In Vivo Pharmacodynamics of RNAi-based Cancer Therapies

基于 RNAi 的癌症疗法的体内药效学

• 批准号: 7983569
• 负责人: MARK E DAVIS
• 金额: $ 18.25万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-03 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983569
• 关键词: Affect; Apoptotic; Biological Markers; Blood; Cell Cycle Inhibition; Cell Death; Cell Line; Cells; Cellular biology; Clinic; Data; Event; Gene Targeting; Genes; Goals; Human; Lead; MAP Kinase Gene; Malignant Neoplasms; Measurement; Measures; Mediating; Melanoma Cell; Messenger RNA; Methodology; MicroRNAs; Modeling; Molecular; Molecular Target; Monitor; Mus; Mutate; Mutation; N-ras Genes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacodynamics; Proteins; RNA Interference; Serum; Signal Transduction; Small Interfering RNA; System; Techniques; Testing; Therapeutic; Time; Translations; Treatment Efficacy; Xenograft procedure; base; cancer cell; cancer therapy; cancer type; in vivo; killings; knock-down; meetings; melanoma; minimally invasive; nanoparticle; p21 N-Ras Protein; pharmacodynamic model; ras Proteins; research study; response; small hairpin RNA; targeted delivery; therapeutic target; tumor

Rapid translation from validated molecular targets in cancer to treatments that benefit patients has been hampered by difficulties in rapidly developing effective, targeted therapeutics, as many targets are not druggable by traditional medicinal chemistry approaches. We propose here to invesfigate a new methodology to accelerate the translation of understandings of molecular events in cancer cell biology into new therapies by using RNA interference-based therapeutics (targeted nanoparticle based systems are used here) combined with multi-time point blood/serum-based miRNA profiling. This strategy will be demonstrated using a previously undruggable target, the oncogenic N-Ras mutation in melanoma. We propose to evaluate the hypothesis that the integration of targeted delivery of RNA interference-based therapeutics that allow quick translation from concept to clinic with multi-time point blood/serum monitoring of cancer-specific miRNA biomarkers can rapidly lead to mechanistically verified cancer treatments with blood/serum biomarkers that can provide minimally invasive proof of function in patients. Specific Aims: 1. Demonstrate tumor targeting, N-Ras knock-down, and anti-tumor effects with systemically delivered nanoparticles carrying siRNA. 2. Demonstrate that minimally invasive, multi-time point blood/serum miRNA measurements correlate with multi-time point miRNA profiles in tumors after initiation of RNAi that inhibits the N-Ras gene product. 3. Demonstrate that systemically delivered nanoparticles carrying anti-N-Ras siRNA can provide antitumor effects and that the time course of the N-Ras gene inhibition can be monitored via blood/serum miRNA profiles

快速开发有效的靶向治疗方法的困难阻碍了从癌症中经过验证的分子靶点到使患者受益的治疗方法的快速转化，因为许多靶点不能通过传统的药物化学方法药物化。我们建议研究一种新的方法，通过使用基于RNA干扰的治疗方法（这里使用靶向纳米颗粒系统）结合多时间点血液/血清miRNA分析，加速将对癌细胞生物学分子事件的理解转化为新的治疗方法。这一策略将被证明使用以前不可药物的目标，在黑色素瘤的致癌N-Ras突变。我们建议评估这样一种假设，即基于RNA干扰的靶向递送治疗方法可以快速从概念转化为临床，同时对癌症特异性miRNA生物标志物进行多时间点血液/血清监测，可以快速导致通过血液/血清生物标志物进行机制验证的癌症治疗，从而为患者提供微创功能证明。