拚在台、美申請臨床試驗煉丹四年、Si2C首顆新藥成果將發表。生技整合育成中心（Si2C）最快首季將發表第一個新藥開發成果，是由台大醫學院、陽明醫學院共同合作的抗末期肝癌新藥SC-43，最快今年向美國／台灣食品藥物管理局（FDA／TFDA）申請臨床試驗（IND）。SC-43是抗末期肝癌新藥，已故Si2C前首席顧問蘇懷仁博士所欽點，科技部、生技醫藥國家型計畫（NRPB）、Si2C迄今最大力支持的早期新藥產品，也是市場首見的藥物（First in Class）。該產品最快3月將由科技部、台大、陽明、Si2C等單位共同宣布，規劃成立新創公司，也將是Si2C育成的第一家新藥公司。目前，有四到五家國內新藥公司有意願合作，國內大型創投基金也積極問津，另外，由國發基金、大和基金合作的「大和台日生技創投基金」也傳出參股意願。這顆由政府注資上億元，台大醫學院陳昆鋒醫師、陽明大學生物藥學研究所蕭崇瑋副教授組成的頂尖團隊，所開發的抗末期肝癌新藥，三年前由蘇懷仁領頭盤點，未來可能由現任台大校長、Si2C新藥組初審召集人楊泮池繼續督軍。Si2C指出，每年全球約有70萬以上的肝癌新增病例，而末期肝癌病患，目前僅有國際大廠拜耳與Onyx共同開發的sorafenib，被證實能延長末期肝癌病患約2.8個月的存活期，其餘治療的成效均不理想，而這也是SC-43的利基。SC-43開發團隊指出，大多數的肝癌病患常同時併有肝硬化與慢性肝炎，所以在肝腫瘤形成與惡化的過程中，與發炎息息相關的STAT3扮演相當關鍵的角色，在肝癌細胞中的SHP-1是一個調控STAT3活化的關鍵。在肝癌細胞內，SHP-1因結構的改變而無法表現功能，由陳昆鋒、蕭崇瑋領軍的SC-43開發團隊，以SHP-1增敏劑為藥效標的，設計一系列SC小分子藥物，在初期動物實驗證明：比目前唯一肝癌標靶藥sorafenib療效高16倍，預計於2015年底、明年初向美國與台灣FDA申請進行人體臨床試驗許可。
科技部：轉型民企 言之過早生技整合育成中心（Si2C）一路走來頗為辛苦，還好目前有中央研究院院長翁啟惠的支持，而科技部也在預算上給予奧援；不過，自首席顧問蘇懷仁去世後，下一步的定位問題，將成為該中心未來存續的關鍵，是否人亡政息，有待觀察。科技部表示，Si2C到2016年預算大抵沒有問題，但未來是否與中研院的生技育成中心整併、遷入南港國家生技園區，則需要各界進一步討論，目前未有定論，至於Si2C是否轉型為民間企業，還言之過早。目前，Si2C由陳恆德擔任醫務長、陳家進為技術長；其他協助選題的專家則包括：台大校長楊泮池與工研院生醫所所長卲耀華分別擔任新藥、醫材育苗計畫初審召集人，而翁啟惠則是案源的複審（總）召集人。至於蘇懷仁過去擔任的「首席顧問」一職是否找人遞補，科技部強調，現在不是誰來接替蘇懷仁的問題，而是「把事情做好」才是當務之急，短期內應沒有誰來接此一職務的規劃。科技部表示，蘇懷仁有其人脈、光環與國際經驗，但現在Si2C面臨的是沒有蘇博士的時代，一切必須務實考量，只有把自己做好，讓成果凸顯出來，未來在南港國家生技中心落成後，也能繼續擔任選題育成的中心。
Oncogene. 2015 Jan 26. doi: 10.1038/onc.2014.445. [Epub ahead of print]
SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Fan LC1, Shiau CW2, Tai WT1, Hung MH3, Chu PY4, Hsieh FS1, Lin H1, Yu HC1, Chen KF1. Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. Src homology region 2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3Tyr705 oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here we first reported that endogenous SHP-1 protein levels were significantly down regulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3Tyr705 and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished transforming growth factor-β1 (TGF-β1)-induced p-STAT3Tyr705 and EMT, as well inhibited migration and invasion but further rescued by signal transducer and activator of transcription factor 3 (STAT3) overexpression. Depletion of SHP-1 could induce a more increase in TGF-β1-induced p-STAT3Tyr-705 and EMT characteristics, further supporting the mechanism that suppression of TGF-β1-induced EMT is dependent on SHP-1-mediated STAT3 inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A-mutated SHP-1 markedly reduced TGF-β1-induced p-STAT3Tyr705 and EMT features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine phosphatase activity that directly downregulated p-STAT3Tyr705. Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus highlighting that SC-43-SHP-1 axis may serve as a potential therapeutic target that antagonized p-STAT3Tyr705 and thereby prevented HCC EMT and metastasis.
Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res. 2013;15(4):R63.
Liu CY, Tseng LM, Su JC, Chang KC, Chu PY, Tai WT, Shiau CW, Chen KF. INTRODUCTION: Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various cancers including breast cancer and has emerged as a novel potential anti-cancer target. STAT3 has been demonstrated to be a target of sorafenib, and a protein tyrosine phosphatase Src homology 2-domain containing tyrosine phosphatase 1 (SHP-1) has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism.
METHODS: Breast cancer cell lines were used for in vitro studies. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of sorafenib, SC-1 and SC-43 was tested in xenografted nude mice. RESULTS: SC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation of p-STAT3 and its downstream proteins cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA-MB-468, MDA-MB-231, MDA-MB-453, SK-BR3, MCF-7). Overexpression of STAT3 in MDA-MB-468 cells protected the cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p-STAT3 downregulation than sorafenib in MDA-MB-468 xenograft tumors. CONCLUSIONS: Novel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells.
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