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

描述（由申请人提供）：胰腺癌（PC）仍然是最难治疗的癌症之一，具有高转移倾向，对现有疗法的反应差，几十年来没有实质性改善的生存期短。大多数PC患者将在诊断后的第一年内死亡，不到6%的患者能存活5年。目前，美国每年有超过40,000例新的PC病例和17,000例死亡，预计几年内PC将成为癌症死亡的第三大原因。手术切除肿瘤在不到20%的PC患者中是可能的，化疗通常只能提供几个月的延长生存期。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，尽管几十年的努力，KRAS蛋白已被证明难以通过小分子方法进行药物治疗。这一申请的两位调查员，dr。Gunderson和goracniak发明了一种新的基因沉默技术，称为U1适配器。在一项大型概念验证研究中，最近显示，针对BCL2癌基因的U1适配器在每周两次低剂量（0.034 mg/kg）给药时，可有效抑制小鼠人类黑色素瘤异种移植肿瘤的生长，无明显毒性。与前几代基因沉默寡核苷酸相比，U1适配器在体内高度稳定，易于选择性地递送到病变细胞中，与其新的作用机制一致。我们已经与其他研究人员合作，他们带来了胰腺癌（Carpizo博士）和癌症分子遗传学（Brenneman博士）的专业知识，以开发和验证胰腺癌小鼠模型中的抗kras U1适配器。靶向治疗和个性化/精准医疗的时代即将到来，患者基因组数据正在推动新型基因靶向治疗的发展。这是U1适配器技术非常适合的领域。U1适配器基因沉默技术，通过基本原理设计，有可能快速产生有效的抗kras U1适配器寡核苷酸，这将是进一步开发用于人体试验的先导化合物。从广义上讲，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，研究通过胰腺肿瘤基质高效递送抗kras U1适配器的方法；(3)评估现有最佳小鼠胰腺癌模型的体内疗效，特别是抑制小鼠KPC模型和患者来源的胰腺癌异种移植物的肿瘤生长。我们的长期目标是开发一种革命性的胰腺癌治疗方法。该项目的成功也将使KRAS U1适配器应用于其他部位的实体瘤，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.