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Improving Radiation Therapy For Pancreatic Cancer

改善胰腺癌的放射治疗

基本信息

批准号：
8880445
负责人：
Xinhui Wang
金额：
$ 18.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880445
关键词：
Adenocarcinoma Adenocarcinoma Cell Agreement Alcoholism Allogenic Apoptosis Autologous Binding Biological Models Breast Cancer Cell Cell Line Cells Clinical Complex Copper Copper Gluconate Cytotoxic T-Lymphocytes Cytotoxic agent Diagnosis Disease Disulfiram Down-Regulation Ductal Early Diagnosis Epitopes Excision FDA approved Face Fluorouracil Foundations Generations Genes Goals Helper-Inducer T-Lymphocyte Human Immunotherapy In Vitro Ionizing radiation Knowledge MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of pancreas Messenger RNA Methodology Modality Mus Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Oral Oral Administration Oxidation-Reduction Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Physiological Play Protein Isoforms Radiation Radiation therapy Radiation-Induced Cancer Radiation-Sensitizing Agents Reaction Reactive Oxygen Species Recurrence Regimen Resectable Resistance Role Signal Transduction Source Staging Survival Rate T-Lymphocyte Testing Therapeutic Time Toxic effect Trace Elements Tumorigenicity Up-Regulation alcoholism therapy aldehyde dehydrogenase 1 aldehyde dehydrogenases base beta catenin cancer cell cancer stem cell cancer therapy chemoradiation chemotherapy clinical application comparative efficacy dietary supplements improved in vivo inhibitor/antagonist irradiation killings mouse model neoplastic cell novel novel strategies novel therapeutics nutrition outcome forecast pancreatic cancer cells pancreatic neoplasm prevent public health relevance radioresistant response stem stemness tumor

项目摘要

DESCRIPTION (provided by applicant): Radiation therapy plays a key role in pancreatic ductal adenocarcinoma (PDAC) treatment. However, it faces challenges from the fact that pancreatic cancer stem cells (PCSC) are resistant to ionizing radiation. Moreover, a recent finding indicates that radiation can reprogram nonstem- cancer cells into cancer stem cells, which is in agreement with our finding, namely iPCSC. Compelling evidence show that PDAC cells in expressing elevated levels of aldehyde dehydrogenase 1 (ALDH1), ALDHbrightcells, are PCSC/iPCSC. In the past, we demonstrated that cytotoxic T cells (CTL) specifically recognizing an epitope from the ALDH1A1 isoform eliminate ALDHbright cells in vitro and in vivo. However, the clinical applicability of adoptive T cell-based immunotherapy is limited by HLA class I restriction and requires ex vivo expansion of autologous or allogeneic T cells using a variety of methodologies. To overcome the limitations of CTL-targeting of ALDHbright cells, we tested the novel approach of using disulfiram (DSF) to target PCSC. DSF is a dithiocarbamate and an FDA-approve inhibitor of ALDH for treatment of alcoholism. Its toxicity to PDAC cells has been shown to be enhanced by the binding of the essential trace element copper (Cu++) to form DSF/Cu complexes. We found recently using PDAC cell lines that: i) PCSC increased two days after in vitro fractionated irradiation; ii) DSF/Cu depleted PCSC during the treatment gap, and abolished in vitro sphere formation of irradiated cells; iii) DSF/Cu downregulated Wnt pathway, a key cancer stem cell pathway, in irradiated PDAC cells, and iv) DSF/Cu blocked radiation induced re-expressing mRNA of stemness genes. These findings provide the rationale for our central hypothesis that DSF/Cu depletes pre-existing PCSC and radiation-induced PCSC which results in significant increases in the efficacy of radiation therapy. In Aim1, we will determine that DSF/Cu eliminates both PCSC and iPCSC in vitro and in vivo. In Aim2, we will examine that RT combined with DSF/Cu can effectively eliminate stem- and nonstem- PDAC cells in a neoadjuvant setting using xeno- and syngeneic- pancreatic tumors in mice. In Aim3, we will compare the efficacy of combination of DSF/Cu, RT and 5-Fluorouracil (5-FU), a commonly used radiosensitizer for PDAC vs conventional chemoradiation consisting of RT and 5-FU in a neoadjuvant setting in xeno- and syngeneic- PDAC mouse model systems . At the conclusion of the proposed studies, we will have evaluated DSF/Cu as a cytotoxic agent of pre-existing PSCS/iPSCS and as a blocker of generation of iPCSC, obtained knowledge of the mechanism(s) by which DSF/Cu enhances efficacy of radiation and chemoradiation therapy, and formed the foundation of a novel neoadjuvant therapy for improved efficacy of radiation and chemoradiation by combination with a FDA approved drug DSF and a nutrition supplement Copper gluconate.