Hedgehog/Gli1-targeted therapies to overcome ovarian cancer chemoresistance and disease recurrence

Hedgehog/Gli1 靶向疗法可克服卵巢癌化疗耐药性和疾病复发

• 批准号: 10087900
• 负责人: Komaraiah Palle
• 金额: $ 5.37万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087900
• 关键词: Adult; Aggressive behavior; BRCA deficient; BRCA1 gene; Biological Assay; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; ChIP-on-chip; ChIP-seq; Characteristics; Chemoresistance; Clinical Trials; Comb animal structure; Combination Drug Therapy; Combined Modality Therapy; Cytogenetics; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA biosynthesis; DNA lesion; Data; Development; Disease; Disease Progression; Down-Regulation; Drug Combinations; Drug Design; Erinaceidae; Exhibits; FANCD2 protein; FDA approved; GLI gene; Genes; Genome Stability; Glioma; Goals; Immunofluorescence Immunologic; In Vitro; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Methods; Modeling; Molecular; Mus; Oncogenes; Oncogenic; Operative Surgical Procedures; PARP inhibition; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Platinum; Pre-Clinical Model; Prognosis; Progression-Free Survivals; Proteins; Rad51 recombinase; Recurrence; Recurrent disease; Recurrent tumor; Regulation; Relapse; Reporter; Role; Signal Transduction; Testing; Therapeutic; Transcriptional Regulation; Tumor Suppressor Proteins; Up-Regulation; Western Blotting; Work; base; cancer cell; cancer stem cell; cancer therapy; carcinogenesis; chemotherapy; combat; design; efficacy testing; homologous recombination; improved; in vitro Assay; indexing; inhibitor/antagonist; member; mortality; mouse model; mutant; neoplastic cell; novel; novel therapeutics; ovarian neoplasm; patient derived xenograft model; patient population; preclinical evaluation; prevent; promoter; protein expression; recombinational repair; repaired; replication stress; research clinical testing; response; small molecule inhibitor; smoothened signaling pathway; stem cell genes; stem cells; stemness; synergism; targeted treatment; therapeutically effective; tumor; tumor xenograft

Abstract Ovarian cancer (OC) is deadly and incurable for patients that recur after primary cancer is treated with surgery and platinum-based chemotherapy. Unfortunately, OC has a high rate of disease recurrence (70-80%) and most recurrent tumors are chemoresistant. Currently, therapeutic options are quite limited for these patients, and thus unlike with other cancers, the mortality in OC has not improved in decades. This dreadful situation highlights a drastic need for new and improved therapeutics to eliminate and treat recurrent and chemoresistant disease. In this context our studies identified increased Hedgehog (Hh)/GLI signaling in chemoresistant OC cells and tumors, and GLI1 expression significantly correlated with upregulated FA-BRCA and homologous recombination (HR) genes, cancer stem cell signaling and poor prognosis of OC patients. Our preliminary data demonstrate that GLI1 regulates expression of DNA repair genes BRCA1, FANCD2 and RAD51 in OC cells and tumors and its inhibition induces a state known as “BRCAness”, which is characterized by inefficient repair of DNA double strand breaks (DSB). Additionally, Hh/GLI1 inhibition or downregulation decreased cell survival and ability to form tumor spheroids (stem cell characteristic), and enabled synthetic lethality with PARP inhibitors. In this proposal we aim to elucidate the molecular mechanisms by which Hh/GLI1 regulates FA-BRCA and HR genes that promote oncogenic replication (Aim 1), and determine the efficacy of Hh/GLI1 inhibitors in both BRCA-proficient and deficient OC cells in cell line and ovarian cancer orthotopic mouse models (Aim 2). Towards the goal of identifying effective therapeutic combinations that work synergistically and induce synthetic lethality, we will evaluate effective therapeutic combinations involving Hh/GLI1 and PARP inhibitors. The most efficient drug combinations will be examined in a mouse orthotopic and patient derived xenograft models of OC to evaluate their efficacy in combatting acquired chemoresistance and OC disease progression (Aim 3). Chemotherapeutic drugs examined in this proposal are FDA approved or currently undergoing clinical and preclinical evaluation (ex. vismodegib, sonidegib, GANT61, olaparib, rucaparib, niraparib); thus, the effective drug combinations discovered can quickly be transitioned into clinical trials and developed into treatments for OC patients.

抽象的 卵巢癌 (OC) 对于原发性癌症手术治疗后复发的患者来说是致命且无法治愈的 和铂类化疗。不幸的是，OC 的疾病复发率很高 (70-80%)，并且 大多数复发性肿瘤具有化疗耐药性。目前，这些患者的治疗选择非常有限， 因此，与其他癌症不同的是，OC 的死亡率几十年来一直没有改善。这种可怕的情况 强调迫切需要新的和改进的疗法来消除和治疗复发性和 化学耐药性疾病。在这种情况下，我们的研究发现 Hedgehog (Hh)/GLI 信号传导增加 化疗耐药 OC 细胞和肿瘤，GLI1 表达与 FA-BRCA 上调显着相关 和同源重组 (HR) 基因、癌症干细胞信号传导和 OC 患者的不良预后。我们的 初步数据表明，GLI1 调节 DNA 修复基因 BRCA1、FANCD2 和 OC 细胞和肿瘤中的 RAD51 及其抑制会诱导一种称为“BRCAness”的状态，其特征是 DNA 双链断裂 (DSB) 的低效修复。此外，Hh/GLI1 抑制或下调 降低细胞存活率和形成肿瘤球体的能力（干细胞特征），并能够合成 PARP 抑制剂的致死率。在本提案中，我们旨在阐明分子机制 Hh/GLI1 调节促进致癌复制的 FA-BRCA 和 HR 基因（目标 1），并确定 Hh/GLI1 抑制剂对 BRCA 丰富和缺陷的 OC 细胞系和卵巢癌的功效 原位小鼠模型（目标 2）。实现确定有效的治疗组合的目标 协同作用并诱导合成致死，我们将评估有效的治疗组合，包括 Hh/GLI1 和 PARP 抑制剂。最有效的药物组合将在小鼠原位进行检查 和患者衍生的 OC 异种移植模型，以评估其对抗获得性化疗耐药性的功效 和 OC 疾病进展（目标 3）。本提案中审查的化疗药物已获得 FDA 批准或 目前正在进行临床和临床前评估（例如 vismodegib、sonidegib、GANT61、olaparib、 鲁卡帕尼、尼拉帕尼）；因此，发现的有效药物组合可以快速转化为临床 试验并开发成针对 OC 患者的治疗方法。