据美国BussinessWire 1月10日报道称，杰隆（Geron）发表临床前研究数据显示，其端粒酶抑制剂药物imetelstat（GRN163L）在小儿科神经肿瘤当中可选择性瞄准癌症干细胞，这一发现为儿童肿瘤的临床试验提供了支持。该研究发表于2011年1月1日的Clinical Cancer Research杂志上
近年来有关端粒酶抑制的研究日益增多，成为癌症治疗的一个热点方向，GRN163L是此类药物开发中最前沿的一个候选药物。2002年3月，Geron从Lynx Therapcutics获得了用GRN163和GRN163L两种化合物的核心专利。早期研究显示，GRN163对十四种不同癌症细胞均表现出有意义的端粒酶活性抑制作用，它可以一直黑色素瘤等细胞的生长，因脂质修饰物GRN163L更易进入细胞发挥端粒酶抑制作用，后续临床前及临床试验均为GRN163L。2005年，FDA同意GRN163L在患慢性淋巴细胞白血病患者的临床实验。2007年，Geron公司开始GRN163L单独治疗多发性骨髓瘤的I期临床试验。2008年开始了GRN163L治疗乳腺癌的I期临床实验。同年12月，Geron发布了有关GRN163L治疗再发的和难治的多发性骨髓瘤的暂时性临床试验数据。2009年，Greron发布了Geron163L对抗癌症干细胞的实验活动，包括非小型细胞肺癌、乳癌、胰脏炎、前列腺癌、小儿科神经肿瘤。公司发表Geron163L治疗乳癌的假定癌症干细胞与胰脏炎症系数据。数据显示，在以Geron163L治疗後，人类乳癌细胞MCF7的假定干细胞数量与自我再生的能利大幅减弱。目前Geron163L正处于临床II期试验中。
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.
生物谷推荐详细内容阅读
中科院上海生科院生化与细胞所 周金秋研究员
端粒—稳定线性染色体的末端结构
http://www.bioon.com/trends/comment/411939.shtml
吴巧稚，吴楠，黄志纾，王友群，王霆.端粒酶抑制剂GRN163L研究进展[J] 中国新药杂志, 2010,V19(16): 1411-1414
生物谷推荐英文摘要
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.
