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An improved IL-24 gene-based therapeutic for cancer

改进的基于 IL-24 基因的癌症疗法

基本信息

批准号：
10544003
负责人：
Rajagopal Ramesh
金额：
$ 34.39万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544003
关键词：
Address Adenovirus Vector Adenoviruses Adopted Angiogenesis Inhibitors Antineoplastic Agents Apoptotic Biodistribution Biological CXCR4 gene Cancer Biology Cancer Patient Cell Survival Clinic Clinical Complementary DNA Cytokine Gene Diagnosis Drug resistance Excision Exhibits Gene Delivery Genes Goals Human IL24 gene In Vitro Individual Innovative Therapy Interleukin-24 Interleukins Invaded Laboratories Ligands Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic Neoplasm to the Lung Modality Modeling Molecular Mus Neoplasm Metastasis Normal tissue morphology Pathology Patients Phosphorylation Phosphorylation Site Process Property Proteins RNA Reporting Research Personnel Signal Transduction Site Survival Rate System TFRC gene Testing Therapeutic Therapeutic Agents Time Toxic effect Transferrin Treatment Efficacy Tumor Suppressor Proteins antagonist anti-cancer anticancer activity cancer therapy cell growth chemokine receptor clinical translation clinically relevant combinatorial delivery vehicle effective therapy improved in vivo inhibitor innovation interest lipid nanoparticle lung cancer cell migration multidisciplinary nanoparticle neoplastic cell novel novel therapeutics preclinical study programmed cell death ligand 1 research clinical testing statistics subcutaneous therapeutic gene tumor tumor growth tumor xenograft

项目摘要

Effective control of lung cancer continues to remain a clinical challenge resulting in poor five-year survival rate. Currently available therapies while showing promise have had limitations. Therefore, continued efforts for developing new therapeutic agents and systemic treatment modalities are warranted for treating lung cancer. This application addresses focuses on testing an improved interleukin (IL)-24 gene-based non-viral therapeutic for cancer. The PI’s laboratory has identified by modifying a phosphorylation (p) site in the wild-type IL-24 tumor suppressor/cytokine gene, the antitumor activity is improved and enhanced. Preliminary studies demonstrated replacement of a specific phosphorylation site in the wild-type IL-24 cDNA produced IL-24 protein (herein referred to as IL-24mt) that exhibited increased intracellular protein stability, secretion, and enhanced antitumor activity against lung cancer cells when compared to wild-type IL-24 (IL-24wt). Furthermore, inhibition of Gli1, and PD-L1 by IL-24wt both of which are known to support tumor growth, drug resistance, and metastasis was observed. Combinatorial approach with Gli1 inhibitor produced greater inhibitory activity on tumor cell growth, migration and invasion compared to individual treatments in vitro. Next, for applying IL-24-based therapeutic in vivo we adopted a non-viral delivery approach and used a cationic lipid-based nanoparticle (NP) system. The NP was decorated with a tumor-targeted ligand such as transferrin (Tf) for selective delivery of IL-24mt to tumor depots. Bio-distribution studies demonstrated TfNP preferentially accumulated in subcutaneous tumor and lung metastasis. Further, systemic administration of IL-24 contained in TfNP (IL-24-TfNP) in mice demonstrated a marked delay in lung tumor growth. To our knowledge, apart from our own observation reported herein, there are no prior reports demonstrating IL-24mt exhibited improved and enhanced anticancer activity over IL-24wt and it’s testing as a cancer therapeutic for lung cancer. On the basis of our new findings, we hypothesize that IL-24mt will demonstrate superior anticancer efficacy over IL-24wt both in vitro and in vivo that will be further enhanced when combined with inhibitors against Gli1, or PD-L1. To test our hypothesis we have identified three specific aims: Aim 1. Conduct biologic and molecular studies of IL-24mt and demonstrate its superior antitumor activity over IL-24wt in vitro. Aim 2. Deliver IL-24mt contained in TfNP and demonstrate the improved therapeutic efficacy in murine and human tumor xenograft tumor models. Aim 3. Conduct IL-24mt combinatorial studies with inhibitors against Gli1, and PDL1 in in vitro and in vivo tumor models. Demonstrating improved efficacy for IL-24mt over IL-24wt will lead to advanced studies aiding in clinical translation. Our findings will also have application against broad-spectrum of human cancers.

肺癌的有效控制仍然是一项临床挑战，导致五年生存率很低。费率。目前可用的治疗方法虽然显示出希望，但也有局限性。因此，继续努力为开发新的治疗药物和系统的治疗方式是治疗肺癌的必要手段。这项申请的重点是测试一种改进的基于白细胞介素24基因的非病毒疗法治疗癌症。 PI的实验室已经通过修改野生型IL-24肿瘤中的磷酸化(P)位点进行了鉴定抑制子/细胞因子基因，抗肿瘤活性得到改善和增强。初步研究表明替换野生型IL-24基因中特定的磷酸化位点产生IL-24蛋白(在此被称为IL-24mt)，表现出细胞内蛋白质的稳定性、分泌性和增强的抗肿瘤作用与野生型IL-24(IL-24wt)相比，对肺癌细胞的活性。此外，对Gli1的抑制，和通过IL-24wt的PD-L1，这两个已知都支持肿瘤的生长、耐药和转移观察到的。与Gli1抑制剂联合使用对肿瘤细胞生长产生更大的抑制活性，在体外与单独处理相比，迁移和入侵。接下来，将以IL-24为基础的治疗应用于体内，我们采用了非病毒递送方法，并使用了阳离子脂基纳米粒(NP)系统。这个用肿瘤靶向配体如转铁蛋白(Tf)修饰NP，以选择性地将IL-24mt输送到肿瘤仓库。生物分布研究表明，TfNP优先聚集在皮下肿瘤和肺组织中转移。此外，TfNP中包含的IL-24(IL-24-TfNP)在小鼠体内全身给药显示出肺癌生长明显延缓。据我们所知，除了我们在这里报道的自己的观察之外，还有以前没有报告表明IL-24mt比IL-24wt显示出更好的抗癌活性吗？它正在作为肺癌的癌症治疗药物进行测试。根据我们的新发现，我们假设IL-24mt将显示出优越的抗癌效果。在体外和体内均超过IL-24wt，与Gli1抑制剂联合使用时将进一步增强，或PD-L1。为了验证我们的假设，我们确定了三个具体目标：目标1.进行生物学和分子对IL-24mt的体外抗肿瘤活性研究表明，其抗肿瘤活性优于IL-24wt。目标2.交付IL-24mt 包含在TfNP中，并证明了对小鼠和人肿瘤移植瘤的改善治疗效果肿瘤模型。目的3.体外进行IL-24mt与抗Gli1和PDL1抑制剂的联合研究和体内肿瘤模型。证明IL-24mt的疗效优于IL-24wt将导致有助于临床的进一步研究翻译。我们的发现也将适用于广谱的人类癌症。