Developing Therapy for the Treatment of Cholangiocarcinoma

 描述（由申请人提供）：胆管癌（CCA）是一种致死性疾病，5年生存率为0- 30%。对于大多数患者来说，化疗是唯一的治疗选择，几乎所有患者都会复发。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。单用吉西他滨或吉西他滨和顺铂均不能产生持久缓解。这种疾病的分子病因学知之甚少，最初有反应的肿瘤都会复发。 为了促进CCA的分子表征和有效疗法的开发，我们建立了一组CCA的患者来源的异种移植物（PDX）模型。我们建议使用这些模型来研究新型化合物JQ 1的抗肿瘤功效和作用机制，JQ 1是一种尚未评估用于治疗CCA的药剂。此外，本申请中的数据表明，JQ 1+吉西他滨的组合将在CCA肿瘤中产生协同细胞毒性;因此，我们将评估该组合的抗肿瘤功效 使用我们独特的CCA模型面板。 JQ 1是BET（布罗莫结构域和末端外结构域）蛋白的抑制剂，其调节转录聚集体与组蛋白的乙酰化赖氨酸残基在特异性转录水平上的结合。 染色体位点JQ 1和吉西他滨联合用药的理由令人信服。首先，JQ 1抑制BET蛋白的活性，并且还抑制c-Myc的表达，c-Myc是一种致癌转录因子，其促成许多实体瘤的致瘤表型并且可能在吉西他滨耐药性中起作用。其次，本申请中的数据证明了JQ 1下调DNA损伤反应蛋白Chk 1的新发现。这一发现特别相关，因为文献中的多项研究表明，抑制Chk 1 使实体瘤细胞对吉西他滨敏感。第三，来自我们实验室的未发表的数据表明，JQ 1通过与吉西他滨不同的机制诱导DNA损伤，这表明这两种药物至少有相加诱导DNA损伤的潜力。第四，我们的体外数据显示，JQ 1+吉西他滨在胰腺癌细胞（一种与CCA密切相关的细胞类型）中具有非常强的协同作用。我们假设JQ 1和吉西他滨将在CCA肿瘤中诱导协同细胞毒性。 我们将使用我们的PDX CCA模型评估这种组合的抗肿瘤功效，并确定观察到的c-Myc和Chk 1的下调是否对JQ 1的细胞毒性以及JQ 1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以及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，其长期目标是鉴定对吉西他滨和JQ 1敏感或耐药的生物标志物。

 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.