Inducing Chromosomal Damage Responses in Pancreatic Cancer

描述(申请人提供)：我们和我们的合作者已经证明，与端粒3‘悬垂序列互补的11或16碱基寡核苷酸(T-寡核苷酸)在大多数谱系的正常人类细胞中诱导短暂的细胞周期停滞，但在人类胰腺癌细胞以及人类淋巴瘤、黑色素瘤和前列腺癌中引起凋亡。在初步数据中，我们发现T-寡糖增强了紫杉烷类化合物对胰腺癌细胞的活性。在体内研究中，我们还证明了给予IV、SC或IP的11-或16-聚T-寡核苷酸在人类异种移植模型和自发性侵袭性人类淋巴瘤模型中产生了显著的全身抗肿瘤反应，而没有毒性。我们推测，这些T-寡核苷酸可能为胰腺恶性肿瘤的治疗提供了一种新的方法。在我们的初步研究中，我们已经证明了新的16-聚T-寡核苷酸对多种恶性的人胰腺癌细胞株具有显著的靶向性细胞毒作用，这些细胞系是晚期胰腺恶性肿瘤的代表。同样的寡核苷酸对正常培养的人上皮细胞没有影响。我们建议：1)验证和优化T-寡核苷酸对胰腺癌细胞的细胞毒性/细胞病变效应；2)阐明T-寡核苷酸的细胞毒性及其与化疗协同作用的分子机制；3)在人胰腺癌异种移植瘤模型上检测T-寡核苷酸的体内抗肿瘤活性和安全性。本文提出的研究将为这种方法治疗胰腺癌的临床发展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，也相对非特异性，因为它们损害正常组织和恶性组织，导致与放射治疗和化疗相关的副作用和毒副作用。我们开发了一种利用小DNA分子靶向治疗胰腺癌的新方法，初步研究表明，这种药物对动物无毒，具有很强的抗癌作用，并提高了胰腺癌化疗药物的活性。我们提出的研究将为这种新疗法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.