Targeted Chemoprevention of Breast Cancer: From the Bench to Clinical Testing

描述(申请人提供)：目前，靶向药物正在进行治疗ER-乳腺癌的临床测试，但尚未进行充分的预防测试。这是因为，如果没有对人类乳腺癌发病生物学的更好了解，预防ER乳腺癌的靶向药物的I/II阶段测试将过于冒险和昂贵。为了应对这些挑战，我们的目标是在我们的高危队列中确定在ER乳腺癌启动期间激活的关键信号网络，并利用这些网络进行有针对性的预防。正常的乳腺动态平衡需要信号网络的协调调节。目前，我们对1)侵袭性ER-乳腺癌中被激活的信号网络是否在乳腺异型性中也被激活，以及2)如果是，特定信号网络的激活是否预测癌症的发生和发展缺乏了解。在这里，我们将调查异型性中的信号网络激活是否预测随后的癌症病因。Akt/mTOR、IL6/STAT3、EGRF/MEK/ERK和线粒体生存通路的激活可以预测ER乳腺癌的侵袭性生物学行为。我们的初步数据提供了证据，证明在高危女性的乳房非典型性中可以检测到这些预后不良的信号网络的激活。然而，仅仅因为我们可以识别受试者之间具有高类别间变异系数的特征，并不一定意味着这些过程对癌症病因学很重要。这里将检验这样一个假设，即在高危女性的乳房异型性中可以检测到构成ER-乳腺癌侵袭行为的信号通路，以及这些信号通路是否可以用于预测癌症的发生和指导有针对性的预防策略。目的1将测试在ER乳腺癌中识别的磷蛋白特征是否存在于高风险女性的癌前病变中。目的2将前瞻性地研究磷蛋白信号是否预测ER-乳腺癌的发生。AIM 3将研究RPPM签名是否能预测体外对靶向药物的敏感性。AIM 4将进行试点测试，并使用磷蛋白签名来选择和跟踪对靶向药物的反应，以预防患有乳房非典型性疾病的高危女性患乳腺癌。意义：在这里，我们将确定在乳腺癌启动过程中被激活的蛋白质信号通路。从这项提案中获得的信息将使我们能够识别异型性中激活的信号通路，测试通路激活是否预测癌症病因，并使用这些信息来选择和跟踪靶向药物的反应。

DESCRIPTION (provided by applicant): Currently, targeted agents are in clinical testing for treatment of ER- breast cancer, but have not been adequately tested for prevention. This is because, without a better understanding of the biology of human breast cancer initiation, Phase I/II testing of targeted agents for preventing ER- breast cancer will be too risky and expensive. To meet these challenges, we aim to identify key signaling networks activated during initiation of ER- breast cancer in women in our high-risk cohort and use these networks to target prevention. Normal mammary gland homeostasis requires the coordinated regulation of signaling networks. Currently we lack an understanding of 1) whether the signaling networks that are activated in aggressive ER- breast cancer are also activated in mammary atypia, and 2) if so, whether activation of specific signaling networks predicts cancer initiation and progression. Here we will investigate whether signaling network activation in atypia predicts subsequent cancer etiology. Activation of Akt/mTOR, IL6/Stat3, EGRF/MEK/ERK, and mitochondrial survival pathways are known to predict aggressive biology in ER- breast cancer. Our Preliminary Data provide evidence that activation of these poor-prognosis signaling networks can be detected in mammary atypia from high risk women. However, just because we can identify signatures with high inter-class coefficients of variation between subjects, does not necessarily imply those processes are important for cancer etiology. Here will test the hypothesis that signaling pathways that underlie the aggressive behavior of ER- breast cancer can be detected in mammary atypia from high-risk women, and whether these signaling pathways can be used to predict cancer initiation and guide targeted prevention strategies. Aim 1 will test whether phosphoprotein signatures identified in ER- breast cancers are present in premalignant lesions in high-high risk women. Aim 2 will prospectively investigate whether phosphoprotein signatures predict initiation of ER- breast cancer. Aim 3 will investigate whether RPPM signatures predict in vitro sensitivity to targeted agents. Aim 4 will perform Pilot Testing and use phosphoprotein signatures to select and track response to targeted agents to prevent breast cancer in high-risk women with mammary atypia. Significance: Here we will identify protein signaling pathways that are activated during breast cancer initiation. Information gained in this proposal will allow us to identify activated signaling pathways in atypia, test whether pathway activation predicts cancer etiology, and use this information to select, and track response to, targeted agents.