Project 2

项目总结/摘要 乳腺癌（BC）仍然是绝经前妇女（前MW）最常见的癌症 在世界范围内，其发病率在发达国家正在增加。前MW中的BC更有可能是 侵袭性内在亚型、更高级别和晚期，与MW后的BC相比。预MW， ER+/HER 2- BC通常通过化疗（CT）、内分泌治疗（ET）和卵巢功能治疗 抑制（OFS）。SOFT和TEXT佐剂试验的长期数据表明，芳香化酶 抑制剂（AI）+OFS改善了无病生存期，但尚未改善总生存期（OS）， 他莫昔芬（TAM）或TAM+OFS。此外，在一项研究（ABCSG 12）中，与对照组相比，AI+OFS导致OS更差。 TAM+OFS。这些研究中缺乏生存益处可能与早产儿的有害副作用有关 绝经期（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，ER+/HER 2-前MW的替代内分泌策略 BC是迫切需要的，特别是对于前MW谁不能容忍OFS。Endoxifen（ENDX）是一种活性TAM 代谢物，和PI的已经导致ENDX作为一种新的ET BC的发展。通过完成阶段 I和II试验，我们已经证明ENDX是安全的，耐受性良好，具有相当大的口服生物利用度， 对内分泌治疗（ET）耐药的BC的疗效上级优于TAM。此外，PI已经确定了一种新的机制， ENDX的上级抗癌作用的基础;即新的ENDX靶点PKCβI。在这里，我们建立在 通过进行前瞻性新辅助内分泌研究，比较无OFS的ENDX与 AI+OFS在ER+/HER 2- BC的前MW新辅助治疗中的作用。我们还将广泛研究 鉴于我们的初步数据表明ENDX与PKC β I的结合是唯一的， 并靶向其进行蛋白酶体降解，导致ERα、细胞周期蛋白D1和E2 F1蛋白水平下调 同时显著抑制BC细胞增殖。重要的是，在PKCβI中未观察到这些效应。 激酶抑制剂，提示PKCβI的新的非激酶相关功能。此外，他们没有遵守 或AI。基于这些数据，该建议的中心假设是ENDX是一种上级ET， 部分原因是其能够双重靶向ER和PKCβI。我们进一步假设， ER+/HER 2- BC的pre-MW可以使用ENDX单一疗法实现，而不需要OFS。来测试我们 假设，我们将1）开发ENDX用于ER+/HER 2- BC的前MW; 2）阐明 PKCβI有助于内分泌敏感性疾病的ENDX反应性;和3）确定预测和 PKCβI在接受TAM和ENDX治疗的ER+/HER 2- BC患者中的预后价值鉴于越来越 前MW中BC的发病率，沿着与OFS相关的已知发病率，拟定的研究是 对于改善前MW中ER+/HER 2- BC的内分泌管理至关重要。

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.