PLK1 and EGFR targeted nanoconstruct as a monotherapy and a radiation sensitizer for lung cancer

PLK1 和 EGFR 靶向纳米结构作为肺癌的单一疗法和放射增敏剂

基本信息

批准号：
10766651
负责人：
Worapol Ngamcherdtrakul
金额：
$ 40万
依托单位：
PDX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10766651
关键词：
A549 Abscopal effect Accounting Antibodies Apoptotic Benchmarking Bilateral Biodistribution Biological Availability Biological Markers Biomedical Engineering Blood Blood Chemical Analysis Blood Circulation Body Weight CD8-Positive T-Lymphocytes Cancer Etiology Cancer Patient Cancer cell line Cell Cycle Arrest Cell Death Cell Line Cell Survival Cell division Cells Cessation of life Cetuximab Circulation Cisplatin Clinic Clinical Trials Collaborations Colon Carcinoma DNA Repair Data Dose Drug Kinetics Epidermal Growth Factor Receptor Exhibits FDA approved G2/M Arrest Genes Half-Life Health Hematology Histology Home Homing Immune Immunohistochemistry In Vitro Investigational New Drug Application Laboratories Lead Lipids Liver Luciferases Lung Lung Neoplasms M cell Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Methods Mitosis Modeling Molecular Target Monitor Monkeys Mus Names Non-Small-Cell Lung Carcinoma Normal Cell Organ Outcome PLK1 gene Particle Size Patients Pharmaceutical Preparations Pharmacologic Substance Phase Positioning Attribute Radiation Radiation induced damage Radiation therapy Radiation-Sensitizing Agents Radiosensitization Renal function Resistance Reverse Transcriptase Polymerase Chain Reaction Role Safety Saline Small Business Innovation Research Grant Small Interfering RNA Solid Neoplasm Specificity Surface Therapeutic Therapeutic Agents Therapeutic Index Toxic effect Toxicology Tumor Burden cancer cell cancer therapy cell killing chemotherapy clinically relevant cost humanized mouse in vivo inhibitor knock-down lead candidate liver function lung cancer cell malignant breast neoplasm manufacture molecular targeted therapies mortality mouse model mutational status nano nanoparticle nanoparticle delivery nanotherapeutic new therapeutic target nonhuman primate novel novel therapeutics overexpression panitumumab particle patient derived xenograft model personalized medicine precision medicine prototype siRNA delivery small molecule inhibitor success synergism targeted agent targeted delivery targeted treatment therapy outcome tumor tumor growth uptake

项目摘要

Lung cancer is the leading cause of cancer mortality, exceeding deaths from colon, breast, and prostate cancers combined. Resistance to chemo and targeted therapy is very common. Radiation therapy (RT) remains a key treatment in about 60% of lung cancer patients. We seek to develop a novel nanotherapeutic (termed PETTRA) that homes to EGFR+ lung tumors and delivers siRNA against Polo-like kinase 1 (siPLK1). EGFR is an ideal homing target since it is routinely profiled; and is overexpressed in 50% of lung cancer patients. PLK1 is among the strongest cancer targets due to its crucial roles in cell division and DNA repair, and inhibiting PLK1 leads to G2/M cell cycle arrest and apoptotic death. Cells in G2/M arrest are also most sensitive to radiation. Thus, PETTRA is hypothesized to be effective as a monotherapy and as a radiation sensitizer for lung cancer. Or prototype PETTRA has demonstrated good safety and efficacy for such dual proposes in cells and in mice. Herein, we propose to further optimize the material to enhance the efficacy and safety. While lipid-based particles have been effective at delivering siRNAs to the liver with 4 FDA approved drugs in the past few years, no platform has been successful in solid tumors yet. We have solved the limitations of nanoparticle delivery and achieved long circulation half-life (e.g., 25 hrs in monkeys), 10-fold increased siRNA accumulation in tumors, specific delivery to target cells (by 5 to 8- fold over normal cells), excellent PLK1 gene knock-down (e.g., by 84%), and tumor inhibition (e.g., by 90%) in mouse models. Tech-transfer for GMP manufacturing of our nanoparticles has been accomplished. Phase I: In Aim 1, we will optimize (by evaluating various EGFR antibody drugs (Ab) and increasing the loading of EGFR antibody and siPLK1 by at least 3-fold) and screen for the lead constructs that yield hydrodynamic size <120 nm, 75% gene knockdown, 7-fold greater uptake to EGFR+ over EGFR- cells, >70% cell death in EGFR+ lung cancer cells, and safety to normal cells (<15% death). Proof of concept efficacy and safety of the lead nanoconstruct will be performed in metastatic lung tumor mice. Phase II: In Aim 2, efficacy of the optimal PETTRA will be assessed, both alone and in combination with RT. Clinically relevant orthotopic NSCLC mouse models will be utilized, and findings will be validated in humanized mice bearing patient-derived tumors. Free drug counterparts, nanoparticle delivering single agents, and first- line chemo will be used as benchmarks. In Aim 3, the pharmacokinetics, biodistribution, and safety profile of PETTRA will be evaluated in tumor-bearing mice and in non-human primates. Results will provide important data towards an investigational new drug application to the FDA. Successful siRNA delivery has the potential to create hundreds of new targeted therapies for difficult to drug genes at low costs, benefiting both precision and personalized medicines. This project is a collaboration among PDX Pharmaceuticals, Biomedical Engineering Department, and the Knight Cancer Institute of OHSU.

肺癌是癌症死亡率的主要原因，超过了结肠，乳房和前列腺的死亡癌症合并。对化学疗法和靶向治疗的耐药性非常普遍。放射治疗（RT）在约60％的肺癌患者中，仍然是关键治疗方法。我们试图开发一种新型的纳米疗法（称为Pettra），该纳米疗法居住在EGFR+肺部肿瘤和对类似polo的激酶1（SIPLK1）提供siRNA。 EGFR是一个理想的归巢目标，因为它经常介绍。并在50％的肺癌患者中过表达。 PLK1是由于其最强的癌症靶标的在细胞分裂和DNA修复中的关键作用，并抑制PLK1导致G2/M细胞周期停滞和凋亡死亡。 G2/M停滞中的细胞也对辐射最敏感。因此，假设Pettra有效作为单一疗法和作为肺癌的辐射敏化剂。或原型Pettra表现出了很好的表现这种双重提出在细胞和小鼠中提出的安全性和功效。在此，我们建议进一步优化材料以增强功效和安全性。虽然基于脂质的颗粒已有效地传递在过去的几年中，siRNA siRNA用4个FDA批准的药物到肝脏，没有任何平台在固体方面取得成功肿瘤。我们已经解决了纳米颗粒输送的局限性，并达到了长期循环半衰期（例如，在猴子中25小时），肿瘤中siRNA的积累增加了10倍，特定于靶细胞的递送（降低5至8-- 在正常细胞上折叠），出色的PLK1基因敲低（例如，84％），肿瘤抑制（例如，90％）鼠标模型。已经完成了用于GMP制造我们纳米颗粒的技术转移。 I阶段：在AIM 1中，我们将优化（通过评估各种EGFR抗体药物（AB）并增加至少3倍）将EGFR抗体和SIPLK1的加载和屏幕筛选为产生的铅构建体流体动力大小<120 nm，基因敲低75％，对EGFR+的摄取7倍，> 70％ EGFR+肺癌细胞中的细胞死亡以及对正常细胞的安全性（<15％死亡）。概念证明功效和铅纳米结构的安全性将在转移性肺肿瘤小鼠中进行。 II阶段：在AIM 2中，将单独和与RT结合使用最佳PETTRA的功效。将使用临床相关的原位NSCLC小鼠模型，并将在人源化中验证发现带有患者衍生肿瘤的小鼠。免费的药物对应物，纳米颗粒提供单药，首先线化疗将用作基准。在AIM 3中，药代动力学，生物分布和安全性 PETTRA将在承重肿瘤小鼠和非人类灵长类动物中进行评估。结果将为对FDA的研究新药应用提供重要数据。成功的 siRNA的递送有可能在低点创建数百种新的靶向疗法，以使其难以吸毒基因成本，使精度和个性化药物都受益。这个项目是PDX之间的合作药品，生物医学工程系和OHSU骑士癌症研究所。