Mechanism-based combination therapy for cholangiocarcinoma

基于机制的胆管癌联合治疗

• 批准号: 10650049
• 负责人: Karina J Yoon
• 金额: $ 20.83万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650049
• 关键词: Acetylation; Affect; Analysis of Variance; Apoptosis; BRCA2 Protein; BRCA2 gene; BRD2 gene; Bile duct carcinoma; Binding; Binding Sites; Bromodomain; Bromodomains and extra-terminal domain inhibitor; CASP3 gene; Caring; Cells; Characteristics; Cholangiocarcinoma; Cisplatin; Clinical Trials; Combined Modality Therapy; Complex; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA sequencing; DNA-dependent protein kinase; Data; Diagnosis; Disease remission; Drug Combinations; Drug resistance; Event; FGFR2 gene; Fluorouracil; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hematopoietic; Hepatic; Histones; In Vitro; Incidence; KRAS2 gene; Laboratories; Lesion; Literature; Lysine; Mediating; Modeling; Molecular; Mutation; Nature; Neoplasm Metastasis; Oncogenes; Paclitaxel; Parents; Pathway interactions; Patients; Pattern; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Proliferation Marker; Protein Family; Proteins; Regimen; Renal function; Reporting; Resistance; Resistance development; Survival Rate; TP53 gene; Tertiary Protein Structure; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Tumor Volume; Work; XRCC5 gene; advanced disease; chemotherapy; clinical efficacy; clinically relevant; cohort; cytotoxicity; effective therapy; efficacy evaluation; gemcitabine; gene product; genome sequencing; homologous recombination; improved; in vivo; in vivo Model; inhibitor; interest; liver function; novel; overexpression; patient derived xenograft model; peripheral blood; relapse patients; response; standard of care; subcutaneous; synergism; targeted agent; transcriptome sequencing; treatment group; tumor; tumor DNA; whole genome

PROJECT SUMMARY/ABSTRACT Cholangiocarcinoma (CCA) is an aggressive bile duct cancer. A majority of patients present with advanced disease and die within a year. For these patients, chemotherapy is the main therapeutic option. Current standards of care include gemcitabine-based regimens such as gemcitabine + cisplatin. However, the 5-year survival rate has not been improved for several decades; tumors that respond initially become resistant, and patients relapse. The literature documents that overexpression of DNA repair proteins contributes to resistance to DNA damaging agents such as gemcitabine and cisplatin, current frontline agents for CCA. This proposal seeks to identify gemcitabine-based combinations that overcome drug resistance and produce durable remissions for patients with CCA. To identify effective regimens and characterize molecular events that contribute to chemosensitivity or resistance, we developed a panel of patient-derived xenograft (PDX) CCA models: CCA1-5 and gemcitabine- resistant counterparts of CCA1 and CCA2 (CCA1.gemR and CCA2.gemR), with resistance acquired in vivo. We propose to use these models to identify effective treatments for CCA. Our data support the hypothesis that gemcitabine + a BET inhibitor (BETi) + a PARP inhibitor (PARPi) comprises effective treatment for this tumor type. Bromodomain and extra-terminal domain (BET) proteins regulate the association of transcription complexes to acetylated lysine residues of histones at specific chromosomal loci. BETi decrease expression of genes whose expression is BET-dependent. Multiple BETi are in clinical trial. Our data demonstrate: 1) that BETi + PARPi and also that BETi + gemcitabine are synergistic in vitro; 2) the novel finding that gemR cells are more sensitive to BETi + PARPi than to gemcitabine + cisplatin; and 3) that the BETi JQ1 + gemcitabine was more effective than gemcitabine as a single agent in the CCA1.gemR PDX in vivo model (P<0.001). Further, our data suggest that sequential administration of BETi → gemcitabine will produce BETi-mediated decreases in expression of DNA repair proteins and minimize gemcitabine resistance. Proposed work evaluates the anti-tumor efficacy of the clinical BETi OTX015 + the PARPi olaparib + gemcitabine, cisplatin, or gemcitabine + cisplatin in models of local and metastatic CCA. We will determine if any of these regimens is superior to current standard of care, and perform whole genome sequencing of all models to identify genetic and molecular characteristics associated with resistance. We will also generate expression profiles of treated vs control tumors and of primary vs metastatic tumors. These data will provide a basis for future work toward long-term goals of identifying gene products and pathways that contribute to drug resistance or metastasis of CCA, and to develop effective treatment regimens using targeted agents.

项目总结/摘要 胆管癌（CCA）是一种侵袭性胆管癌。大多数患者存在 病情恶化，一年内死亡。对于这些患者，化疗是主要的治疗选择。电流 护理标准包括基于吉西他滨的方案，例如吉西他滨+顺铂。然而，5年 存活率几十年来没有提高;最初有反应的肿瘤变得有抗性， 患者复发。文献记载，DNA修复蛋白的过表达有助于耐药 DNA损伤剂，如吉西他滨和顺铂，目前用于CCA的一线药物。这项建议 旨在确定以吉西他滨为基础的复方制剂， 缓解CCA患者。 确定有效的治疗方案，并描述导致化疗敏感性的分子事件， 耐药性，我们开发了一组患者来源的异种移植物（PDX）CCA模型：CCA 1 -5和吉西他滨。 CCA 1和CCA 2的抗性对应物（CCA1.gemR和CCA2.gemR），具有体内获得的抗性。我们 我们建议使用这些模型来确定CCA的有效治疗方法。我们的数据支持这样的假设， 吉西他滨+BET抑制剂（BETi）+PARP抑制剂（PARPi）包括对该肿瘤的有效治疗 类型.溴结构域和末端外结构域（BET）蛋白调节转录的关联 复合物乙酰化赖氨酸残基的组蛋白在特定的染色体位点。BETi降低了 其表达依赖于BET的基因。多个BETi正在进行临床试验。 我们的数据表明：1）BETi + PARPi以及BETi +吉西他滨在体外是协同的; 2） 新发现，gemR细胞对BETi + PARPi比对吉西他滨+顺铂更敏感;和3） BETi JQ 1+吉西他滨在CCA 1.gemR PDX中作为单药比吉西他滨更有效， 体内模型组与模型组比较P<0.001。此外，我们的数据表明，序贯给予BETi →吉西他滨将 产生BETi介导的DNA修复蛋白表达的降低，并使吉西他滨耐药性最小化。 建议的工作评估临床BETi OTX 015 + PARPi奥拉帕尼+ 吉西他滨、顺铂或吉西他滨+顺铂在局部和转移性CCA模型中的作用。我们将确定是否 这些方案中的任何一种都上级于当前的护理标准， 用于识别与抗性相关的遗传和分子特征的模型。我们还将产生 治疗肿瘤与对照肿瘤以及原发性肿瘤与转移性肿瘤的表达谱。这些数据将提供 为今后的工作奠定了基础，以实现确定有助于药物代谢的基因产物和途径的长期目标。 CCA的耐药或转移，并开发使用靶向药物的有效治疗方案。