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）：癌症是一群毁灭性的疾病，是美国人最常见的死亡原因。 当前对晚期疾病的疗法是有毒的，而且常常无效。我们的小组最近证明了人类细胞具有强大的先天诱导能力，可以识别并响应受损的DNA，这是癌细胞的特征。此外，我们已经表明，与端粒3'链同源的DNA片段（ttaggg的串联重复序列）激活了相同的保护性DNA损伤响应，大概是通过模仿端粒循环中断的生理DNA DNA损伤信号，从而暴露了3'悬垂物。 端粒同源性寡核苷酸（T-橄榄核）诱导并激活各种DNA损伤反应和细胞中的肿瘤抑制途径，包括由ATM，p53，p73，p73，p73，p95/nbs-1，braca1，braca1，e2f1和p16介导的细胞。在正常细胞中，T-Oligos诱导瞬时细胞周期停滞并促进通常通过DNA损伤引起的分化行为，例如黑素细胞中的黑色素生成（TANNING）和角质形成细胞中的免疫调节细胞因子释放。然而，与正常细胞相比，恶性细胞的反应夸大了导致细胞凋亡或永久性状态（衰老）或这些反应的组合，具体取决于细胞类型。使用多个谱系的恶性人类细胞系，我们已经证明所有这些都对T-Oligos的体外反应很大。 使用SCID小鼠模型用于人类黑色素瘤，我们证明了48小时对具有T-Oligo的侵袭性MM-AN细胞系预处理，将其局部和转移性生长潜力降低了85-95％，并导致剩余黑色素瘤细胞的分化。我们进一步显示了先前未经治疗的MM-AN侧面黑色素瘤结节的急剧回归或消失，这是在T-Oligos的遗传性，静脉内或腹膜内给药后，在SCID小鼠中。保护使用T-Oligos作为癌症疗法的专利正在待处理，并已获得波士顿大学获得Semaco，Inc的许可，以鼓励其商业化。 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.