Synergistic combination of Proteolysis Targeting Chimera with a translational formulation for the treatment of intractable lung carcinoma

蛋白水解靶向嵌合体与转化制剂的协同组合用于治疗难治性肺癌

基本信息

批准号：
10580447
负责人：
Ketankumar D. Patel
金额：
$ 49.2万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580447
关键词：
3-Dimensional Accounting Affinity American Cancer Society Apoptosis Body Weight Cancer Etiology Cancer Patient Cancer cell line Cell Line Cell Survival Cells Cessation of life Characteristics Cisplatin Clinical DNA Sequence Alteration Development Distant Drug Delivery Systems Drug Formulations Drug Kinetics Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Evaluation Exposure to Formulation Gefitinib Generations Hematology Hepatotoxicity Human Immunohistochemistry Individual Injectable Intravenous infusion procedures KRAS2 gene Kinetics Knowledge Laboratories Ligand Binding Ligands Malignant Neoplasms Malignant neoplasm of lung Migration Assay Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Oncoproteins Oral Organ Paclitaxel Pathway interactions Patients Plasma Play Proliferating Protac Proteins Research Resistance Resistance development Role Route Solid Neoplasm Solubility Solvents Survival Rate Tablets Technology Therapeutic Toxic effect Tumor Volume Tyrosine Kinase Domain Tyrosine Kinase Inhibitor Xenograft Model Xenograft procedure alternative treatment angiogenesis anti-cancer anticancer activity aqueous biodegradable polymer biomaterial compatibility c-myc Genes cancer drug resistance cancer therapy chemotherapy clinical translation clinically relevant comparative compliance behavior cytotoxicity design driver mutation efficacy study efficacy testing gemcitabine graduate student improved in vitro Assay in vivo inhibitor innovation interest lung Carcinoma lung cancer cell mortality mouse model mutational status nanomolar novel drug class receptor recruit research and development side effect small molecular inhibitor subcutaneous synergism targeted cancer therapy targeted treatment translational potential tumor tumor growth tumor progression tumor xenograft ubiquitin-protein ligase undergraduate student

项目摘要

Abstract Lung cancer is one of the most aggressive malignant tumors with non-small cell lung cancer (NSCLC) accounting for 85 % of the total cases. As per American Cancer Society, estimated new cases of lung cancer in 2020 were 228,820. Given that more than 60% of non-small cell lung carcinomas (NSCLCs) express EGFR, Tyrosine Kinase Inhibitors targeting EGFR became first- line treatments. Despite robust clinical benefits, vast majority of patients develop resistance to treatment within few months due to either T790M or C797S mutations. In regard to this, countless strides have been discovered and explored, but a remedy still remains subtle for the vast majority of lung cancer patients with EGFR mutations. Considering the central role of KRAS, MYC and EGFR in lung cancer progression, metastasis and resistance, we hypothesized that simultaneously targeting these three key oncogenic drives could be a promising approach. In our laboratory, we have identified and characterized the synergistically lethal combination of PROteolysis TArgeting Chimera (PROTAC) selectively degrading - EGFR and BRD4. Drug delivery of PROTAC class of molecules is very challenging. Drug delivery technology and route of administration play a paramount role in achieving effective concentration, minimizing off target side effects and improving patient compliance. Therefore, we propose to develop a self-injectable extended-release depot of BPRO+EPRO and evaluate anticancer efficacy in lung cancer xenograft model with different EGFR mutation status. We propose two specific aims: Specific aim 1. Optimization of BPRO and EPRO loaded depot formulation (BERD) and In vitro assays to evaluate selectivity Specific aim 2. Anticancer efficacy study of BERD in EGFR-TKIs sensitive and EGFR-TKIs resistant human lung carcinoma xenograft model. Considering the lacuna of therapeutic alternatives for the treatment of TKIs resistant lung cancer, the proposed project has significant clinical relevance.

抽象的肺癌是患有非小细胞肺癌的最具侵略性的恶性肿瘤之一（NSCLC）占总案件的85％。根据美国癌症协会的估计 2020年的肺癌病例为228,820。鉴于超过60％的非小细胞肺 Carcinomas（NSCLCS）表达EGFR，靶向EGFR的酪氨酸激酶抑制剂首先线路处理。尽管有强大的临床益处，但绝大多数患者对由于T790M或C797S突变，在几个月内进行治疗。关于这一点，无数已经发现和探索了大步，但是对于绝大多数的补救措施仍然很微妙 EGFR突变患者的肺癌患者。考虑到Kras，Myc和 EGFR在肺癌的进展，转移和抗性中，我们同时假设针对这三个关键的致癌驱动器可能是一种有前途的方法。在我们的实验室中，我们已经确定并表征了蛋白水解靶向的协同致命组合嵌合体（Protac）有选择地退化-EGFR和BRD4。 Protac类药物的药物输送分子非常具有挑战性。药物输送技术和行政途径发挥最重要的角色在实现有效浓度，最大程度地减少目标副作用和改善患者合规性。因此，我们建议开发自注射的扩展释放 BPRO+EPRO的仓库，并评估肺癌异种移植模型中的抗癌功效不同的EGFR突变状态。我们提出了两个具体目标：特定目标1。优化 BPRO和EPRO负载配方（BERD）和体外测定法以评估选择性特定目的2。在EGFR-TKIS敏感和EGFR-TKIS中BERD的抗癌疗效研究抗性人类肺癌异种移植模型。考虑治疗性的空隙拟议的项目具有明显临床相关性。