Colon cancer nanotherapy targeting STRAP

针对 STRAP 的结肠癌纳米疗法

• 批准号: 10016635
• 负责人: PRAN K DATTA
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016635
• 关键词: Adjuvant Therapy; Age-Years; Apoptosis; Area; Biodistribution; Biomedical Research; Cancer Etiology; Carcinoma in Situ; Cell Proliferation; Cells; Cessation of life; Chemoresistance; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Development; Disseminated Malignant Neoplasm; Drug Kinetics; Drug resistance; Epithelial; Epithelial Cells; Family member; Fluorouracil; Genetic; Health; Healthcare; Human; In Vitro; Inhibition of Apoptosis; Injections; Intestinal Neoplasms; Knock-in Mouse; Knock-out; Lipids; MEKs; Malignant Neoplasms; Mediating; Modeling; Mus; Neoplasm Metastasis; Oleic Acids; Oncogenes; Oncogenic; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Play; Polyps; Population; Proteins; Ras/Raf; Rectal Cancer; Regulation; Research; Research Priority; Risk; Risk Behaviors; Role; Signal Transduction; Signaling Protein; Small Interfering RNA; Smoking; Testing; Therapeutic; Therapeutic Effect; Transforming Growth Factor beta; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Genes; Tumor-Derived; Tumorigenicity; Up-Regulation; Veterans; Woman; Xenograft Model; base; beta catenin; cell growth; chemotherapy; colon cancer metastasis; colon cancer patients; colorectal cancer metastasis; colorectal cancer progression; conditional knockout; copolymer; human model; improved; in vivo; innovation; interest; intestinal epithelium; men; migration; military veteran; mouse model; nanocarrier; nanoformulation; nanoparticle; nanotherapy; novel; novel therapeutics; oxaliplatin; pre-clinical; protein expression; self-renewal; serine-threonine kinase receptor-associated protein; stem; stem-like cell; therapeutic target; tumor; tumor xenograft

Although activation of the Ras/Raf/MEK/ERK pathway is involved in cell growth, inhibition of apoptosis, induction in stem-like phenotype, and drug resistance, little is known about its dynamic control and plasticity. Recent studies have suggested that the functional crosstalk between APC/Wnt/ß-catenin and RAS-ERK pathways plays an important role in colorectal cancer (CRC) progression and metastasis. Our initial data suggest that the MEK/ERK pathway and subsequently Wnt/ß-catenin signaling are activated by STRAP (Serine Threonine Kinase Receptor Associated Protein) that we cloned several years ago. We have shown that STRAP is upregulated in more than 70% of CRCs and induces cell proliferation, tumorigenicity, self- renewal of cancer stem-like cells (CSC), and drug resistance. We have observed that conditional knockout of Strap in mice decreases the number and size of intestinal tumors induced by genetically inactivated APC (Apc Min). We showed that STRAP induces CRC metastasis in vivo in a spontaneous metastasis model. In CRC patients, upregulation of STRAP is associated with worse survival following adjuvant therapy. In contrast, patients carrying tumors with normal or low STRAP expression benefited from the treatment, suggesting its potential role in chemoresistance. Interestingly, we showed that reduced expression of STRAP enhances drug (5-FU and Oxaliplatin)-induced apoptosis and sensitizes cells to chemotherapy in vitro and in vivo. Therefore, these in vitro and in vivo studies provide the proof-of-concept that abrogating STRAP signaling in CRC will decrease tumorigenicity and metastasis and will sensitize CRC tumors to chemotherapy. We already have developed a nanocarrier PMBOx-PMPOy-PMEOz to achieve in vivo codelivery of STRAP siRNA and 5-FU-Oxp- OA (oleic acid motif). We have observed that nanoparticle-mediated delivery of STRAP siRNA decreases cell proliferation, migration and invasion. Based on the preliminary information, we have formulated the hypothesis: Therapeutic targeting of pro-oncogenic functions of STRAP by siRNA-based nanoformulation will be effective in treating CRC patients as well as sensitizing CRC patients with 5-FU and/or Oxaliplatin based chemotherapy. The following Specific Aims are proposed: Aim 1: Determine how STRAP activates MEK/ERK pathway and subsequently Wnt/ß-catenin signaling in colorectal cancer. Aim 2: Characterize tumor-promoting functions of STRAP in vivo and determine its role in the development and progression of spontaneous intestinal tumors. Aim 3: Develop a novel therapy that is based on siRNA-mediated silencing of STRAP using nanoparticles (NPs) alone and in combination with codelivery of 5-FU and Oxaliplatin. Impact: As 1) STRAP inhibits the tumor suppression function of TGF-ß; 2) it promotes CSC self- renewal and drug resistance; 3) upregulation of STRAP exerts tumor promoting effects including invasion and metastasis; 4) its upregulation in CRC patients contributes to worse survival with chemotherapy; 5) it induces tumorigenicity through inactivated APC signaling, activated Wnt/ß-catenin, and MEK/ERK pathways; and 6) its knockout in cells and mice have no effect on normal physiological functions; STRAP is a promising and unique therapeutic target. Therefore, this first attempt of targeting STRAP by improved siRNA-mediated silencing strategy using a multifunctional nanomicellar carrier alone and in combination with codelivery of 5-FU and Oxaliplatin will provide strong translational potential to develop pre-therapeutic leads for colon cancer. Smoking has been shown to have causal effects on colon and rectal cancers in significant percentage of veteran men and women especially over 50 years of age. Therefore, this innovative and preclinical biomedical research has the potential for significant advances in healthcare for veterans. This project will include two priority research areas of specific interest to BLR&D, 1) risky behavior related to smoking and 2) women veteran's health (RFA# BX-19-001).

尽管Ras/Raf/MEK/ERK通路的激活参与细胞生长，但细胞凋亡的抑制， 诱导茎样表型和耐药性，对其动态控制和可塑性知之甚少。 最近的研究表明，APC/Wnt/β-catenin和RAS-ERK之间的功能性串扰可能是由于它们之间的相互作用而引起的。 在结直肠癌（CRC）的进展和转移中起重要作用。我们的初始数据 提示MEK/ERK通路和随后的Wnt/β-连环蛋白信号被STRAP激活 （丝氨酸苏氨酸激酶受体相关蛋白），我们几年前克隆的。我们已经表明 STRAP在超过70%的CRCs中上调，并诱导细胞增殖、致瘤性、自身免疫性和免疫抑制性。 癌症干细胞样细胞（CSC）的更新和耐药性。我们已经观察到，条件性敲除 Strap可减少由基因失活APC（Apc）诱导的小鼠肠道肿瘤的数量和大小 Min）。我们发现，在自发转移模型中，STRAP在体内诱导CRC转移。在CRC 在患者中，STRAP的上调与辅助治疗后较差的生存率相关。与此相反， 携带STRAP表达正常或低表达肿瘤的患者从治疗中获益，这表明其 在化学抗性中的潜在作用。有趣的是，我们发现减少STRAP的表达可以增强药物治疗效果。 (5-FU和奥沙利铂）诱导的细胞凋亡并使细胞对体外和体内化疗敏感。因此，我们认为， 这些体外和体内研究提供了概念验证，即消除CRC中的STRAP信号传导将 降低致瘤性和转移性，并使CRC肿瘤对化疗敏感。我们已经有 开发了一种纳米载体PMBOx-PMPOy-PMEOz，以实现STRAP siRNA和5-FU-Oxp的体内共递送。 OA（油酸基序）。我们已经观察到，纳米颗粒介导的STRAP siRNA的递送减少了细胞凋亡。 扩散、迁移和入侵。根据初步资料，我们制订了 假设：通过基于siRNA纳米制剂对STRAP的原癌功能的治疗靶向将 有效治疗CRC患者，并使CRC患者对基于5-FU和/或奥沙利铂的药物敏感 化疗目的1：确定STRAP如何激活MEK/ERK 途径和随后的Wnt/β-连环蛋白信号传导。目的2：表征肿瘤促进 在体内的STRAP功能，并确定其在自发性的发展和进展中的作用， 肠道肿瘤目的3：开发一种基于siRNA介导的STRAP沉默的新疗法， 单独的纳米颗粒（NP）和与5-FU和奥沙利铂的共递送组合。 影响：由于1）STRAP抑制TGF-β 1的肿瘤抑制功能; 2）它促进CSC自我调节， 更新和耐药性; 3）STRAP的上调发挥肿瘤促进作用，包括侵袭， 转移; 4）其在CRC患者中的上调导致化疗的生存率更差; 5）其诱导 通过失活的APC信号传导、活化的Wnt/β-连环蛋白和MEK/ERK途径的致瘤性;和6）其 在细胞和小鼠中敲除对正常生理功能没有影响; STRAP是一种有前途的和独特的 治疗靶点因此，通过改进siRNA介导的沉默靶向STRAP的首次尝试， 单独使用多功能纳米胶束载体以及与5-FU和 奥沙利铂将为开发结肠癌的治疗前先导药物提供强大的转化潜力。 吸烟已被证明对结肠癌和直肠癌有因果关系， 特别是50岁以上的老兵。因此，这种创新的临床前生物医学 研究有可能在退伍军人的医疗保健方面取得重大进展。该项目将包括两个 BLR&D特别感兴趣的优先研究领域，1）与吸烟有关的危险行为，2）女性 退伍军人健康（RFA# BX-19-001）。