Project 2

项目摘要/摘要 乳腺癌(BC)仍然是绝经前妇女(Pre-MW)最常见的诊断癌症 在世界范围内，其发病率在发达国家呈上升趋势。前兆瓦中的BCS更有可能是 侵袭性的内在亚型，分级更高，与BCS相比，在MW后处于晚期。预兆瓦，带 ER+/HER2-BC通常采用化疗(CT)、内分泌治疗(ET)和卵巢功能治疗 抑制(OFS)。来自软佐剂和文本佐剂试验的长期数据表明，芳香酶 与以下药物相比，抑制剂(AI)+OFS提高了无病生存率，但尚未提高总体生存率(OS 他莫昔芬()或+氧氟沙星。此外，在一项研究(ABCSG 12)中，AI+OFS导致的OS比 +OFS。这些研究中缺乏生存益处可能与早产的有害副作用有关。 更年期(PM)，已知与心脏病、高血压、糖尿病、 高脂血症、骨质疏松症和死亡。因此，对于ER+/HER2-的前MW患者，替代内分泌策略 BC是非常需要的，特别是对于不能忍受OFS的MW前患者。艾诺昔芬是一位活跃的 代谢物和PI导致ENDX作为一种新型的内毒素用于BC的开发。通过阶段的完成 I和II试验，我们已经证明ENDX是安全的，耐受性良好，具有显著的口服生物利用度和 内分泌治疗(ET)耐药BC优于。此外，私家侦探还发现了一种新的机械装置 ENDX优越的抗癌作用的基础；即新的ENDX靶点PKCβI。在此，我们建立在 这一基础是通过进行一项前瞻性的新辅助内分泌研究，比较不使用OFS的ENDX和 AI+OFS在ER+/HER2-BC新辅助治疗前MW中的应用我们还将广泛研究这些角色 PKcβI在介导eNDX效应中的作用，我们的初步数据显示eNDX与pkcβI唯一结合 并将其作为蛋白酶体降解的靶点，导致ERα、细胞周期蛋白D1和E2F1蛋白水平下调 同时对BC细胞增殖有明显抑制作用。重要的是，在pkcβi中没有观察到这些影响。 激酶抑制剂，提示PKCβI的新的非激酶相关功能。 与或人工智能合作。基于这些数据，这一建议的中心假设是ENDX是一种更好的ET 部分是因为它有能力同时针对ER和PKCβI。我们进一步假设，最优治疗 使用ENDX单一疗法可以实现ER+/HER2-BC的前MW，而不需要OFS。测试我们的 假设，我们将1)开发针对ER+/HER2-BC的前MW的ENDX；2)阐明 PKCβI有助于内分泌敏感疾病的ENDX反应性；以及3)确定预测性和 βI在联合恩诺昔单抗治疗ER+/HER2-BC患者中的预后价值鉴于不断增加的 在妊娠前期的BC发病率，以及与OFS相关的已知发病率，拟议的研究包括 在MW前改善ER+/HER2-BC内分泌管理的关键重要性。

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) remains the most commonly diagnosed cancer in premenopausal women (pre-MW) worldwide and its incidence is increasing in developed countries. BCs in pre-MW are more likely to be of an aggressive intrinsic subtype, higher grade, and advanced stage compared to BCs in post-MW. Pre-MW with ER+/HER2- BC are commonly treated with chemotherapy (CT), endocrine therapy (ET) and ovarian function suppression (OFS). Long-term data from the SOFT and TEXT adjuvant trials demonstrated that aromatase inhibitors (AI)+OFS improved disease free survival but have yet to improve overall survival (OS), compared to tamoxifen (TAM) or TAM+OFS. Furthermore, in one study (ABCSG 12), AI+OFS led to worse OS compared to TAM+OFS. The lack of a survival benefit in these studies may relate to the detrimental side-effects of premature menopause (PM), known to be associated with higher rates of cardiac disease, hypertension, diabetes, hyperlipidemia, osteoporosis and death. Therefore, alternative endocrine strategies for pre-MW with ER+/HER2- BC are critically needed, especially for pre-MW who cannot tolerate OFS. Endoxifen (ENDX) is an active TAM metabolite, and the PI’s have led the development of ENDX as a novel ET for BC. Through completion of phase I and II trials, we have demonstrated that ENDX is safe, well-tolerated, has substantial oral bioavailability and is superior to TAM in endocrine therapy (ET) resistant BC. Furthermore, the PI’s have identified a novel mechanistic basis for the superior anti-cancer effects of ENDX; namely, the novel ENDX target, PKCβI. Here, we build upon this foundation by performing a prospective neoadjuvant endocrine study comparing ENDX without OFS vs AI+OFS in the neoadjuvant treatment of pre-MW with ER+/HER2- BC. We will also extensively study the roles of PKCβI in mediating ENDX efficacy, given our preliminary data demonstrating that ENDX uniquely binds PKCβI and targets it for proteasomal degradation, resulting in downregulation of ERα, cyclin D1, and E2F1 protein levels concurrent with marked inhibition of BC cell proliferation. Importantly, these effects are not observed with PKCβI kinase inhibitors, suggesting novel non-kinase related functions of PKCβI. Furthermore, they are not observed with TAM or AI. Based on these data, the central hypothesis of this proposal is that ENDX is a superior ET in part due to its ability to dually target both ER and PKCβI. We further hypothesize that the optimal treatment of pre-MW with ER+/HER2- BC can be achieved using ENDX monotherapy without the need for OFS. To test our hypotheses, we will 1) develop ENDX for pre-MW with ER+/HER2- BC; 2) elucidate the mechanisms by which PKCβI contributes to ENDX responsiveness in endocrine sensitive disease; and 3) determine the predictive and prognostic value of PKCβI in ER+/HER2- BC patients treated with TAM and ENDX. Given the increasing incidence of BC in pre-MW, along with the known morbidity associated with OFS, the proposed studies are of critical importance towards improving the endocrine management of ER+/HER2- BC in pre-MW.