New Therapuetics for Pancreatic Cancer

胰腺癌的新疗法

基本信息

批准号：
10617320
负责人：
Michael T Barrett
金额：
$ 58.64万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-03 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617320
关键词：
ATAC-seq Acetylation Adenocarcinoma Adjuvant Adjuvant Therapy Automobile Driving Biological CDKN2A gene Cancer Etiology Cell Survival Cells Cessation of life Chemicals Chromatin Clinical Colon Cytoplasm Data Diagnosis Disease Drug Targeting Duct (organ) structure Enzymes Epigenetic Process Event Foundations Gene Expression Genetic Genetic Transcription Genome Genomics Histology Histones Human Immunodeficient Mouse Immunofluorescence Immunologic Impairment Incidence Individual Intercellular Junctions KRAS2 gene Lesion Lung Lysine Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Maps Measures Mediating Medical Methylation Minor Modeling Molecular Mutation Operative Surgical Procedures Organoids Outcome Pancreatic Ductal Adenocarcinoma Patients Pattern Persons Pharmaceutical Preparations Phenotype Precision therapeutics Proteins Recurrence Regulatory Element Reporting Resectable Role SOX5 gene Sampling Signal Pathway Solid Sorting Squamous cell carcinoma Stomach Surgical Management TP53 gene Testing Therapeutic Time Tissues Tumor stage Variant Xenograft procedure candidate identification cell growth chemotherapeutic agent chemotherapy chromatin modification cohort data integration epigenome epigenomics expectation gemcitabine genomic locus histone methyltransferase in vivo insight irinotecan keratinization novel strategies novel therapeutic intervention pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm population based pre-clinical response therapeutic target transcription factor transcriptome transcriptome sequencing tumor tumor growth

项目摘要

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.

概括我们的建议将发展最大的胰腺腺癌癌（ASCP）模型并表征这种破坏性肿瘤的基因组和表观基因组景观胰腺导管腺癌（PDAC），期望鉴定可以是的表观遗传特征利用以选择性损害一个或两种亚型细胞的生长。 ASCP是胰腺的罕见亚型癌症占所有胰腺癌的2-4％年。令人惊讶的是，ASCP显示出比更多的转移潜力和更差的临床结果普通（占病例的90-95％）PDAC。但是，大型基于人群的分析未检测到任何差异 PDAC和ASCP诊断时的肿瘤阶段。尽管有积极的手术管理据报道，少数出现可切除疾病的患者的中位生存期为始终不到1年。此外，没有标准辅助治疗或转移性的第一线疗法患者已为这种侵略性的胰腺癌亚型建立。我们的初步观察建议独特的ASCP基因组和表观基因组景观，并证明我们的分子研究如何确定我们现在旨在验证使用的候选治疗靶标和策略独特的临床前ASCP模型。我们的假设是ASCP从与PDAC相同的谱系演变然而，包含驱动ASCP侵略性表型的不同表观基因组学特征。我们提出了这一点调节ASCP表观基因组将使ASCP细胞对现有化学疗法（例如，吉西他滨和 Irinotecan）用作PDAC和其他固体恶性肿瘤的第一线治疗方法。此外，我们将评估关键表观遗传蛋白耗竭对维持ASCP表观组和细胞活力的影响，以及表观遗传靶向药物与化学治疗剂对ASCP肿瘤的影响增长旨在确定ASCP的精确治疗。我们的研究将提供有关维持ASCP和PDAC表型的表观遗传机制，将与鳞状来自其他组织（例如结肠，肺和胃）的癌。此外，成功完成提案将为ASCP患者和可能其他癌症的新治疗选择提供基础混合组织学。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

EGFR Reloaded: Finding New Ways to Shape Pancreatic Cancer Epigenome.

DOI：
10.1016/j.jcmgh.2023.02.003
发表时间：
2023
期刊：
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
影响因子：
7.2
作者：
Larue, Kayla C.;Fernandez-Zapico, Martin E.
通讯作者：
Fernandez-Zapico, Martin E.

Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers.

DOI：
10.1172/jci.insight.158060
发表时间：
2022-11-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Hogenson, Tara L.;Xie, Hao;Phillips, William J.;Toruner, Merih D.;Li, Jenny J.;Horn, Isaac P.;Kennedy, Devin J.;Almada, Luciana L.;Marks, David L.;Carr, Ryan M.;Toruner, Murat;Sigafoos, Ashley N.;Koenig-Kappes, Amanda N.;Olson, Rachel L. O.;Tolosa, Ezequiel J.;Zhang, Cheng;Li, Hu;Doles, Jason D.;Bleeker, Jonathan;Barrett, Michael T.;Boyum, James H.;Kipp, Benjamin R.;Mahipal, Amit;Hubbard, Joleen M.;Hanson, Temperance J. Scheffler;Petersen, Gloria M.;Dasari, Surendra;Oberg, Ann L.;Truty, Mark J.;Graham, Rondell P.;Levy, Michael J.;Zhu, Mojun;Billadeau, Daniel D.;Adjei, Alex A.;Dusetti, Nelson;Iovanna, Juan L.;Bekaii-Saab, Tanios S.;Ma, Wen Wee;Fernandez-Zapico, Martin E.
通讯作者：
Fernandez-Zapico, Martin E.