Stopping PDA progression using inhibitors of CSC dissemination and immunotherapy

使用 CSC 传播抑制剂和免疫疗法阻止 PDA 进展

• 批准号: 10286890
• 负责人: Sunil R Hingorani
• 金额: $ 25万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286890
• 关键词: Abraxane; Address; Biology; Blood Circulation; Breast Carcinoma; Cells; Chemoresistance; Clinical Oncology; Competence; Development; Disease; Distant; Elements; Future; Genetically Engineered Mouse; Global Change; Goals; Growth; Hematogenous; Immunity; Immunosuppression; Immunotherapy; Lead; Listeria; Liver; Lung; Malignant neoplasm of pancreas; Measures; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nonmetastatic; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Policies; Primary Neoplasm; Process; RUNX3 gene; Regimen; Site; Solid Neoplasm; Symptoms; Therapeutic Effect; Therapeutic Studies; Time; United States National Institutes of Health; Work; advanced disease; aggressive breast cancer; cancer cell; cancer stem cell; conditioning; cost; data sharing; gemcitabine; genomic data; improved; inhibitor/antagonist; malignant breast neoplasm; migration; neoplastic cell; pancreatic neoplasm; parent grant; prevent; programs; recruit; standard of care; stem; therapy design; therapy resistant; transcription factor; treatment strategy; tumor growth; tumor microenvironment

PROJECT SUMMARY Pancreatic Ductal Adenocarcinoma (PDA) is often called the silent serial killer, because it rarely causes symptoms and metastases have already spread from the pancreas to distant organs before the primary tumor can be detected. Moreover, the existing metastases may give rise to new metastases through dissemination of cancer stem cells as seen in breast carcinoma. Current standard of care regimens for advanced disease, such as Abraxane plus gemcitabine or FOLFIRINOX, have modestly improved survival, albeit at the cost of significant morbidity, and neither is curative. This underlines the need for new and/or additional approaches. Two issues need to be addressed in a concerted manner: 1) blocking the dissemination of cancer cells from the primary and metastatic sites, and 2) simultaneously eradicating existing primary tumors and metastases because metastases support continuous new CTC dissemination with metastasis-seeding potential. The intersection between cell- autonomous mechanisms, such as the RUNX3 developmental program; and non-cell autonomous processes, such as tumor microenvironment of metastasis (TMEM) windows, cooperate to drive and sustain the high metastatic competency of PDA. The Runx3 developmental transcription factor coordinates a secretory program that stimulates migration and invasion of cancer cells and preconditions the metastatic niche for successful dissemination of tumor cells. Therefore, our main goal is to focus on evaluating dissemination mechanisms and therapeutic effects in mice with either low or high Runx3 expression.

项目总结