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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：
10207554
负责人：
YUESHENG ZHANG
金额：
$ 55.14万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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 2022-04-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207554
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 Prognosis 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 humanized mouse improved in vivo inhibitor/antagonist 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.

HER 2是一种致癌受体酪氨酸激酶（RTK）。它在大约20%的乳腺癌（BC）中过表达由于基因扩增，称为HER 2阳性BC（HER 2 + BC）。有几种HER 2抑制剂可用在临床上并显著改善了疾病结果。然而，原发性和获得性耐药很常见大多数晚期疾病患者在治疗一段时间后显示疾病进展。耐药性是HER 2 + BC中一个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，我们建议研究重组人蛋白，即，PEPDG 278 D，用于克服HER 2 + BC的耐药性。PEPDG 278 D是肽酶D的无酶活性突变体 (also称为脯氨酰二肽酶）。外源性PEPDG 278 D与HER 2及其家族成员结合在过度表达RTKs的癌细胞中，PEPDG 278 D破坏它们的信号传导单位，引导它们用于溶酶体降解，并在体外和体内抑制细胞生长。PEPDG 278 D抑制HER 2 + 在体外和体内对当前HER 2抑制剂具有抗性的BC细胞。然而，PEPDG 278 D在小鼠中耐受性良好。小鼠研究显示对正常组织中的HER 2和EGFR几乎没有影响，非常低。缺乏HER 2和EGFR的癌细胞对PEPDG 278 D也不敏感。的目标该建议是：1）确定PEPDG 278 D在HER 2+中的治疗活性和作用机制 BC，和2）评估PEPDG 278 D的安全性，并了解PEPDG 278 D如何在正常细胞中心假设是PEPDG 278 D特异性靶向HER 2和EGFR，其独特的结合模式使其能够强烈和选择性地靶向过表达的HER 2和EGFR，抑制耐药性HER 2 + BC而不引起毒性。该提案的理由是，这项研究可能会推动PEPDG 278 D进入临床评估。我们提出了三个具体目标，以测试假设：1）阐明PEPDG 278 D的靶特异性，2）评估其治疗活性， 3）确定其靶向选择性以及它如何在正常人中保留HER 2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临床验证的分子变化的细胞、细胞和肿瘤，这些分子变化赋予对当前HER 2的抗性抑制剂、原代正常人细胞和人源化小鼠。这项研究意义重大，因为它解决了HER 2 + BC中的一个主要问题，即，耐药性这项工作的预期成果包括： 1)显示HER 2和EGFR是PEPDG 278 D的唯一治疗靶标; 2）显示PEPDG 278 D 抑制对当前HER 2抑制剂具有抗性的HER 2 + BC和潜在机制; 3）表明， HER 2仍然是耐药性HER 2 + BC的关键治疗靶标;以及4）显示PEPDG 278 D是对正常细胞和组织无毒，并了解分子基础。我们的发现将对重要的积极影响，因为他们将产生对PEPDG 278 D临床研究的强烈热情。