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临床挑战，导致五年生存率差速度。目前可用的疗法表现出承诺有局限性。因此，继续努力有必要开发新的治疗剂和全身治疗方法来治疗肺癌。该申请的重点是测试改进的白介素（IL）-24基于基因的非病毒疗法用于癌症。 PI的实验室通过修改野生型IL-24肿瘤中的磷酸化（P）位点来识别抑制剂/细胞因子基因，抗肿瘤活性得到改善和增强。初步研究表明在野生型IL-24 cDNA中替换特定的磷酸化位点产生的IL-24蛋白（此处称为IL-24MT），暴露于增加细胞内蛋白质稳定性，分泌和增强的抗抗毒液与野生型IL-24（IL-24WT）相比，对肺癌细胞的活性。此外，抑制Gli1， IL-24WT和PD-L1众所周知，这两个都支持肿瘤生长，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，与体外治疗相比，迁移和入侵。接下来，用于应用IL-24基于IL-24的治疗方法体内我们采用了一种非病毒递送方法，并使用了基于阳离子脂质的纳米粒子（NP）系统。这 NP用靶向肿瘤的配体（例如转铁蛋白（TF））进行装饰，以选择性递送IL-24MT向肿瘤沉积物。生物分布研究表明，TFNP优选地累积在皮下肿瘤和肺中转移。此外，在小鼠中包含TFNP（IL-24-TFNP）中的IL-24的全身给药表现出A 肺部肿瘤生长的明显延迟。据我们所知，除了我们在此报告的观察外，没有证明IL-24MT暴露的IL-24MT改善和增强的IL-24WT抗癌活性的报告它是作为肺癌的癌症疗法的测试。根据我们的新发现，我们假设IL-24MT将证明较高的抗癌效率在体外和体内的IL-24WT上，当与Gli1抑制剂结合使用时，它将进一步增强或PD-L1。为了检验我们的假设，我们确定了三个特定目的：目标1。进行生物学和分子 IL-24MT的研究表明，其在体外优于IL-24WT。目标2。交付IL-24MT 包含在TFNP中，并证明了鼠和人类肿瘤特征的治疗效率提高肿瘤模型。 AIM 3。用抑制剂对GLI1进行IL-24MT组合研究，并在体外进行PDL1 和体内肿瘤模型。证明IL-24MT超过IL-24WT的提高效率将导致有助于临床的高级研究翻译。我们的发现还将针对人类癌症的广泛谱。