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.

抽象的肺癌是最具侵袭性的恶性肿瘤之一，其中非小细胞肺癌居首位（非小细胞肺癌）占总病例的85%。据美国癌症协会估计，新 2020年肺癌病例数为228,820例。鉴于超过 60% 的非小细胞肺癌症（NSCLC）表达 EGFR，针对 EGFR 的酪氨酸激酶抑制剂成为首个 - 线治疗。尽管临床疗效显着，但绝大多数患者对药物产生耐药性由于 T790M 或 C797S 突变，几个月内接受治疗。对此，无数已经发现和探索了一些进步，但对于绝大多数人来说，补救措施仍然很微妙 EGFR突变的肺癌患者。考虑到 KRAS、MYC 和 EGFR 在肺癌进展、转移和耐药中的作用，我们假设同时针对这三个关键的致癌驱动因素可能是一种有前途的方法。在我们的实验室里，我们已鉴定并表征了蛋白水解靶向的协同致死组合嵌合体 (PROTAC) 选择性降解 - EGFR 和 BRD4。 PROTAC类药物输送分子的研究非常具有挑战性。药物输送技术和给药途径发挥着重要作用在实现有效集中、最大限度地减少脱靶副作用和提高患者的依从性。因此，我们建议开发一种可自注射的缓释剂 BPRO+EPRO 的储库并评估肺癌异种移植模型的抗癌功效不同的EGFR突变状态。我们提出两个具体目标：具体目标 1. 优化 BPRO 和 EPRO 负载储库制剂 (BERD) 和体外测定以评估选择性具体目标2.BERD对EGFR-TKI敏感及EGFR-TKI的抗癌疗效研究耐药人肺癌异种移植模型。考虑到治疗的空白治疗 TKI 耐药性肺癌的替代方案，该项目具有重大意义临床相关性。