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途径的激活参与细胞生长，抑制凋亡，但 茎状表型和耐药性的诱导知之甚少，对其动态控制和可塑性知之甚少。 最近的研究表明，APC/Wnt/ß-catenin和Ras-erk之间的功能性串扰 途径在结直肠癌（CRC）进展和转移中起重要作用。我们的初始数据 建议MEK/ERK途径和随后的Wnt/ß-catenin信号通过皮带激活 （丝氨酸苏氨酸激酶受体相关蛋白）几年前我们克隆了。我们已经显示了 该表带在超过70％的CRC中进行了更新，并诱导细胞增殖，肿瘤性，自我 癌症干细胞（CSC）的更新和耐药性。我们已经观察到有条件的淘汰 小鼠的皮带减少了一般灭活的APC诱导的肠道肿瘤的数量和大小（APC 最小）。我们表明，皮带在赞助转移模型中诱导体内CRC转移。在CRC中 患者，皮带的上调与调整治疗后的生存率较差有关。相比之下， 携带正常或低皮带表达肿瘤的患者受益于治疗 在化学上的潜在作用。有趣的是，我们表明表带的表达降低会增强药物 （5-FU和奥沙利铂）诱导的细胞凋亡，并在体外和体内感觉到细胞进行化学疗法。所以， 这些体外和体内研究提供了以下概念验证，即废除CRC中的皮带信号将会 降低了肿瘤性和转移，并将CRC肿瘤感知化学疗法。我们已经有 开发了纳米载体PMBOX-PMPOY-PMEOZ，以实现皮带siRNA和5-FU-OXP-的体内代码分子 OA（油酸基序）。我们已经观察到纳米颗粒介导的皮带siRNA的递送会降低细胞 扩散，迁移和入侵。根据初步信息，我们已经制定了 假设：基于siRNA的纳米制剂将皮带的促进功能的治疗靶向将 有效治疗CRC患者以及基于5-FU和/或奥沙利铂的CRC患者的敏感 化学疗法。提出了以下特定目的：目标1：确定表带如何激活MEK/ERK 途径以及随后的结直肠癌中的Wnt/ß-catenin信号传导。 AIM 2：促进肿瘤的特征 皮带在体内的功能，并确定其在赞助的发展和发展中的作用 肠道肿瘤。 AIM 3：开发一种基于siRNA介导的皮带沉默的新型疗法 单独使用纳米颗粒（NP），并与5-FU和Oxaliptin的代码传递结合使用。 影响：AS 1）绑带抑制TGF-ß的肿瘤抑制功能； 2）它促进CSC自我 更新和耐药性； 3）皮带的上调发挥肿瘤促进作用，包括侵袭和 转移; 4）在CRC患者中，其上调对化学疗法的生存较差； 5）它引起 通过灭活的APC信号传导，活化的Wnt/ß-catenin和MEK/ERK途径通过肿瘤性。 6）它 细胞和小鼠的敲除对正常的生理功能没有影响。皮带是一个有前途且独特的 治疗靶标。因此，通过改进siRNA介导的沉默靶向皮带的第一次尝试 单独使用多功能纳米固定载体并与5-FU的代码传递结合使用策略 奥沙利铂将提供强大的翻译潜力，以开发结肠癌的治疗铅。 已证明吸烟对结肠和直肠癌有因果影响 经验丰富的男女，尤其是50岁以上。因此，这种创新和临床前的生物医学 研究有可能在退伍军人方面取得重大进展。这个项目将包括两个 BLR＆D的优先研究领域，1）与吸烟有关的冒险行为和2）妇女 退伍军人健康（RFA＃BX-19-001）。