PhScN as a Potent Agent for Use with Radiation in Pancreatic Cancer

PhScN 作为胰腺癌放射治疗的有效药物

基本信息

批准号：
8450705
负责人：
DONNA Lucy LIVANT
金额：
$ 7.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450705
关键词：
Acetylation Amino Acids Apoptosis Apoptosis Promoter Basement membrane Binding Biological Assay CD29 Antigen Caspase Cells Cleaved cell Clinical Data Dendrimers Development Disease Progression Disseminated Malignant Neoplasm Dose Effectiveness Endothelial Cells Exposure to Extravasation Fibronectin Receptors Fibronectins Human In Vitro Induction of Apoptosis Infusion procedures Integrins Interstitial Collagenase Intravenous infusion procedures Isomerism Lead Licensing Link Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Methods Mono-S Neoplasm Metastasis Pathway interactions Peptide Hydrolases Peptides Pharmaceutical Preparations Phase I Clinical Trials Plasma Play Polylysine Pre-Clinical Model Probability Publications Publishing Radiation Radiation Dosage Radiation Tolerance Radiation therapy Radiosensitization Relapse Relative (related person)Research Resistance Schedule Serine Subcutaneous Injections Surface Systemic Therapy Time Toxic effect Up-Regulation acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide amidation angiogenesis base cancer cell caspase-3 improved in vivo inhibitor/antagonist malignant breast neoplasm pancreatic cancer cells prevent receptor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Radiotherapy is used to manage pancreatic cancer; however, there is a high probability of both loco-regional relapse and metastasis. We have shown that radiation rapidly induces human pancreatic cancer cell invasion, and that it is caused by surface upregulation of activated alpha5 beta1 integrin fibronectin receptors. Our results suggest that systemic inhibition of alpha5 beta1-mediated invasion and survival might be an effective way to reduce radiation-induced pancreatic cancer cell invasion, as well as increasing the effectiveness of radiotherapy as an inhibitor of clonogenic survival and inducer of apoptosis in pancreatic cancer cells. Since we have shown that activated alpha5 beta1 receptors mediate both metastatic and angiogenic invasion, they are key to cancer progression. We devised the PHSCN peptide, Ac-PHSCN-NH2, as an inhibitor of alpha5 beta1- mediated invasion by both metastatic cancer cells and their associated microvasculature. Systemic PHSCN prevented disease progression for prolonged periods in multiple preclinical models, in our lab and in others'. PHSCN monotherapy also prevented disease progression for 4-14 months in Phase I clinical trial, without toxicity. However, because PHSCN must be administered thrice weekly as a large subcutaneous injection or infusion, a more potent form is essential for further clinical development. Recently, we found that replacing the His (H) and Cys (C) residues of the PHSCN peptide with their D-isomers, h and c, to form Ac-PhScN-NH2, yields an invasion inhibitor that is 200,000-fold more potent than PHSCN. Hence, we propose to utilize irradiated Panc-1 and BxPC-3 human pancreatic cancer cells to (1) evaluate the increase in potency of PhScN, relative to PHSCN, as an inhibitor of radiation-induced, surface alpha5 beta1 integrin and MMP1 upregulation, and basement membrane invasion in vitro; (2) evaluate the increase in potency of PhScN, relative to PHSCN, as an inhibitor of clonogenic survival and as an inducer of radiation-induced apoptosis; and (3) determine the optimal scheduling of PhScN exposure with radiation in vitro. The proposed research is necessary to allow development of PhScN as a practical systemic therapy, to be administered in combination with radiation. In support of this proposal we present the following preliminary data, in addition to our publications: 1) PhScN is 2 x 105-fold more potent than PHSCN as an inhibitor of a5b1-mediated BxPC-3 invasion; 2) PHSCN blocks radiation-induced Panc-1 invasion of basement membranes; 3) PHSCN inhibits radiation-induced surface alpha5 beta1 upregulation in Panc-1 and BxPC-3 cells; 4) PhScN exposure reduces viability, perhaps by inducing Caspase-3 activation; and 5) prior exposure to PhScN can significantly radiosensitize BxPC-3 cells. The proposed research is unique and original because it represents the first time that a fully endoproteinase- resistant agent has been utilized in pancreatic cancer. Moreover, it also represents the first time that alpha5 beta1 integrin has been targeted in pancreatic cancer.

描述（由申请人提供）：放疗用于治疗胰腺癌；然而，有可能是洛克区域复发和转移的概率。我们已经表明，辐射会迅速诱导人胰腺癌细胞的侵袭，并且它是由活化的α5β1整合素纤连蛋白受体的表面上调引起的。我们的结果表明，全身抑制Alpha5 beta1介导的浸润和存活可能是减少辐射诱导的胰腺癌细胞侵袭的有效方法，并提高了放射疗法作为克隆性生存的抑制剂和pancreaticic癌细胞中凋亡诱导剂的抑制剂的有效性。由于我们已经表明活化的α5β1受体介导转移性和血管生成性侵袭，因此它们是癌症进展的关键。我们设计了PHSCN肽AC-PHSCN-NH2，是转移性癌细胞及其相关的微脉管系统的α5β1β1-介导的侵袭的抑制剂。全身性PHSCN可防止多个临床前模型，在我们的实验室和其他人中的多个临床前模型中的疾病进展。 PHSCN单药治疗还可以在I期临床试验中预防4-14个月的疾病进展，而无需毒性。但是，由于必须将PHSCN每周进行三次施用，作为大量的皮下注射或输注，因此更有效的形式对于进一步的临床发育至关重要。最近，我们发现，用其D-异构体H和C代替PHSCN肽的HIS（H）和CYS（C）残基形成AC-PHSCN-NH2，产生了一种比PHSCN高200,000倍的入侵抑制剂。因此，我们建议利用辐照的PANC-1和BXPC-3人胰腺癌细胞来（1）评估PHSCN相对于PHSCN的效力的增加，作为辐射诱导的，表面alpha5 beta1 beta1整合蛋白和MMP1上的抑制剂，并在体外膜上摄入型体外; （2）评估相对于PHSCN的PHSCN效力的增加，作为克隆生存的抑制剂，并作为辐射诱导的凋亡的诱导剂；（3）确定在体外辐射的最佳调整PHSCN暴露。拟议的研究对于允许将PHSCN作为一种实用的全身疗法的开发是必须与辐射结合使用的。为了支持该提案，我们介绍了以下初步数据，除了我们的出版物外：1）PHSCN比PHSCN作为A5B1介导的BXPC-3入侵的抑制剂的效力比PHSCN高2 x 105倍； 2）PHSCN阻止辐射引起的panc-1地下膜的侵袭； 3）PHSCN抑制PANC-1和BXPC-3细胞中辐射诱导的表面α5β1上调； 4）PHSCN暴露可降低生存能力，也许是通过诱导caspase-3激活； 5）事先暴露于PHSCN可以显着放射敏感BXPC-3细胞。拟议的研究是独特的和原始的，因为它代表了第一次在胰腺癌中使用完全耐甲蛋白酶酶的剂。此外，它还代表了α5β1整联蛋白首次针对胰腺癌。