Colon cancer nanotherapy targeting STRAP

针对 STRAP 的结肠癌纳米疗法

• 批准号: 10355415
• 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/10355415
• 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; translational potential; 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通路的激活参与了细胞的生长，抑制了细胞的凋亡， 诱导分化为茎样表型和耐药，对其动态调控和可塑性知之甚少。 最近的研究表明，APC/Wnt/ç-catenin和RAS-ERK之间的功能串扰 通路在结直肠癌的进展和转移中起着重要作用。我们的初始数据 提示STRAP激活了MEK/ERK信号通路，进而激活了Wnt/B-catenin信号通路 (丝氨酸苏氨酸激酶受体相关蛋白)，我们几年前克隆的。我们已经展示了 该条带在70%以上的癌组织中上调，并诱导细胞增殖、成瘤、自我 肿瘤干细胞(CSC)的更新和耐药性。我们观察到，有条件的淘汰赛 基因灭活APC(APC)诱导的小鼠肠道肿瘤数目和大小的减少 Min)。我们发现STRAP可以在体内自发转移模型中诱导结直肠癌转移。在CRC中 患者，辅助性治疗后，腰带上调与较差的存活率相关。相比之下， 携带正常或低条带表达的肿瘤患者从治疗中受益，表明其 在化疗耐药中的潜在作用。有趣的是，我们发现，STRAP的表达减少会增强药物的作用 (5-FU和奥沙利铂)在体外和体内诱导细胞凋亡并使细胞对化疗敏感。因此， 这些体外和体内研究提供了概念验证，即在结直肠癌中取消STRAP信号将 减少肿瘤的致瘤性和转移，并将使结直肠癌对化疗敏感。我们已经有了 研制了一种纳米载体PMBOx-PMPOy-PMEOz，实现了siRNA和5-FU-Oxp的体内共递送 油酸基序(OA)。我们观察到纳米颗粒介导的siRNA递送使细胞减少。 扩散、迁徙和入侵。根据初步资料，我们已制订 假设：以siRNA为基础的纳米制剂对STRAP促肿瘤功能的治疗靶向将 5-FU和/或奥沙利铂对结直肠癌患者有效治疗和增敏 化疗。提出了以下具体目标：目标1：确定STRAP如何激活MEK/ERK 途径和随后的Wnt/？-catenin信号转导在结直肠癌。目标2：表征促肿瘤作用 皮带在体内的功能及其在自发性发育进展中的作用 肠道肿瘤。目的3：开发一种基于siRNA介导的STRAP沉默的新疗法 纳米粒(NPs)单独以及与5-FU和奥沙利铂联合递送。 影响：1)STRAP抑制转化生长因子的抑瘤作用；2)促进CSC自身 更新与耐药；3)条带上调对肿瘤的促进作用，包括侵袭和 转移；4)在结直肠癌患者中表达上调导致化疗后生存率下降；5)诱导 通过失活的APC信号、激活的Wnt/ç-catenin和MEK/ERK通路的致瘤性；6)ITS 在细胞和小鼠中的基因敲除对正常的生理功能没有影响；STRAP是一种有前途的独特的 治疗靶点。因此，首次尝试通过改进的siRNA介导的沉默来靶向STRAP 单独使用多功能纳米胶束载体并联合5-FU和5-FU联合传递的策略 奥沙利铂将提供强大的翻译潜力来开发结肠癌的治疗前线索。 吸烟已被证明对结肠癌和直肠癌有很大比例的因果影响 老兵，尤指50岁以上的老兵。因此，这一创新的临床前生物医学 这项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和2)女性 退伍军人健康(RFA#BX-19-001)。