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：
10326352
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326352
关键词：
Address Adenovirus Vector Adenoviruses Adopted Antineoplastic Agents Apoptotic Biodistribution Biological CXCR4 gene Cancer Biology Cancer Patient Cations 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-16 Interleukin-24 Interleukin-5 Interleukins Laboratories Ligands Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic Neoplasm to the Lung MicroRNAs Modality Modeling Molecular Mus Neoplasm Metastasis Normal tissue morphology Pathology Patients Phosphorylation Phosphorylation Site Process Property Proteins 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 base 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.

有效控制肺癌仍然是导致五年生存率较差的临床挑战目前可用的疗法虽然显示出希望，但仍存在局限性，因此需要继续努力。开发新的治疗药物和全身治疗方式是治疗肺癌的必要条件。该申请重点测试改进的白介素 (IL)-24 基因非病毒疗法对于癌症。 PI 实验室通过修改野生型 IL-24 肿瘤中的磷酸化 (p) 位点进行了鉴定抑制/细胞因子基因，初步研究证明抗肿瘤活性得到改善和增强。替换野生型IL-24 cDNA中的特定磷酸化位点产生IL-24蛋白（本文中称为 IL-24mt），表现出增加的细胞内蛋白质稳定性、分泌和增强的抗肿瘤作用与野生型 IL-24 (IL-24wt) 相比，对肺癌细胞具有抑制作用。和 IL-24wt 的 PD-L1，已知这两种物质都支持肿瘤生长、耐药性和转移观察到与 Gli1 抑制剂的组合方法对肿瘤细胞生长产生更大的抑制活性。接下来，将基于 IL-24 的治疗应用于体外的迁移和侵袭。在体内，我们采用非病毒递送方法并使用基于阳离子脂质的纳米颗粒（NP）系统。 NP 修饰有肿瘤靶向配体，例如转铁蛋白 (Tf)，用于选择性地将 IL-24mt 递送至肿瘤生物分布研究表明 TfNP 优先在皮下肿瘤和肺部积累。此外，对小鼠全身施用TfNP中所含的IL-24(IL-24-TfNP)显示了转移。据我们所知，除了本文报道的我们自己的观察结果外，肺肿瘤生长明显延迟。之前没有报告证明 IL-24mt 比 IL-24wt 具有改善和增强的抗癌活性它正在测试作为肺癌的癌症治疗方法。根据我们的新发现，我们发现 IL-24mt 将表现出卓越的抗癌功效在体外和体内均优于 IL-24wt，与 Gli1 抑制剂联合使用时，其效果将进一步增强，为了检验我们的假设，我们确定了三个具体目标：目标 1. 进行生物学和分子生物学研究。 IL-24mt 的研究并证明其体外抗肿瘤活性优于 IL-24wt 目标 2. 递送 IL-24mt。包含在 TfNP 中，并证明在小鼠和人类肿瘤异种移植物中具有改善的治疗效果目标 3. 在体外进行 IL-24mt 与 Gli1 和 PDL1 抑制剂的组合研究。和体内肿瘤模型。证明 IL-24mt 相对于 IL-24wt 的功效有所提高，这将导致进一步的研究有助于临床我们的研究结果也适用于广谱人类癌症。