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Role of Downstream Signaling in EGFR/HER2 Inhibitor Radiosentitization

下游信号传导在 EGFR/HER2 抑制剂放射增敏中的作用

基本信息

批准号：
7289870
负责人：
CAROLYN I SARTOR
金额：
$ 18.85万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-21 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7289870
关键词：
Automobile Driving Biological Markers Biological Products Biopsy Breast Cancer Cell Cancer cell line Cell Line Cells Clinical Clinical Treatment Clinical Trials Dependence Development Disease ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exhibits Family GW572016 HER2 inhibition Heterogeneity In Vitro MAPK14 gene MAPK8 gene Mammary Neoplasms Measures Mediating Mediator of activation protein Mus Mutation Neoplasm Transplantation Outcome Pathogenesis Pathway interactions Patient Selection Patients Phase Phosphorylation Phosphotransferases Primary Neoplasm Radiation Radiation therapy Radiation-Sensitizing Agents Radiosensitization Randomized Controlled Clinical Trials Ras/Raf Rate Receptor Inhibition Recurrence Relative (related person)Research Research Personnel Resistance Role Signal Pathway Signal Transduction Signal Transduction Pathway Standards of Weights and Measures Testing Tumor-Derived Tyrosine Kinase Inhibitor United States Food and Drug Administration Xenograft Model Xenograft procedure base cancer therapy clinically relevant experience improved in vivo inhibitor/antagonist malignant breast neoplasm novel pre-clinical resistance mechanism response treatment trial tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Among the most promising novel biological agents are the epidermal growth factor receptor family inhibitors. Although a Phase III randomized trial recently proved that EGFR inhibitors are effective radiosensitizers, the clinical experience of several non-radiosensitization trials show disappointing low response rates. The discordance between strongly positive preclinical and modest clinical outcomes maybe due to the relatively poor ability to select tumors amenable to EGFR inhibitor therapy. In our breast cancer cell line radiosensitization studies using a dual EGFR/HER2 inhibitor, GW572016, we found that inhibition of downstream signaling corresponded with response, but inhibition of receptor phosphorylation did not. Our hypothesis is that response to EGFR/HER2 inhibitors will depend not only on inhibition of the receptor, but also on effective inhibition of the downstream signals (MARK, PI3K, or STAT cascades) that drive radiation response, and that tumors in which MARK, PI3K, or STAT activation is not dependent on EGFR/HER2 will not be radiosensitized. Since cell lines and xenografts derived from cell lines poorly represent the heterogeneity of clinical tumors, we will test our hypothesis in tumors derived from patients, both in the context of a treatment trial and in tumors transplanted directly from patients to mice. In Specific Aim 1, we will determine the signaling pathways involved in GW573016 radiosensitization. In Specific Aim 2, we will determine mechanisms of resistance to radiosensitization. In Specific Aim 3, we will determine whether inhibition of downstream signaling predicts response to GW572016. Our results will show which EGFR/HER2 signals are responsible for breast cancer radiation response, identifying biomarkers to select patients whose breast cancer is likely to respond to EGFR/HER2 inhibitors, improving outcome and avoiding ineffective treatment.

描述(申请人提供)：最有前景的新型生物制剂是表皮生长因子受体家族抑制剂。尽管最近一项III期随机试验证明EGFR抑制剂是有效的放射增敏剂，但几项非放射增敏试验的临床经验显示出令人失望的低应答率。强阳性的临床前结果和适度的临床结果之间的不一致可能是由于选择适合EGFR抑制剂治疗的肿瘤的能力相对较差。在我们使用EGFR/HER2双重抑制剂GW572016进行的乳腺癌细胞株放射增敏研究中，我们发现抑制下游信号与反应相对应，但对受体磷酸化的抑制不对应。我们的假设是，对EGFR/HER2抑制剂的反应不仅取决于受体的抑制，还取决于驱动辐射反应的下游信号(MARK、PI3K或STAT级联)的有效抑制，并且MARK、PI3K或STAT激活不依赖于EGFR/HER2的肿瘤将不会被放射增敏。由于细胞系和来自细胞系的异种移植不能很好地代表临床肿瘤的异质性，我们将在治疗试验和从患者直接移植到小鼠的肿瘤中测试我们的假设。在特定的目标1中，我们将确定GW573016辐射增敏所涉及的信号通路。在特定目标2中，我们将确定放射增敏抵抗的机制。在具体目标3中，我们将确定抑制下游信号是否预测对GW572016的反应。我们的结果将显示哪些EGFR/HER2信号与乳腺癌的辐射反应有关，识别生物标志物以选择可能对EGFR/HER2抑制剂有反应的乳腺癌患者，改善预后并避免无效治疗。