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.项目摘要/摘要 乳腺癌(BC)是一种遗传异质性疾病，其特征是细胞混合。公元前一年 根据雌激素、孕激素和雌激素的不同表达，大致分为鲁米纳、HER2+和基底样蛋白。 以及癌细胞内部和表面发现的HER-2受体蛋白。像基座一样，大约是10- 20%的BC激素受体和HER2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，预后不良 由于其高度转移性表型，治疗后更容易复发(复发)。TNBC患者仍在 有最小的治疗选择，化疗是目前转移性TNBC可用的唯一治疗方法。 尽管包括PD-1和PD-L1在内的检查点抑制剂在初始阶段被发现在TNBC中引起反应 临床试验，这些试验还没有出现乐观的结果。因此，检测到适当的靶标 TNBC治疗和预防的治疗方案对许多实验室来说仍然是一个难以捉摸的挑战。 在我们寻找对肿瘤坏死因子具有抑制作用的分子(S)过程中，我们发现 CCN5/WISP-2是一种29-35 kDa的基质细胞蛋白，属于CCN家族的生长因子，可以 通过对肿瘤进展的抑制作用来调节TNBC。我们已经证明了诱导 人重组CCN5蛋白在TNBC细胞中的表达及抑制作用 致瘤特性和诱导生长停滞。已知CCN5还可以抑制茎的生长，逆转 上皮-间充质转化过程、调控CCN家族蛋白和激活ER-α 细胞。在这些令人兴奋的发现的基础上，我们现在建议创造和建立一种创新的方法来 通过CCN5的合成修饰使CCN5对TNBC的生长和转移具有治疗意义 通过聚乙二醇偶联物(CCN5聚乙二醇化；聚乙二醇化CCN5)合成的蛋白质。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，我们将为以下对象生成聚乙二醇化的CCN5衍生物 TNBC单独治疗或联合抗激素或化疗，这是新的特征 改善诊断和治疗结果的生物标志物。在目标2中，我们将制定药物再利用战略 针对CCN5的靶向激活，用于临床前减缓或阻止乳腺癌的开始或进展的治疗 老鼠模型。最后，在目标3中，通过解剖CCN5对CCN家族蛋白(CCN1和CTGF)的影响， 在TNBC中的主要肿瘤发生驱动因素，我们将确定CCN5如何调控重编程间充质 上皮细胞转化(MET)、细胞凋亡、肿瘤生长抑制和小鼠存活。这些研究是预期的 寻找一种最佳的聚乙二醇化蛋白或CCN5激活剂，以抑制TNBC的生长和进展，并 使TNBC细胞对他莫昔芬和紫杉醇增敏，全身毒性或对健康细胞或 器官。我们将发现CCN5的新的作用机制。因此，这些方法应该显著地 关于CCN5的治疗作用及其在抑制TNBC中的机制的高级知识。 我们将使用多种最先进的技术和我们多学科团队的独特集体专业知识来 完成目标。