Telomere homolog oligonucleotides for cancer therapy

用于癌症治疗的端粒同源寡核苷酸

• 批准号: 6788416
• 负责人: BARBARA A GILCHREST
• 金额: $ 21.25万
• 依托单位: SEMACO, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-05 至 2005-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788416
• 关键词: DNA damage; SCID mouse; apoptosis; biotherapeutic agent; breast neoplasms; cell line; cell senescence; cytotoxicity; disease /disorder model; laboratory mouse; melanoma; metastasis; neoplasm /cancer therapy; neoplastic cell; nonhuman therapy evaluation; nucleic acid repetitive sequence; oligonucleotides; telomere; terminal nick end labeling; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Cancer is a devastating group of diseases, among the most common causes of death for Americans. Current therapies for advanced disease are highly toxic and all too often ineffective. Our group has recently demonstrated a powerful innate inducible ability of human cells to recognize and respond to damaged DNA, a characteristic of cancer cells. Moreover, we have shown that DNA fragments homologous to the telomere 3' strand (tandem repeats of TTAGGG) activate the same protective DNA damage responses, presumably by mimicking the physiologic DNA damage signal of telomere loop disruption that exposes the 3' overhang. The telomere-homologous oligonucleotides (T-oligos) induce and activate various DNA damage response and tumor suppressor pathways in cells, including those mediated by ATM, p53, p73, p95/Nbs-1, BRACA1, E2F1 and p16. In normal cells, the T-oligos induce transient cell cycle arrest and promote differentiated behaviors normally evoked by DNA damage, such as enhanced melanogenesis (tanning) in melanocytes and immunomodulatory cytokine release in keratinocytes. However, compared to normal cells, malignant cells have exaggerated responses that lead either to apoptosis or a permanently non-dividing state (senescence), or to a combination of these responses, depending on cell type. Working with malignant human cell lines of multiple lineages, we have shown all to be dramatically responsive to T-oligos in vitro. Using a SCID mouse model for human melanoma, we demonstrated that 48 hours pretreatment of the aggressive MM-AN cell line with T-oligo reduces its local and metastatic growth potential by 85-95% and leads to differentiation of remaining melanoma cells. We have further shown dramatic regression or disappearance of previously untreated established MM-AN flank melanoma nodules in SCID mice following either intralesional, intravenous, or intraperitoneal administration of T-oligos. Patents protecting the use of T-oligos as a cancer therapy are pending and have been licensed by Boston University to SemaCo, Inc, to encourage their commercialization. The goal of this STTR grant application is to confirm and extend our previous in vitro data, to select an optimal T-oligo for clinical testing, to perform dosing ranging (safety) studies in mice, and then to characterize the therapeutic effects of T-oligos in mouse models of human melanoma and breast carcinoma, using GLP protocols to generate data on which an Investigational New Drug (IND) application can be based.

描述（由申请人提供）：癌症是一组毁灭性的疾病，是美国人最常见的死亡原因之一。 目前治疗晚期疾病的疗法毒性很大，而且常常无效。我们的研究小组最近证明了人类细胞具有强大的先天诱导能力，能够识别受损的 DNA 并对其做出反应，这是癌细胞的一个特征。此外，我们还表明，与端粒 3' 链同源的 DNA 片段（TTAGGG 的串联重复）会激活相同的保护性 DNA 损伤反应，大概是通过模仿端粒环破坏暴露 3' 突出端的生理性 DNA 损伤信号。 端粒同源寡核苷酸 (T-oligos) 诱导并激活细胞中的各种 DNA 损伤反应和肿瘤抑制途径，包括由 ATM、p53、p73、p95/Nbs-1、BRACA1、E2F1 和 p16 介导的途径。在正常细胞中，T-寡核苷酸会诱导短暂的细胞周期停滞，并促进通常由 DNA 损伤引起的分化行为，例如黑素细胞中黑素生成（晒黑）的增强和角质形成细胞中免疫调节细胞因子的释放。然而，与正常细胞相比，恶性细胞的反应过度，导致细胞凋亡或永久不分裂状态（衰老），或导致这些反应的组合，具体取决于细胞类型。通过对多个谱系的恶性人类细胞系进行研究，我们发现所有细胞系在体外都对 T-oligos 具有显着的反应。 使用人类黑色素瘤的 SCID 小鼠模型，我们证明，用 T-oligo 对侵袭性 MM-AN 细胞系进行 48 小时预处理，可使其局部和转移生长潜力降低 85-95%，并导致剩余黑色素瘤细胞的分化。我们进一步显示，在 SCID 小鼠中，病灶内、静脉内或腹膜内施用 T-oligos 后，先前未经治疗的 MM-AN 侧腹黑色素瘤结节显着消退或消失。保护 T-oligos 作为癌症疗法的使用的专利正在申请中，并已由波士顿大学授权给 SemaCo, Inc，以鼓励其商业化。本次 STTR 拨款申请的目的是确认和扩展我们之前的体外数据，选择最佳的 T-oligo 进行临床测试，在小鼠中进行剂量范围（安全性）研究，然后表征 T-oligo 的治疗效果。在人类黑色素瘤和乳腺癌的小鼠模型中使用寡核苷酸，使用 GLP 协议生成研究性新药 (IND) 申请所依据的数据。