BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10512067
• 负责人: Sushanta K. Banerjee
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512067
• 关键词: Address; Affect; Aftercare; American; American Association for the Advancement of Science; Animals; Apoptosis; Area; Aspirin; Award; Back; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer therapy; Breast Epithelial Cells; Cardiac; Cells; Censuses; Chemicals; Classification; Clinic; Clinical; Clinical Trials; Collaborations; Communities; Detection; Diagnosis; Disease; Distant; Dose; Drug Targeting; Drug resistance; ERBB2 gene; Enrollment; Epithelium; Estrogen Receptor alpha; Estrogens; Family; Female; Funding; Genes; Genetic; Genetic Engineering; Goals; Growth; Growth Factor; Healthcare; Healthcare Systems; Hormone Receptor; Human; Immune checkpoint inhibitor; Industry; Invaded; Investments; Knowledge; Laboratories; Laboratory Finding; Letters; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Military Personnel; Modification; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Oncogenes; Organ; Paclitaxel; Pain; Peer Review; Phenotype; Play; Polyethylene Glycols; Population; Printing; Privatization; Process; Progesterone; Prognosis; Property; Protein Family; Proteins; Recombinant Proteins; Recombinants; Recurrence; Regimen; Regulation; Research; Research Personnel; Residual Cancers; Resistance; Role; Scientist; Seminal; Surface; System; TP53 gene; Tamoxifen; Techniques; Testing; Therapeutic; Time; Translating; Tumor Promotion; Tumor Suppressor Proteins; United States; Veterans; Woman; active duty; aggressive breast cancer; anticancer research; breast cancer progression; cancer cell; cancer initiation; cancer prevention; career; chemotherapy; connective tissue growth factor; cyclin-dependent kinase inhibitor 1B; design; differential expression; drug development; drug discovery; drug relapse; drug repurposing; epithelial to mesenchymal transition; falls; health care delivery; hormone therapy; improved; innovation; insight; malignant breast neoplasm; member; migration; mouse model; multidisciplinary; neoplastic; neoplastic cell; novel; novel marker; novel therapeutics; overexpression; pancreatic cancer cells; pre-clinical; prevent; programmed cell death ligand 1; programmed cell death protein 1; programs; receptor; recruit; response; stem; stem cells; stemness; systemic toxicity; targeted treatment; therapy outcome; trafficking; triple-negative invasive breast carcinoma; tumor growth; tumor progression; tumorigenesis; tumorigenic

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.

7. 项目总结/摘要 乳腺癌（BC）是一种遗传异质性疾病，其特征是混合细胞。公元前是 根据雌激素、孕激素的差异表达，大致分为 luminal、HER2+ 和 basal-like 以及在癌细胞内部和表面发现的 HER-2 受体蛋白。类似基底，大约 10- 20% 的 BC 激素受体和 HER2 检测均为阴性，被视为三阴性 BC (TNBC)。三全国广播公司 其特点是对化疗耐药、获得干性状和不良预后 由于其高度转移表型，并且治疗后更有可能复发（复发）。 TNBC 患者仍 治疗选择很少，化疗是目前治疗转移性 TNBC 的唯一方法。 尽管检查点抑制剂，包括 PD-1 和 PD-L1，被发现在最初的 TNBC 中引起反应 临床试验中，这些试验尚未出现乐观的结果。因此，检测适当的目标 TNBC 治疗和预防的治疗方案对于许多实验室来说仍然是一个难以捉摸的挑战。 在我们识别可对 TNBC 发挥抑制作用的分子的计划中，我们发现 CCN5/WISP-2 是一种 29-35 kDa 的基质细胞蛋白，是生长因子 CCN 家族的成员，可以 通过抑制肿瘤进展来调节 TNBC。我们已经证明诱导 TNBC 细胞中 CCN5 的表达或施用人重组 CCN5 蛋白会导致抑制 致瘤特性和诱导生长停滞。 CCN5 还可以抑制干性，逆转 TNBC 中上皮间质转化 (EMT) 过程、调节 CCN 家族蛋白并激活 ER-α 细胞。基于这些令人兴奋的发现，我们现在建议创建和建立一种创新方法 通过CCN5的合成修饰使CCN5对TNBC生长和转移具有治疗意义 蛋白质通过聚乙二醇缀合（CCN5 聚乙二醇化；PEG-CCN5）。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，我们将生成 PEG 化的 CCN5 衍生物 单独或联合抗激素或化疗的 TNBC 疗法并描述新颖的特征 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 CCN5 用于在临床前减缓或阻止乳腺癌发生或进展的治疗 鼠标模型。最后，在目标 3 中，通过剖析 CCN5 对 CCN 家族蛋白（CCN1 和 CTGF）的影响， TNBC 中的主要肿瘤发生驱动因素，我们将确定 CCN5 如何控制间充质重编程 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 确定可抑制 TNBC 生长和进展的最佳聚乙二醇化蛋白或 CCN5 激活剂，以及 使 TNBC 细胞对他莫昔芬和紫杉醇敏感，且对健康细胞的全身毒性或不良影响最小或 器官。 CCN5 的新作用机制将会被发现。因此，这些方法应该显着 进一步了解 CCN5 的治疗效用及其在抑制 TNBC 中的机制见解。 我们将利用多种最先进的技术和我们的多学科团队独特的集体专业知识来 完成目标。