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

• 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
• 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

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.

摘要 肺癌是与非小细胞肺癌并列的最具侵袭性的恶性肿瘤之一 （NSCLC）占总病例的85%。据美国癌症协会估计， 2020年的肺癌病例为228，820例。鉴于60%以上的非小细胞肺癌 由于NSCLC表达EGFR，靶向EGFR的酪氨酸激酶抑制剂成为第一个- 线治疗。尽管有强大的临床益处，但绝大多数患者对 由于T790 M或C797 S突变，在几个月内治疗。对此，无数 已经发现和探索了一些进步，但对绝大多数人来说，补救措施仍然很微妙。 EGFR突变的肺癌患者。考虑到KRAS、MYC和 EGFR在肺癌的进展、转移和耐药中的作用，我们假设， 靶向这三个关键致癌驱动器可能是一种有前途的方法。在我们的实验室里， 已经鉴定并表征了PROteolysis Targeting的协同致死组合 选择性降解EGFR和BRD 4的嵌合体（PROTAC）。PROTAC类药物输送 是非常具有挑战性的。给药技术和给药途径在药物治疗中发挥着重要作用。 在实现有效浓度，最大限度地减少脱靶副作用和 提高患者依从性。因此，我们建议开发一种自注射缓释剂， BPRO+EPRO的储库，并在肺癌异种移植模型中评价抗癌功效， 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载药贮库型制剂（BERD）和评价选择性的体外试验 具体目标2。BERD在EGFR-TKI敏感和EGFR-TKI中的抗癌疗效研究 耐药人肺癌异种移植模型。考虑到治疗的缺陷， 作为治疗TKI耐药肺癌的替代方案，拟议的项目具有重大意义。 临床相关性