Inducing Chromosomal Damage Responses in Pancreatic Cancer

描述（由申请人提供）：我们和我们的合作者已经证明，与端粒的3'突出端序列互补的11-或16-碱基寡核苷酸（T-oligo）在大多数谱系的正常人细胞中诱导短暂的细胞周期停滞，但在人胰腺癌细胞以及人淋巴瘤、黑素瘤和前列腺癌中引起细胞凋亡。在初步的数据中，我们表明T-寡核苷酸增强紫杉烷类对胰腺癌细胞的活性。在体内研究中，我们还证明了IV、SC或IP给予的11-或16-mer T-寡核苷酸在人异种移植模型和侵袭性人淋巴瘤的自发鼠模型中产生显著的全身性抗肿瘤应答，而没有毒性。我们推测这些T-oligos可能为胰腺恶性肿瘤的治疗提供一种新的方法。在我们的初步研究中，我们已经证明了新的16-mer T-oligos对多种恶性人胰腺癌细胞系（代表晚期胰腺恶性肿瘤）具有显著的靶向细胞毒性。相同的寡核苷酸对培养的正常人上皮细胞没有影响。我们建议：1）证明和优化T-oligos对胰腺癌细胞的细胞毒性/细胞病变作用; 2）阐明细胞毒性的分子机制和T-oligos与化疗协同作用的能力;和3）在人胰腺癌异种移植肿瘤模型上测试T-oligos的体内抗肿瘤活性和安全性。本文提出的研究将为该方法治疗胰腺癌的临床开发提供坚实的临床前基础。公共卫生相关性：目前对晚期胰腺癌的治疗相对无效并且也相对非特异性，因为它们损伤正常组织以及恶性组织，导致与放射疗法和化学疗法相关的副作用和毒性。我们已经开发了一种新的靶向方法，使用小DNA分子治疗胰腺癌，并在初步研究中表明，这种药物对动物无毒，产生强烈的抗癌作用，并增强胰腺癌中使用的化疗药物的活性。我们提出的研究将为这种新型治疗剂的后续临床开发提供坚实的临床前基础。

DESCRIPTION (provided by applicant): We and our collaborators have demonstrated that 11- or 16-base oligonucleotides complementary to the 3' overhang sequence of the telomere (T-oligos) induce transient cell cycle arrest in normal human cells of most lineages, but cause apoptosis in human pancreatic cancer cells, as well as human lymphoma, melanoma, and prostate carcinomas. In preliminary data, we show that the T-oligos enhance the activity of taxanes on pancreatic carcinoma cells. In in vivo studies, we have also demonstrated that 11- or 16-mer T-oligos given IV, SC or IP generate dramatic systemic anti-tumor responses, without toxicity, in human xenograft models, and in a spontaneous murine model of aggressive human lymphoma. We hypothesize that these T-oligos may offer a new approach to treatment of pancreatic malignancies. We have demonstrated dramatic targeted cytotoxicity by the new 16-mer T-oligos towards multiple malignant human pancreatic cancer cell lines, representative of advanced pancreatic malignancies, in our preliminary studies. The same oligos had no effects on normal human epithelial cells in culture. We propose to: 1) demonstrate and optimize the cytotoxic / cytopathic effects of T-oligos on pancreatic cancer cells; 2) elucidate the molecular mechanisms of cytotoxicity and the ability of the T-oligos to synergize with chemotherapy; and 3) test the anti-tumor activity and safety of T-oligos in vivo on human pancreatic cancer xenograft tumor models. The studies proposed here will provide a solid preclinical basis for the clinical development of this approach for the treatment of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Current treatments for advanced pancreatic cancer are relatively ineffective and also relatively non-specific, in that they damage normal tissues as well as malignant tissues, leading to the side-effects and toxicities associated with radiation therapy and chemotherapy. We have developed a new targeted approach to the treatment of pancreatic cancer using a small DNA molecule, and have shown in preliminary studies that this agent is non-toxic to animals and produces a strong anti-cancer effect, and enhances the activity of the chemotherapeutic agents used in pancreatic cancer. We propose studies that will provide a solid preclinical basis for the subsequent clinical development of this novel therapeutic.