Preclinical Validation of U1 Adaptors for Suppression of KRAS in Pancreatic Cancer

描述(申请人提供)：胰腺癌(PC)仍然是最难治疗的癌症之一，转移倾向高，对现有治疗方法反应差，生存时间短，几十年来没有显著改善。大多数PC患者将在确诊后的第一年内死亡，6%的患者将存活五年。目前，美国每年报告的PC新增病例超过40,000例，死亡17,000人，预计在几年内PC将成为导致癌症死亡的第三大原因。在不到20%的PC患者中，手术切除肿瘤是可能的，化疗通常只能延长几个月的生存时间。人们普遍认为，KRAS基因的激活突变是胰腺癌的关键驱动因素，然而，尽管经过数十年的努力，KRAS蛋白已被证明对小分子药物治疗无效。研究这一应用的两位研究人员，冈德森博士和戈拉茨尼亚克博士，发明了一种名为U1适配器的新基因沉默技术。在一项大型概念验证研究中，针对bcl2癌基因的U1接头最近被证明能有效地抑制小鼠人黑色素瘤移植瘤的生长，而没有明显的毒性，当以低剂量(0.034 mg/kg)每周两次给药时。与前几代基因沉默寡核苷酸相比，U1接头在体内高度稳定，易于选择性地输送到疾病细胞中，与它们新的作用机制一致。我们已经与更多的研究人员合作，他们带来了胰腺癌(Carpio博士)和癌症分子遗传学(Brenneman博士)方面的专业知识，在胰腺癌小鼠模型中开发和验证抗KRAS U1适配器。靶向治疗和个性化/精确医学的时代已经到来，患者基因组数据现在正在推动新的基因靶向治疗的发展。这是一个U1适配器技术非常适合的领域。通过合理的设计，U1接头基因沉默技术有可能快速产生有效的抗KRAS U1接头寡核苷酸，这些寡核苷酸将成为进一步开发用于人体试验的先导化合物。总而言之，我们的具体目标是：1)设计和确认针对小鼠和人类KRAS基因的活性抗KRAS适配器；(2)以KPC小鼠为模型，开发通过胰腺肿瘤间质高效递送抗KRAS U1适配器的方法；以及(3)评估现有最好的胰腺癌小鼠模型的体内疗效，特别是在小鼠KPC模型和患者来源的胰腺癌异种移植瘤中抑制肿瘤生长。我们的长期目标是开发一种革命性的胰腺癌治疗方法。该项目的成功还将使KRAS U1适配器能够应用于发生在其他部位的实体肿瘤，如肺和结肠。

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) remains one of the least treatable cancers, with high metastatic propensity, poor response to existing therapies and short survivals that have not improved substantially over several decades. Most PC patients will die within the first year after diagnosis and <6% will survive five years. Currently over 40,000 new PC cases and 17,000 deaths a year are reported in the U.S. and it is expected that within a few years PC will become the third leading cause of cancer deaths. Surgical removal of the tumor is possible in less than 20% of PC patients and chemotherapy typically offers only several months of extended survival. It is widely recognized that activating mutations of the KRAS gene are key drivers of pancreatic cancer, yet the KRAS protein has proved refractory to drugging by small-molecule approaches, despite decades of effort. Two investigators on this application, Drs. Gunderson and Goraczniak, invented a new gene silencing technology called U1 Adaptors. In a large proof-of-concept study, U1 Adaptors targeting the BCL2 oncogene were recently shown to effectively suppress growth of human melanoma xenograft tumors in mice, without observable toxicity, when administered twice weekly at low dose (0.034 mg/kg). In comparison to previous generations of gene silencing oligonucleotides, U1 Adaptors are highly stable in vivo and easy to deliver selectively into diseased cells, consistent with their novel mechanism of action. We have teamed with additional investigators who bring expertise in pancreatic cancer (Dr. Carpizo) and cancer molecular genetics (Dr. Brenneman) to develop and validate anti-KRAS U1 Adaptors in mouse models of pancreatic cancer. The era of targeted therapies and personalized/precision medicine is upon us, and patient genomic data is now driving the development of novel gene-targeted therapeutics. This an arena for which U1 Adaptor technology is highly suited. U1 Adaptor gene silencing technology, through rationale design, has potential to rapidly produce potent anti-KRAS U1 Adaptor oligonucleotides that will be lead compounds for further development towards human trials. In broad terms, our specific aims are: 1) design and confirm active anti- KRAS Adaptors targeting the mouse and human KRAS genes; (2) to develop methods for highly efficient delivery of the anti-KRAS U1 Adaptors through the stroma of pancreatic tumors, using the KPC mouse as a model, and (3) to assess in-vivo efficacy in the best available mouse models of pancreatic cancer, specifically to suppress tumor growth in the mouse KPC model and in patient-derived xenografts of pancreatic cancer. Our long term goal is to develop a revolutionary pancreatic cancer therapeutic. Success in this project will also enable application of KRAS U1 Adaptors to solid tumors arising in other sites such as lung and colon.