Role of Downstream Signaling in EGFR/HER2 Inhibitor Radiosentitization

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。

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.