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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：
10663396
负责人：
YUESHENG ZHANG
金额：
$ 44.21万
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/10663396
关键词：
Acceleration 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 HER2 inhibition Human In Vitro Medical Metabolism Methods Mission Modeling Molecular Monoclonal Antibodies Mus Normal Cell Normal tissue morphology Oncogenic Outcome PIK3CG gene Patient Selection Patients Play Point Mutation Pre-Clinical Model Proline Proteins Public Health Receptor Protein-Tyrosine Kinases Recombinants Research Resistance Role Safety Signal Transduction Specificity Testing Therapeutic Time Toxic effect Trastuzumab 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 multidrug resistance inhibition therapy mutant novel overexpression 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) 中过度表达由于基因扩增，称为 HER2 阳性 BC（HER2+ BC）。有多种 HER2 抑制剂可供选择临床上并显着改善疾病结果。然而，原发性和获得性耐药性很常见。大多数晚期疾病患者在治疗一段时间后出现疾病进展。耐药性是 HER2+ BC 中尚未解决的主要问题，我们的长期目标是找到解决方案这个问题。在这个项目中，我们建议研究一种重组人类蛋白，即 PEPDG278D，用于克服 HER2+ BC 的耐药性。 PEPDG278D 是肽酶 D 的无酶活性突变体（也称为脯氨酸酶）。外源给药的 PEPDG278D 与 HER2 及其家族成员结合 EGFR 以及过度表达 RTK 的癌细胞中，PEPDG278D 会破坏其信号传导单元并指导它们用于溶酶体降解，并抑制体外和体内细胞的生长。 PEPDG278D 抑制 HER2+ BC 细胞在体外和体内对当前 HER2 抑制剂具有耐药性。然而，PEPDG278D 在以下情况下具有良好的耐受性：小鼠研究表明，RTK 表达对正常组织中的 HER2 和 EGFR 几乎没有影响非常低。缺乏 HER2 和 EGFR 的癌细胞对 PEPDG278D 也不敏感。的目标该提案是：1）确定PEPDG278D在HER2+中的治疗活性和作用机制 BC，以及 2) 评估 PEPDG278D 的安全性并了解 PEPDG278D 如何在治疗中保护 HER2 和 EGFR 正常细胞。中心假设是PEPDG278D特异性靶向HER2和EGFR及其独特的结合模式使其能够强烈、选择性地靶向过度表达的 HER2 和 EGFR，从而抑制耐药 HER2+ BC，而不引起毒性。该提案的理由是完成该研究的进展可能会推动 PEPDG278D 进入临床评估。我们提出了三个具体目标来测试假设：1) 阐明 PEPDG278D 的靶标特异性，2) 评估其治疗活性和作用机制，3) 确定其靶点选择性以及在正常情况下如何保护 HER2 和 EGFR 细胞。将使用创新的实验方法组合，包括但不限于同基因携带经过临床验证的分子变化的细胞、细胞和肿瘤，这些变化赋予对当前 HER2 的抗性抑制剂、原代正常人类细胞和人源化小鼠。拟议的研究意义重大，因为它解决了 HER2+ BC 的一个主要问题，即耐药性。这项工作的预期成果包括： 1)表明HER2和EGFR是PEPDG278D的唯一治疗靶点； 2) 显示PEPDG278D 抑制对现有 HER2 抑制剂耐药的 HER2+ BC 及其潜在机制； 3）表明 HER2 仍然是耐药 HER2+ BC 的关键治疗靶点； 4) 显示 PEPDG278D 是对正常细胞和组织无毒并了解分子基础。我们的研究结果将有一个重要的积极影响，因为他们将对PEPDG278D的临床研究产生强烈的热情。