Evaluating unique aspects of quiescent ovarian cancer cell biology for therapeutic targets

评估静息卵巢癌细胞生物学的独特方面以寻找治疗靶点

• 批准号: 10750118
• 负责人: Ronald J Buckanovich
• 金额: $ 43.81万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750118
• 关键词: Adjuvant Therapy; Animals; Binding; Bioinformatics; Biologic Characteristic; Biological; Biological Factors; Biology; Cancer Patient; Cell Cycle; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular biology; Cessation of life; Characteristics; Chemoresistance; Combined Modality Therapy; Data; Devices; Disease; Disease Resistance; Exhibits; FDA approved; Follistatin; Gene Expression Profile; Genetic Transcription; Goals; Human; Immunotherapy; Knock-out; Link; Malignant neoplasm of ovary; Mediating; Messenger RNA; Microfluidics; Molecular; Pathway interactions; Patient Care; Patient-Focused Outcomes; Phenotype; Proliferating; Proteasome Inhibitor; Proteins; RNA analysis; Recurrent disease; Refractory; Relapse; Residual Cancers; Residual state; Role; Route; Sea; System; Testing; Therapeutic; Tumor Tissue; Ubiquitin; Up-Regulation; Work; Yeasts; cancer cell; cancer type; chemotherapy; differential expression; effective therapy; genetic approach; improved; improved outcome; in vivo; inhibitor; knock-down; multicatalytic endopeptidase complex; neutralizing antibody; new therapeutic target; novel; novel strategies; novel therapeutics; pharmacologic; prevent; recruit; senescence; small molecule inhibitor; targeted treatment; therapeutic target; therapy resistant; transcriptome sequencing

Most ovarian cancer (OvCa) patients develop fatal chemotherapy-resistant disease. Elucidating mechanisms of chemoresistance in OvCa may identify therapeutic targets to prevent or treat relapsed OvCa. One understudied mechanism of chemotherapy resistance in OvCa is quiescence. Quiescent cells are transiently non-proliferating and thus refractory to standard therapies which target rapidly proliferating cells. The over- arching hypothesis of this project is that hypothesis is that understanding the biology of quiescent OvCa cancer cells will identify critical new therapeutic targets to improve patient outcomes. We have used multiple novel approaches to identify and characterize the transcriptional signature of quiescent OvCa cells. This work indicates that quiescent OvCa (qOvCa) cells have several unique characteristics including: (i) a unique Quiescence Associated Secretory Phenotype (QuASP) which drives chemotherapy resistance in non- quiescent cancer cells, and (ii) altered expression of select components of the ubiquitin-proteosome system (UPS) including induction of UBL7. Indeed, our preliminary data indicate that induction of UBL7 is sufficient to drive a quiescent cell phenotype, including the expression of the QuASP. Bio-informatic analysis of quiescent OvCa cell RNAseq data identified the SRF/MRTF transcription pathway as being inversely correlated with the OvCa quiescent signature. Consistent with this, a small molecule inhibitor of SRF/MRTF-mediated transcription, CCG081, (i) induces UBL7, (ii) drives cells into a dense quiescent state, and (iii), indicating a critical role for the UPS in quiescent cell viability, CCG081 sensitizes OvCa cells to proteasome inhibitors. Based on these discoveries, we propose: SA 1: To characterize the OvCa QuASP. We hypothesize that, characterizing the QuASP will identify critical biologic factors related to quiescence. We will identify QuASP factors, validate the expression of QuASP factors in ovarian cancer and other cancer types, and use knockdown and neutralizing antibodies to evaluate the function of these factors in quiescent OvCa cells.SA 2: To determine the role of the UPS and UBL7 in quiescent cancer cells. We hypothesize that UPS changes contribute to the quiescent cell state and are essential for quiescent cell viability. We will identify which components of the UPS contribute to the quiescent phenotype, including expression of the QuASP, and determine if the proteosome is essential to maintain quiescent OvCa cell viability. Finally, we will SA 3: Evaluate the impact of targeting the proteosome quiescent cells in vivo. We hypothesize that the ability to pharmacologically force these residual cells into a quiescent state and then eliminate these quiescent cells via proteosome inhibition will increase cure rates. We will evaluate the therapeutic potential of combined CCG081 and FDA-approved proteosome inhibitors as consolidative therapy after chemotherapy to eradicate residual quiescent cells. Impact: We will define the regulators of OvCa cell quiescence, providing therapeutic targets eradiate to improve patient outcomes.

大多数卵巢癌(OvCa)患者会患上致命的化疗耐药疾病。阐明机制 卵巢癌化疗耐药的研究可以确定预防或治疗复发的卵巢癌的治疗靶点。一 卵巢癌化疗耐药机制尚不清楚，目前尚处于停滞状态。静止的单元是暂时的 不增殖，因此对以快速增殖的细胞为靶点的标准疗法难以奏效。已经过去了- 这个项目的核心假设是，假设是理解静止的生物学 卵巢癌细胞将确定关键的新治疗靶点，以改善患者的预后。我们有 用多种新方法鉴定和表征静止卵母细胞的转录特征 细胞。这项工作表明，静止的OvCa(QOvCa)细胞具有几个独特的特征，包括：(1) 一种独特的静止期相关分泌表型(QuASP)导致非小细胞肺癌化疗耐药 静止的癌细胞，以及(Ii)泛素-蛋白小体系统部分成分的表达改变 (UPS)包括UBL7的诱导。事实上，我们的初步数据表明，UBL7的诱导足以 驱动静止的细胞表型，包括QuASP的表达。静态生物信息学分析 OvCa细胞RNAseq数据表明，SRF/MRTF转录途径与 OvCa静态签名。与此相一致的是，SRF/MRTF介导的小分子抑制剂 转录，CCG081，(I)诱导UBL7，(Ii)使细胞进入密集静止状态，和(Iii)，表明 UPS在静止细胞活力中的关键作用，CCG081使OvCa细胞对蛋白酶体抑制剂敏感。 基于这些发现，我们建议：SA 1：描述OvCa Quasp.我们假设， 确定QuASP的特征将确定与静止有关的关键生物学因素。我们将确定Quasp 因子，验证QuASP因子在卵巢癌和其他癌症类型中的表达，并使用 敲除和中和抗体以评估这些因子在静止的OvCa细胞中的功能。SA 2： 确定UPS和UBL7在静止期癌细胞中的作用。我们假设UPS改变了 有助于静止的细胞状态，对静止的细胞活力是必不可少的。我们将确定哪些是 UPS的成分有助于静止的表型，包括QuASP的表达，以及 确定蛋白质小体是否是维持静止的OvCa细胞活力所必需的。最后，我们将SA 3： 评估体内靶向蛋白小体静止细胞的影响。我们假设有能力 药物迫使这些残留细胞进入静止状态，然后通过 抑制蛋白酶体将提高治愈率。我们将评估联合应用CCG081的治疗潜力 FDA批准的蛋白小体抑制剂作为化疗后的巩固治疗以消除残留 静止的细胞。影响：我们将定义OvCa细胞静止的调节因素，提供治疗靶点 放射治疗以改善患者预后。