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

基本信息

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
项目类别：
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

项目摘要

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）患者患有致命的化学疗法疾病。阐明机制 OVCA的化学耐药性可能会鉴定出预防或治疗复发的OVCA的治疗靶标。一 OVCA化学疗法耐药性的研究机制是静止的。静止的细胞是瞬时的非增殖，因此对靶向快速增殖细胞的标准疗法难治性。超过该项目的拱门假设是假设是理解静态的生物学 OVCA癌细胞将确定关键的新治疗靶标，以改善患者预后。我们有使用了多种新颖的方法来识别和表征静态OVCA的转录特征细胞。这项工作表明静态的OVCA（QOVCA）细胞具有多种独特的特征，包括：（i）独特的静止与分泌表型（QUASP），可在非 - 静止的癌细胞，以及（ii）泛素蛋白酶系统的精选成分的表达改变（UPS），包括诱导UBL7。确实，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。静止的生物信息分析 OVCA细胞RNASEQ数据确定SRF/MRTF转录途径与 OVCA静止签名。与此相一致，SRF/MRTF介导的小分子抑制剂转录，CCG081，（i）诱导UBL7，（ii）将细胞驱动到一个密集的静态状态，（iii），表明一个 CCG081在UPS中的关键作用在静态细胞活力中，将OVCA细胞敏感到蛋白酶体抑制剂。基于这些发现，我们提出：SA 1：要表征OVCA Quasp。我们假设这一点，表征Quasp将确定与静止有关的关键生物学因素。我们将确定quasp 因素，验证卵巢癌和其他癌症类型中Quasp因子的表达，并使用敲低和中和抗体，以评估这些因素在静止的OVCA细胞中的功能。SA2：确定UPS和UBL7在静止的癌细胞中的作用。我们假设UPS发生了变化有助于静止的细胞状态，对于静止的细胞活力至关重要。我们将确定哪个 UPS的组成部分有助于静止的表型，包括quasp的表达，确定蛋白体对于维持静止的OVCA细胞活力是否必不可少。最后，我们将SA 3：评估靶向体内蛋白体静态细胞的影响。我们假设有能力药理从药理上迫使这些残留细胞进入静止状态，然后通过蛋白体抑制作用将增加治愈率。我们将评估CCG081组合的治疗潜力和FDA批准的蛋白质体抑制剂作为化学疗法后的巩固疗法，以消除残留静止的细胞。影响：我们将定义OVCA细胞静止的调节剂，提供治疗靶标根除改善患者预后。