BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10367722
• 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/10367722
• 关键词: Address; Affect; Aftercare; American; American Association for the Advancement of Science; Animals; Apoptosis; Area; Aspirin; Assimilations; Award; Back; Breast Cancer Cell; Breast Epithelial Cells; Cardiac; Cells; Censuses; Chemicals; Clinic; Clinical; Clinical Trials; Collaborations; Communities; Detection; Diagnosis; Disease; Distant; Dose; Drug Targeting; Drug resistance; ERBB2 gene; Enrollment; Epithelial; Estrogens; Family; Female; Funding; Genes; Genetic; Genetic Engineering; Goals; Growth; Growth Factor; Healthcare; Healthcare Systems; Hormone Receptor; Human; Immune checkpoint inhibitor; Industry; Knowledge; Laboratories; Letters; Malignant Neoplasms; Malignant neoplasm of pancreas; Mesenchymal; Military Personnel; Modification; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Oncogenes; Organ; Paclitaxel; Pain; Patients; Peer Review; Phenotype; Play; Polyethylene Glycols; Population; Prevention; Process; Progesterone; Prognosis; Property; Protein Family; Proteins; Recombinant Proteins; Recombinants; Regimen; Regulation; Research; Research Personnel; Residual Cancers; Resistance; Role; Scientist; Seminal; Surface; System; TP53 gene; Tamoxifen; Techniques; Testing; Therapeutic; Time; Translating; Tumor Suppressor Proteins; United States; Veterans; Woman; active duty; aggressive breast cancer; anticancer research; base; breast cancer progression; cancer cell; cancer initiation; career; chemotherapy; connective tissue growth factor; design; differential expression; drug development; drug discovery; drug relapse; drug repurposing; epithelial to mesenchymal transition; falls; health care delivery; improved; innovation; insight; malignant breast neoplasm; member; migration; mouse model; multidisciplinary; neoplastic; neoplastic cell; novel; novel marker; novel therapeutics; 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; 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，其特征是混合细胞。 BC是 基于雌激素，孕激素，孕酮的差异表达，将广泛分为腔，HER2+和基本样本 HER-2受体蛋白在癌细胞的内部和表面上发现。基础状，大约10- 卑诗省的20％的测试对骑马受体和HER2的测试为阴性，被认为是三阴性BC（TNBC）。 TNBC 以对化学疗法的抵抗力，茎特征的获取和不利的预后为特征 由于其高度转移性表型，并且更有可能在治疗后复发（回来）。 TNBC患者仍然 具有最小的治疗选择，化疗目前是转移性TNBC的唯一治疗方法。 尽管发现检查点抑制剂（包括PD-1和PD-L1）在初始中引起了TNBC的反应 临床试验，这些试验尚未出现乐观的结果。那，检测适当的目标 TNBC治疗和预防的治疗方案对许多实验室仍然是一个难以捉摸的挑战。 在我们识别可以对TNBC起抑制作用的分子的计划期间，我们发现 CCN5/WISP-2，基质29-35 kDa蛋白和CCN生长因子家族的成员，可以 通过对肿瘤进展产生抑制作用来调节TNBC。我们已经证明了诱导的 TNBC细胞中CCN5的表达或人类重组CCN5蛋白的给药导致抑制 众所周知，TCN5抑制了茎，逆转了 上皮 - 间质转变（EMT）过程，调节CCN家庭蛋白质，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CCN5的合成修饰使CCN5对TNBC生长和转移的治疗意义 蛋白质通过聚乙烯乙二醇的结合（CCN5 Pegylation; PEG-CCN5）。我们的长期目标是 将这些发现转换为诊所以治疗TNBC。在AIM 1中，我们将生成一个pegy的CCN5衍生物 TNBC治疗单独或抗激素或化学疗法的组合，并表征了新颖的特征 生物标志物改善诊断和治疗结果。在AIM 2中，我们将制定重新利用策略 用于靶向激活CCN5的疗法，以减慢或阻止乳腺癌开始或临床前的乳腺癌开始或进展 鼠标模型。最后，在AIM 3中，通过剖析CCN5对CCN家庭蛋白（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如何控制重编程中充质至 上皮转变（MET），凋亡，肿瘤生长抑制和小鼠存活。这些研究是预期的 确定最佳的卵蛋白或CCN5激活剂，该蛋白会抑制TNBC的生长和进展以及 对他莫昔芬和紫杉醇的敏感TNBC细胞具有最小的全身性毒性或对健康细胞或不良影响 器官。将发现一种新型的CCN5作用机理。那就是这些方法应该很大 关于CCN5的治疗实用性及其在TNBC抑制中的机理见解的提前知识。 我们将使用多种最新技术以及我们的多学科团队的独特集体专业知识来 完成目标。