New Therapuetics for Pancreatic Cancer

总结 我们的提案将开发最大的胰腺腺鳞癌（ASCP）模型队列 并将这种毁灭性肿瘤的基因组和表观基因组景观与 胰腺导管腺癌（PDAC），期望确定可以 被利用来选择性地损害一种或两种亚型的细胞的生长。ASCP是胰腺癌的一种罕见亚型， 胰腺癌占所有胰腺癌的2-4%，发病率< 1例/100，000人/ 年引人注目的是，ASCP显示出更高的转移潜力和更差的临床结果， 常见（90-95%的病例）PDAC。然而，一项基于人口的大型分析并未发现任何差异， 诊断时肿瘤分期介于PDAC和ASCP之间。尽管积极的手术治疗， 对于那些存在可切除疾病的少数患者，据报道中位生存期为 一直不到一年。此外，没有标准的辅助治疗或转移性肿瘤的一线治疗， 对于这种侵袭性胰腺癌亚型，我们的初步观察 提出了一个独特的ASCP基因组和表观基因组景观，并展示了我们的分子研究如何能够 确定这种令人沮丧的癌症的候选治疗靶点和策略，我们现在的目标是使用 独特的临床前ASCP模型。我们的假设是ASCP和PDAC是从同一谱系进化而来的 还包含驱动ASCP侵袭性表型的独特表观基因组特征。我们建议 调节ASCP表观基因组将使ASCP细胞对现有化疗敏感（例如，吉西他滨和 伊立替康）用作PDAC和其他实体恶性肿瘤的一线治疗。此外，我们将评估 消除关键表观遗传蛋白对ASCP表观基因组和细胞活力维持的影响， 以及表观遗传靶向药物联合化疗药物对ASCP肿瘤的影响 生长，目的是确定ASCP的精确治疗。我们的研究将提供深入了解 维持ASCP和PDAC表型并与鳞状细胞癌相关的表观遗传机制 来自其它组织的癌（例如，结肠、肺和胃）。此外，成功完成这一 该提案将作为ASCP患者和潜在其他癌症的新治疗选择的基础 混合组织学

SUMMARY Our proposal will develop the largest cohort of Adenosquamous cancer of the pancreas (ASCP) models and characterize the genomic and epigenomic landscapes of this devastating tumor in comparison with that of pancreatic ductal adenocarcinoma (PDAC), with the expectation of identifying epigenetic features that can be exploited to selectively impair growth of cells of one or both subtypes. ASCP is a rare subtype of pancreatic cancer representing 2-4% of all pancreatic cancers with an incidence rate of < 1 case per 100,000 people per year. Strikingly, ASCP displays a higher metastatic potential and a worse clinical outcome than the more common (90-95% of cases) PDAC. Yet, a large population-based analysis did not detect any differences in tumor stage at the time of diagnosis between PDAC and ASCP. Despite aggressive surgical management for those few patients who present with resectable disease, the median survival has been reported to be consistently less than 1 year. Furthermore, no standard adjuvant therapy, or first line therapies for metastatic patients, has been established for this aggressive subtype of pancreatic cancer. Our preliminary observations suggest a unique ASCP genomic and epigenomic landscape and demonstrate how our molecular studies can identify candidate therapeutic targets and strategies for this dismal cancer that we now aim to validate using unique preclinical ASCP models. It is our HYPOTHESIS that ASCP evolve from the same lineage as PDACs yet contain distinct epigenomic features driving the aggressive phenotype of ASCP. We propose that modulating ASCP epigenome will sensitize ASCP cells to existing chemotherapies (e.g., gemcitabine and irinotecan) used as first line of treatments for PDAC and other solid malignancies. Further, we will evaluate the effects of depletion of key epigenetic proteins on the maintenance of the ASCP epigenome and cell viability, and the impact of epigenetically targeted drugs in combination with chemotherapeutic agents on ASCP tumor growth with the aim of identifying precision treatments for ASCP. Our studies will provide insight into the epigenetic mechanisms that maintain the ASCP and PDAC phenotypes and will be relevant to squamous carcinomas from other tissues (e.g., colon, lung and stomach). Further, the successful completion of this proposal will serve as a foundation for new treatment options for ASCP patients and potentially other cancers with mixed histologies.