Developing Therapy for the Treatment of Cholangiocarcinoma

 描述(申请人提供)：胆管细胞癌(CCA)是一种致命的疾病，五年存活率为0-30%。对于大多数患者来说，化疗是唯一的治疗选择，而且几乎所有的患者都会复发。吉西他滨是治疗CCA的一线药物，吉西他滨联合顺铂是目前的治疗标准。单独使用吉西他滨或吉西他滨和顺铂都不能持久缓解。这种疾病的分子病因学知之甚少，最初有反应的肿瘤一致复发。 为了便于CCA的分子表征和有效治疗方法的开发，我们建立了一组患者来源的CCA异种移植(PDX)模型。我们建议使用这些模型来研究新型化合物JQ1的抗肿瘤效果和作用机制，JQ1是一种尚未被评估用于治疗CCA的药物。此外，本应用中的数据表明，JQ1+吉西他滨联合应用将在CCA肿瘤中产生协同细胞毒性；因此，我们将评估该联合应用的抗肿瘤效果。 使用我们独特的CCA模型面板。 JQ1是一种BET(溴结构域和末端外结构域)蛋白的抑制剂，它调节组蛋白在特定位置的转录聚集体与乙酰化赖氨酸残基的结合。 染色体基因座。联合使用JQ1和吉西他滨的理由是令人信服的。首先，JQ1抑制BET蛋白的活性，也抑制c-Myc的表达，c-Myc是一种癌基因转录因子，与许多实体瘤的致瘤表型有关，并可能在吉西他滨耐药中发挥作用。其次，本申请中的数据记录了JQ1下调DNA损伤反应蛋白Chk1的新发现。这一发现具有特别的相关性，因为文献中的多项研究表明，对Chk1的抑制 使实体瘤细胞对吉西他滨敏感。第三，我们实验室未发表的数据表明，JQ1诱导DNA损伤的机制与吉西他滨不同，这表明这两种药物至少可能相加地诱导DNA损伤。第四，我们的体外数据显示，JQ1+吉西他滨对胰腺癌细胞有很强的协同作用，胰腺癌细胞是一种与CCA密切相关的细胞类型。我们假设JQ1和吉西他滨将在CCA肿瘤中诱导协同细胞毒作用。 我们将使用我们的PDX CCA模型评估这种组合的抗肿瘤效果，并确定所观察到的c-Myc和Chk1的下调是否对JQ1的细胞毒性以及JQ1和吉西他滨的协同作用至关重要。我们还将确定这种组合是否在吉西他滨耐药和敏感肿瘤中产生协同抗肿瘤细胞毒性，并将产生吉西他滨敏感和耐药CCA肿瘤的表达谱，长期目标是确定对吉西他滨和JQ1敏感或耐药的生物标记物。

 DESCRIPTION (provided by applicant): Cholangiocarcinoma (CCA) is a fatal disease, with a five year survival of 0-30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA and the combination of gemcitabine and cisplatin is the current treatment standard. Neither gemcitabine alone or gemcitabine and cisplatin produce durable remissions. The molecular etiology of this disease is poorly understood, and tumors that respond initially uniformly relapse. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We propose to use these models to investigate the anti-tumor efficacy and mechanism of action of the novel compound JQ1, an agent that has not been evaluated for the treatment of CCA. Further, data in this application indicate that the combination of JQ1 + gemcitabine will produce synergistic cytotoxicity in CCA tumors; therefore, we will evaluate the anti-tumor efficacy of this combination using our unique panel of CCA models. JQ1 is an inhibitor of BET (bromodomain and extra-terminal domain) proteins, which regulate the association of transcriptional aggregates to acetylated lysine residues of histones at specific chromosomal loci. The rationale for combining JQ1 and gemcitabine is compelling. Firstly, JQ1 inhibits the activity of BET proteins and also inhibits expression of c-Myc, an oncogenic transcription factor that contributes to the tumorigenic phenotype of many solid tumors and likely plays a role in gemcitabine resistance. Secondly, data in this application document the novel finding that JQ1 down-regulates the DNA damage response protein Chk1. This finding is of particular relevance in that multiple studies in the literature demonstrate that inhibition of Chk1 sensitizes solid tumor cells to gemcitabine. Thirdly, unpublished data from our lab indicate that JQ1 induces DNA damage by a mechanism distinct from that of gemcitabine, suggesting the potential for at least additive induction of DNA damage by these two agents. Fourthly, our in vitro data show that JQ1 + gemcitabine are very strongly synergistic in pancreatic cancer cells, a cell type closely related to CCA. We hypothesize that JQ1 and gemcitabine will induce synergistic cytotoxicity in CCA tumors. We will evaluate the anti-tumor efficacy of this combination using our PDX CCA models, and determine if the observed downregulation of c-Myc and Chk1 is critical to the cytotoxicity of JQ1 and to the synergy of JQ1 and gemcitabine. We will also determine whether this combination produces synergistic anti-tumor cytotoxicity in gemcitabine-resistant as well as -sensitive tumors, and will generate expression profiles of gemcitabine-sensitive and -resistant CCA tumors, with a long-range goal of identifying biomarkers of sensitivity or resistance to gemcitabine and JQ1.