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.

描述（由适用提供）：放射治疗在胰腺导管腺癌（PDAC）治疗中起关键作用。然而，由于胰腺癌干细胞（PCSC）对电离辐射具有抗性，因此面临挑战。此外，最近的发现表明，辐射可以将非茎癌细胞重新编程为癌细胞，这与我们的发现一致，即IPCSC。令人信服的证据表明，表达醛含量升高的醛脱氢酶1（ALDH1），AldhbrightCells中的PDAC细胞是PCSC/IPCSC。过去，我们证明了细胞毒性T细胞（CTL）特异性地识别来自AldH1A1同工型的表位，从而消除了体外和体内的Aldhbright细胞。但是，基于自适应T细胞的免疫疗法的临床适用性受到HLA I类限制的限制，并且需要使用多种方法在体内扩展自体或同种异体T细胞。为了克服Aldhbright细胞CTL靶向的局限性，我们测试了使用二硫兰（DSF）靶向PCSC的新方法。 DSF是一种二硫代氨基酯，是ALDH的FDA-Approve抑制剂，用于治疗酒精中毒。它对PDAC细胞的毒性已被证明通过基本痕量元素铜（CU ++）与形成DSF/CU复合物的结合增强。我们最近发现使用PDAC细胞系：i）PCSC在体外分馏后两天增加； ii）在处理间隙期间，DSF/CU耗尽的PCSC耗尽，并消除了辐照细胞的体外球体； iii）DSF/CU下调的Wnt途径，辐照PDAC细胞中的关键癌症干细胞途径和IV）DSF/CU阻断了辐射诱导的干性基因的重新表达mRNA。这些发现为我们的中心假设提供了理由，即DSF/CU耗尽了预先存在PCSC和辐射诱导的PCSC的理由，从而导致放射治疗的有效性显着提高。在AIM1中，我们将确定DSF/CU在体外和体内消除了PCSC和IPCSC。在AIM2中，我们将检查与DSF/CU结合使用的RT可以有效地消除新辅助设置中使用小鼠中的异性胰胰腺肿瘤的新辅助和非茎PDAC细胞。在AIM3中，我们将比较DSF/CU，RT和5-氟尿嘧啶（5-FU）的组合效率，这是一种用于PDAC与常规化学放疗的常用放射性敏感剂，由RT和5-FU组成，由RT和5-FU组成，由新辅助设置在Xeno-和Syngeneic-PDAC PDAC PDAC鼠标模型中。在提出的研究结束时，我们将评估DSF/CU作为先前存在的PSC/IPSC的细胞毒性药物，并作为IPCSC产生的阻止者，获得了对DSF/CU的机制的了解，通过这些知识，通过这些机制，通过这些机制增强了宽度和化学疗法的基础，并提高了辐射疗法的基础，并提高了Nepaid NeoAdant的基础，并提高了NEOADJ的基础。结合FDA批准的药物DSF和营养补充剂铜葡萄糖酸盐。