據(jù)美國(guó)BussinessWire 1月10日?qǐng)?bào)道稱,，杰隆（Geron）發(fā)表臨床前研究數(shù)據(jù)顯示,，其端粒酶抑制劑藥物imetelstat（GRN163L）在小兒科神經(jīng)腫瘤當(dāng)中可選擇性瞄準(zhǔn)癌癥干細(xì)胞,，這一發(fā)現(xiàn)為兒童腫瘤的臨床試驗(yàn)提供了支持。該研究發(fā)表于2011年1月1日的Clinical Cancer Research雜志上
近年來有關(guān)端粒酶抑制的研究日益增多,，成為癌癥治療的一個(gè)熱點(diǎn)方向,，GRN163L是此類藥物開發(fā)中最前沿的一個(gè)候選藥物。2002年3月,，Geron從Lynx Therapcutics獲得了用GRN163和GRN163L兩種化合物的核心專利,。早期研究顯示,，GRN163對(duì)十四種不同癌癥細(xì)胞均表現(xiàn)出有意義的端粒酶活性抑制作用，它可以一直黑色素瘤等細(xì)胞的生長(zhǎng),，因脂質(zhì)修飾物GRN163L更易進(jìn)入細(xì)胞發(fā)揮端粒酶抑制作用,，后續(xù)臨床前及臨床試驗(yàn)均為GRN163L。2005年,，F(xiàn)DA同意GRN163L在患慢性淋巴細(xì)胞白血病患者的臨床實(shí)驗(yàn),。2007年，Geron公司開始GRN163L單獨(dú)治療多發(fā)性骨髓瘤的I期臨床試驗(yàn),。2008年開始了GRN163L治療乳腺癌的I期臨床實(shí)驗(yàn),。同年12月，Geron發(fā)布了有關(guān)GRN163L治療再發(fā)的和難治的多發(fā)性骨髓瘤的暫時(shí)性臨床試驗(yàn)數(shù)據(jù),。2009年,，Greron發(fā)布了Geron163L對(duì)抗癌癥干細(xì)胞的實(shí)驗(yàn)活動(dòng)，包括非小型細(xì)胞肺癌,、乳癌,、胰臟炎、前列腺癌,、小兒科神經(jīng)腫瘤,。公司發(fā)表Geron163L治療乳癌的假定癌癥干細(xì)胞與胰臟炎癥系數(shù)據(jù)。數(shù)據(jù)顯示,，在以Geron163L治療後,，人類乳癌細(xì)胞MCF7的假定干細(xì)胞數(shù)量與自我再生的能利大幅減弱。目前Geron163L正處于臨床II期試驗(yàn)中,。
Cancers of the brain and nervous system are the most common solid tumors in children and the leading cause of morbidity and death from pediatric cancers. These preclinical data show that imetelstat specifically targets the cancer stem cells in pediatric neural tumors, which we believe may be responsible for progression and recurrence of the disease,” said Stephen M. Kelsey, M.D., Geron’s executive vice president and chief medical officer, oncology. “The findings are important and support the rationale for conducting a clinical trial in pediatric tumors.
生物谷推薦詳細(xì)內(nèi)容閱讀
中科院上海生科院生化與細(xì)胞所 周金秋研究員
端粒—穩(wěn)定線性染色體的末端結(jié)構(gòu)
http://www.bioon.com/trends/comment/411939.shtml
吳巧稚,，吳楠，黃志紓,，王友群,，王霆.端粒酶抑制劑GRN163L研究進(jìn)展[J] 中國(guó)新藥雜志, 2010,V19(16): 1411-1414
美國(guó)商業(yè)電訊報(bào)道全文
http://www.businesswire.com/news/home/20110110005661/en/Geron-Announces-Publication-Demonstrating-Activity-Imetelstat-Cancer
生物谷推薦英文摘要
Clin Cancer Res; 17(1); 111–21. 2011 AACR.
Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition
Pedro Castelo-Branco1, Cindy Zhang1, Tatiana Lipman2,3, Mayumi Fujitani2, Loen Hansford2, Ian Clarke1, Calvin B. Harley4, Robert Tressler4, David Malkin3,5, Erin Walker1,5, David R. Kaplan2,3,6, Peter Dirks1, and Uri Tabori1,3,5
Authors' Affiliations:1The Arthur and Sonia Labatt Brain Tumor Research Centre, 2Cell Biology Program, The Hospital for Sick Children, 3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; 4Geron Corporation, Menlo Park, California; 5Genetics and Genome Biology Program, The Hospital for Sick Children, and 6Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal.
Methods: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo.
Results: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo.
Conclusions: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin.
