Overcoming Drug Resistance in HER2-positive Breast Cancer

克服 HER2 阳性乳腺癌的耐药性

基本信息

批准号：
10639498
负责人：
YUESHENG ZHANG
金额：
$ 41.09万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639498
关键词：
Address Binding Breast Cancer Cell Cancer Burden Cancer Patient Cell Line Cells Clinical Clinical Research Codon Nucleotides Collagen Combined Modality Therapy Development Dipeptidases Dipeptides Disease Disease Outcome Disease Progression Drug Modelings Drug resistance ERBB2 gene Epidermal Growth Factor Receptor Extracellular Domain FDA approved Family member Gene Amplification Glycine Goals Human In Vitro Lead Medical Metabolism Methods Mission Modeling Molecular Monoclonal Antibodies Mus Normal Cell Normal tissue morphology Oncogenic Outcome Patient Selection Patients Play Point Mutation Pre-Clinical Model Proline Protein Tyrosine Kinase Proteins Public Health Receptor Protein-Tyrosine Kinases Recombinants Research Resistance Role Safety Signal Transduction Specificity Testing Therapeutic Time Toxic effect Trastuzumab Tumor-Derived Work Xaa-Pro dipeptidase acquired drug resistance advanced disease cancer cell cell growth clinically relevant disease prognosis humanized mouse improved in vivo inhibitor innovation malignant breast neoplasm mutant novel overexpression receptor receptor expression refractory cancer research clinical testing resistance mechanism targeted treatment therapeutic target tumor tumor xenograft

项目摘要

HER2 is an oncogenic receptor tyrosine kinase (RTK). It is overexpressed in about 20% breast cancer (BC) due to gene amplification, known as HER2-positive BC (HER2+ BC). Several HER2 inhibitors are available clinically and have significantly improved disease outcome. However, primary and acquired drug resistance is common. Most patients with advanced disease show disease progression after some time on treatment. Drug resistance is a major unresolved problem in HER2+ BC, and our long-term goal is to find a solution to this problem. In this project, we propose to investigate a recombinant human protein, i.e., PEPDG278D, for overcoming drug resistance in HER2+ BC. PEPDG278D is an enzymatically inactive mutant of peptidase D (also known as prolidase). Exogenously-administered PEPDG278D binds to HER2 and its family member EGFR, and in cancer cells overexpressing the RTKs, PEPDG278D disrupts their signaling units, directs them for lysosomal degradation, and inhibits the growth of the cells in vitro and in vivo. PEPDG278D inhibits HER2+ BC cells that are resistant to current HER2 inhibitors in vitro and in vivo. Yet, PEPDG278D is well tolerated in mouse studies and shows little effect on HER2 and EGFR in normal tissues where expression of the RTKs is very low. Cancer cells lacking HER2 and EGFR are insensitive to PEPDG278D as well. The objectives of this proposal are: 1) to determine the therapeutic activity and mechanism of action of PEPDG278D in HER2+ BC, and 2) to assess PEPDG278D safety and to understand how PEPDG278D spares HER2 and EGFR in normal cells. The central hypothesis is that PEPDG278D targets HER2 and EGFR specifically and its unique binding mode enables it to target overexpressed HER2 and EGFR strongly and selectively, thereby inhibiting drug-resistant HER2+ BC without causing toxicity. The rationale for the proposal is that completion of the research may propel PEPDG278D into clinical evaluation. We propose three specific aims to test the hypothesis: 1) to elucidate the target specificity of PEPDG278D, 2) to assess its therapeutic activity and mechanism of action, and 3) to determine its target selectivity and how it spares HER2 and EGFR in normal cells. An innovative combination of experimental methods will be used, including but not limited to isogenic cells, cells and tumors carrying clinically verified molecular changes that confer resistance to current HER2 inhibitors, primary normal human cells and humanized mice. The proposed research is significant, because it addresses a major problem in HER2+ BC, i.e., drug resistance. Expected outcome of this work includes: 1) showing that HER2 and EGFR are the sole therapeutic targets of PEPDG278D; 2) showing that PEPDG278D inhibits HER2+ BC resistant to current HER2 inhibitors and the underlying mechanisms; 3) showing that HER2 remains a critical therapeutic target in drug-resistant HER2+ BC; and 4) showing that PEPDG278D is non-toxic to normal cells and tissues and understanding the molecular basis. Our findings will have an important positive impact, because they will generate strong enthusiasm for clinical study of PEPDG278D.

HER2是一种致癌受体酪氨酸激酶（RTK）。它在约20％的乳腺癌（BC）中过表达由于基因扩增，称为HER2阳性BC（HER2+ BC）。有几种HER2抑制剂可用在临床上，并显着改善了疾病结果。但是，初级和获得的耐药性很常见。一段时间后，大多数患有晚期疾病的患者表现出疾病的进展。耐药性是HER2+ BC中的一个主要未解决的问题，我们的长期目标是找到解决方案这个问题。在这个项目中，我们建议研究重组人蛋白，即PEPDG278D，用于在HER2+ BC中克服耐药性。 PEPDG278D是肽酶D的酶非活性突变体D （也称为衍生酶）。外源管理PEPDG278D与HER2及其家人结合 eGFR，在过表达RTK的癌细胞中，PEPDG278D破坏了它们的信号单位，指导它们用于溶酶体降解，并抑制细胞在体外和体内的生长。 PEPDG278D抑制HER2+ 在体外和体内对当前HER2抑制剂具有抗性的BC细胞。但是，PEPDG278D的耐受性很高小鼠研究，显示对RTKs表达的正常组织中HER2和EGFR的影响很小很低。缺乏HER2和EGFR的癌细胞对PEPDG278D也不敏感。目标的目标该建议是：1）确定PEPDG278D在HER2+中的治疗活性和作用机理 BC和2）评估PEPDG278D安全性，并了解PEPDG278D如何避免HER2和EGFR 正常细胞。中心假设是PEPDG278D专门针对HER2和EGFR及其独特绑定模式使其能够靶向过表达的HER2和EGFR，从而强烈，有选择地靶向抑制耐药的HER2+ BC而不会引起毒性。提案的理由是完成在研究中，可以将PEPDG278D推向临床评估。我们提出了三个特定目标，以测试假设：1）阐明PEPDG278D的目标特异性，2）评估其治疗活性和作用机理，以及3）确定其目标选择性以及如何在正常情况下及时及格。细胞。将使用实验方法的创新组合，包括但不限于等源性携带临床验证的分子变化的细胞，细胞和肿瘤，以赋予当前HER2的抗性抑制剂，原发性正常人细胞和人源化小鼠。拟议的研究很重要，因为它解决了HER2+ BC的一个主要问题，即耐药性。这项工作的预期结果包括： 1）表明HER2和EGFR是PEPDG278D的唯一治疗靶标； 2）显示PEPDG278D 抑制HER2+ BC对当前HER2抑制剂和潜在机制的抗性； 3）显示 HER2仍然是耐药性HER2+ BC的关键治疗靶点； 4）表明PEPDG278D是对正常细胞和组织无毒，并了解分子基础。我们的发现将有一个重要的积极影响，因为它们将对PEPDG278D的临床研究产生强烈的热情。