BLRD Research Career Scientist Award Application

7.项目总结/摘要 乳腺癌（BC）是一种遗传异质性疾病，其特征在于细胞的混合袋。BC是 基于雌激素，孕激素， 以及在癌细胞内部和表面发现的HER-2受体蛋白。基底状，大约10- 20%的BC，激素受体和HER 2检测均为阴性，被认为是三阴性BC（TNBC）。TNBC 其特点是对化疗耐药，获得干细胞特征， 由于其高转移性表型，并且在治疗后更可能复发。TNBC患者仍然 只有最少的治疗选择，化疗是目前唯一可用于转移性TNBC的治疗方法。 尽管发现检查点抑制剂（包括PD-1和PD-L1）在TNBC中引起了初始免疫应答，但在TNBC中，PD-1和PD-L1在TNBC中引起了初始免疫应答。 尽管进行了临床试验，但这些试验尚未出现乐观的结果。因此，检测适当的针对性 TNBC治疗和预防的治疗方案对许多实验室来说仍然是难以实现的挑战。 在我们鉴定可以对TNBC起抑制作用的分子的程序中，我们发现， CCN 5/WISP-2是一种29-35 kDa的基质细胞蛋白，是CCN家族生长因子的成员， 通过赋予对肿瘤进展的抑制作用来调节TNBC。我们已经证明，诱导 CCN 5的表达或在TNBC细胞中施用人重组CCN 5蛋白导致抑制CCN 5的表达。 致瘤特性和诱导生长停滞。CCN 5还已知抑制干性，逆转 上皮-间质转化（EMT）过程，调节CCN家族蛋白，并激活TNBC中的ER-α 细胞在这些令人兴奋的发现的基础上，我们现在建议创建和建立一种创新的方法， 通过CCN 5的合成修饰制备CCN 5用于TNBC生长和转移的治疗意义 通过聚乙二醇的缀合（CCN 5 PEG化; PEG-CCN 5）来修饰蛋白质。我们的长期目标是 将这些发现转化为临床治疗TNBC。在目标1中，我们将产生聚乙二醇化CCN 5衍生物， 单独的TNBC疗法或抗激素或化疗的组合， 生物标志物，以改善诊断和治疗结果。在目标2中，我们将制定药物再利用策略 用于靶向激活CCN 5，用于在临床前治疗中减缓或阻止乳腺癌的发生或进展， 小鼠模型。最后，在目的3中，通过剖析CCN 5对CCN家族蛋白（CCN 1和CTGF）的作用， 作为TNBC中的主要肿瘤发生驱动因素，我们将确定CCN 5如何调控间充质重编程， 上皮转化（MET）、细胞凋亡、肿瘤生长抑制和小鼠存活。这些研究预计 鉴定将抑制TNBC生长和进展的最佳PEG化蛋白质或CCN 5激活剂， 使TNBC细胞对他莫昔芬和紫杉醇敏感，对健康细胞具有最小的全身毒性或不良影响， 机关CCN 5的一种新的作用机制将被发现。因此，这些方法将显着 推进对CCN 5的治疗效用及其在抑制TNBC中的机制见解的认识。 我们将使用多种最先进的技术和我们的多学科团队的独特集体专业知识， 完成目标。

7. Project Summary/Abstract Breast cancer (BC) is a genetically heterogeneous disease characterized by a mixed bag of cells. BC is broadly classified into luminal, HER2+, and basal-like based on differential expression of estrogen, progesterone, and HER-2 receptor proteins found inside and on the surface of the cancer cells. Basal-like, which is about 10- 20% of BC, tests negative for both hormone receptors and HER2, considered triple-negative BC (TNBC). TNBC is characterized by resistance to chemotherapy, acquisition of the stem character, and unfavorable prognoses due to its highly metastatic phenotype and more likely to recur (come back) after treatment. TNBC patients still have minimal treatment options, and chemotherapy is currently the only treatment available for metastatic TNBC. Although checkpoint inhibitors, including PD-1 and PD-L1, were found to elicit a response in TNBC in initial clinical trials, optimistic results have not yet emerged from these trials. Thus, the detection of appropriate targeted therapeutic regimens for TNBC therapy and prevention has remained an elusive challenge to many laboratories. During our program of identifying molecule(s) that could play an inhibitory role against TNBC, we found that CCN5/WISP-2, a matricellular 29-35 kDa protein and a member of the CCN family of growth factors, can modulate TNBC by imparting an inhibitory effect on tumor progression. We have demonstrated that induced expression of CCN5 or administration of human recombinant CCN5 protein in TNBC cells resulted in suppressing tumorigenic properties and induction of growth arrest. CCN5 is also known to inhibit the stemness, reverse the epithelial-mesenchymal transition (EMT) process, modulate CCN-family proteins, and activate ER-α in TNBC cells. Building on these exciting findings, we now propose creating and establishing an innovative approach to make CCN5 for a therapeutic implication of TNBC growth and metastasis by synthetic modification of CCN5 protein through the conjugation of polyethylene glycol (CCN5 PEGylation; PEG-CCN5). Our long-term goal is to translate these findings to the clinic to treat TNBC. In Aim 1, we will generate a PEGylated CCN5 derivative for TNBC therapy alone or in a combination of an anti-hormone or chemotherapy and Characterize the novel biomarkers to improve diagnosis and therapeutic outcome. In Aim 2, we will develop drug repurposing strategies for targeted activation of CCN5 for therapies to slow or arrest breast cancer initiation or progression in pre-clinical mouse models. Lastly, in Aim 3, by dissecting the effect of CCN5 on CCN-family proteins (CCN1 and CTGF), major tumorigenesis drivers in TNBC, we will determine how CCN5 governs reprogramming mesenchymal to epithelial transition (MET), apoptosis, tumor growth inhibition, and mouse survival. These studies are expected to identify an optimal PEGylated protein or a CCN5-activator that will inhibit TNBC growth and progression and sensitize TNBC cells to tamoxifen and Paclitaxel with minimal systemic toxicity or ill effects on healthy cells or organs. A novel mechanism of action of CCN5 will be found. Thus, these approaches should significantly advance knowledge on the therapeutic utility of CCN5 and its mechanistic insights in the suppression of TNBC. We will use multiple state-of-art techniques and our multi-disciplinary team's unique collective expertise to complete the goal.