An improved IL-24 gene-based therapeutic for cancer

改进的基于 IL-24 基因的癌症疗法

• 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
• 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

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个临床挑战，导致五年生存率低 率目前可用的疗法虽然显示出希望，但也有局限性。因此，继续努力， 需要开发新的治疗剂和全身治疗方式来治疗肺癌。 本申请致力于测试一种改进的基于白细胞介素（IL）-24基因的非病毒治疗药物， 治疗癌症 PI的实验室通过修饰野生型IL-24肿瘤中的磷酸化（p）位点， 抑制因子/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 cDNA中的特异性磷酸化位点产生IL-24蛋白（本文 称为IL-24 mt），其表现出增加的细胞内蛋白稳定性、分泌和增强的抗肿瘤活性。 与野生型IL-24（IL-24 wt）相比，此外，抑制Gli 1， 和PD-L1通过IL-24 wt，这两者都已知支持肿瘤生长、耐药性和转移， 观察与Gli 1抑制剂的组合方法对肿瘤细胞生长产生更大的抑制活性， 与体外单独处理相比，迁移和侵袭。接下来，为了将基于IL-24的治疗剂应用于 在体内，我们采用了非病毒递送方法并使用了阳离子脂质基纳米颗粒（NP）系统。的 用肿瘤靶向配体如转铁蛋白（Tf）修饰NP，以选择性地将IL-24 mt递送至肿瘤 仓库。生物分布研究表明TfNP优先在皮下肿瘤和肺中蓄积 转移此外，在小鼠中全身施用包含在TfNP中的IL-24（IL-24-TfNP）证明了对小鼠的免疫应答。 肺肿瘤生长明显延迟。据我们所知，除了我们自己的观察报告， 没有先前的报道表明IL-24 mt表现出比IL-24 wt改善和增强的抗癌活性 它正在测试作为肺癌的癌症治疗剂。 基于我们的新发现，我们假设IL-24 mt将显示出上级抗癌功效 当与针对Gli 1的抑制剂组合时，其在体外和体内均超过IL-24 wt， 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。进行生物和分子 IL-24 mt的研究，并证明其在体外比IL-24 wt具有上级抗肿瘤活性。目标2.交付IL-24 mt 并在鼠和人肿瘤异种移植物中显示出改善的治疗功效 肿瘤模型目标3.在体外进行IL-24 mt与Gli 1和PDL 1抑制剂的组合研究 和体内肿瘤模型。 证明IL-24 mt相对于IL-24 wt的改善的功效将导致有助于临床应用的高级研究。 翻译.我们的研究结果也将应用于广谱的人类癌症。