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Pancreatic Cancer Therapy with GRP Receptor-Targeted Imageable Diphenyl difluorok

使用靶向 GRP 受体的可成像二苯基二氟化合物治疗胰腺癌

基本信息

批准号：
7773690
负责人：
VIBHUDUTTA AWASTHI
金额：
$ 7.33万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7773690
关键词：
Acetates Adverse effects Animals Antineoplastic Agents Autopsy Binding Biological Assay Biological Markers Bombesin Bombesin Receptor Cancer Etiology Cancer Patient Cancer cell line Cancerous Cell Culture Techniques Cell Survival Cessation of life Chelating Agents Curcuma longa Curcumin Cytotoxic agent Development Diagnosis Disease Dose Drug Delivery Systems Early Diagnosis Ensure Equilibrium Erlotinib Figs - dietary GRP gene Goals Histology Human Image In Vitro Inhibitory Concentration 50 Investigation Kinetics Laboratories Life Ligands Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Minority Modification Monitor Mus Nature Neoplasm Metastasis Nuclear Nude Mice Operative Surgical Procedures Outcome Pancreatic Adenocarcinoma Pancreatic carcinoma Patients Peptides Peripheral Pharmaceutical Preparations Pharmacologic Substance Photons Plasma Positron-Emission Tomography Property Radioisotopes Radiolabeled Radionuclide Imaging Recruitment Activity Reducing Agents Research Scheme Series Technetium 99m Techniques Testing Therapeutic Tissues Toxic effect Tumeric Tumor Volume United States Food and Drug Administration Work Xenograft procedure analog anticancer activity antiproliferative agents antiproliferative drugs base cancer cell cancer therapy chemotherapy cytotoxic cytotoxicity design diphenyl drug development fluorodeoxyglucose gemcitabine improved in vitro testing in vivo interest molecular imaging mouse model non-invasive monitor novel outcome forecast palliative pancreatic neoplasm public health relevance radiotracer receptor research study response single photon emission computed tomography standard of care stannous chloride targeted delivery tomography tricine tumor tumor growth whole body imaging

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. While early diagnosis is still a challenge, the standard of care after diagnosis is palliative in nature, and mostly ineffective in improving the prognosis in pancreatic cancer patients. Anticancer drugs are the cornerstone in managing pancreatic cancer, but they can cause severe adverse-effects in therapeutic doses. A more selective delivery of the cytotoxic agents to the primary and metastatic tumors would allow a dose escalation without a parallel increase in peripheral toxicity. It is therefore important not only to develop new chemotherapeutic molecules, but also ensure preferential drug delivery in cancerous tissue. The strategy should also include an in vivo assay to monitor adequacy and selectivity of drug accumulation in cancer. Our goal is to target a recently developed antiproliferative agent in pancreatic cancer, and enable molecular imaging of the targeted agent's distribution in live animals by nuclear techniques. We are developing a series of curcumin-based antiproliferative drugs including a diphenyl difluoroketone (DPDK) compound. DPDK is a potently cytotoxic in several cancer forms; we found it effective against cultured pancreatic cancer cells. We propose to target DPDK through the gastrin-releasing peptide receptors (GRPrs) which are over-expressed in pancreatic cancer tissue. We will modify the DPDK molecule to carry bombesin7-14 peptide which is a ligand for GRPr. The peptide will also harbor a chelator for Tc-99m radionuclide. The Tc-99m radiolabel will allow noninvasive imaging of bombesin-DPDK's distribution after administration. Our null hypothesis is that the targeted DPDK is not more antiproliferative than the non-targeted DPDK. For the rejection of this null hypothesis, the specific aims are: 1. To synthesize bombesin-DPDK conjugate amenable to radiolabeling with 99mTc radionuclide, and 2. To evaluate anticancer activity of bombesin-DPDK in a mouse model of pancreatic cancer. The experiments to accomplish these specific aims are designed to proceed from lab-based synthetic work to in vitro testing of the synthesized compounds in cell culture conditions, and finally to in vivo investigations in a mouse model of xenograft pancreatic tumor. We anticipate that the targeted delivery will help in localized higher concentration of DPDK in pancreatic cancer, allowing efficacy comparable to that achieved by larger doses of non-targeted drug. The strategy to develop a bifunctional molecule that can be monitored by non-invasive imaging is novel application of bombesin-GRPr interaction. The imaging will be useful to assess availability of the drug in the primary/metastatic pancreatic cancer tissue. Recent emphasis by the NCI and the FDA on imaging biomarkers provides support to the utility of imaging in drug development. PUBLIC HEALTH RELEVANCE: Effective non-surgical therapies are needed to alter the outcome and bleak prognosis in pancreatic cancer patients. The proposed research pertains to the development of a novel anticancer drug that can be delivered to the pancreatic cancer tissue in targeted manner, and that such preferential drug delivery can be monitored by non-invasive imaging.

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因。虽然早期诊断仍然是一个挑战，但诊断后的护理标准本质上是姑息性的，并且在改善胰腺癌患者的预后方面大多无效。抗癌药物是治疗胰腺癌的基石，但在治疗剂量下，它们会引起严重的副作用。将细胞毒性剂更有选择性地递送至原发性和转移性肿瘤将允许剂量递增，而不会平行增加外周毒性。因此，重要的是不仅开发新的化疗分子，而且确保癌组织中的优先药物递送。该策略还应包括体内测定，以监测癌症中药物蓄积的充分性和选择性。我们的目标是靶向最近开发的胰腺癌抗增殖剂，并通过核技术实现靶向剂在活体动物中分布的分子成像。我们正在开发一系列基于姜黄素的抗增殖药物，包括二苯基二氟酮（DPDK）化合物。DPDK在几种癌症形式中具有强效细胞毒性;我们发现它对培养的胰腺癌细胞有效。我们建议通过在胰腺癌组织中过表达的胃泌素释放肽受体（GRPrs）靶向DPDK。我们将修饰DPDK分子以携带蛙皮素7 -14肽，这是GRPr的配体。该肽还将含有Tc-99 m放射性核素的螯合剂。Tc-99 m放射性标记将允许给药后蛙皮素-DPDK分布的非侵入性成像。我们的零假设是靶向DPDK的抗增殖作用并不比非靶向DPDK强。对于这个零假设的拒绝，具体的目的是：1。合成适于99 mTc标记的蛙皮素-DPDK偶联物。评价蛙皮素-DPDK在小鼠胰腺癌模型中的抗癌活性。完成这些特定目标的实验设计为从基于实验室的合成工作进行到在细胞培养条件下对合成化合物进行体外测试，最后在异种移植胰腺肿瘤的小鼠模型中进行体内研究。我们预计，靶向递送将有助于胰腺癌中局部更高浓度的DPDK，从而使疗效与较大剂量的非靶向药物所达到的疗效相当。开发一种可以通过非侵入性成像监测的双功能分子的策略是蛙皮素-GRPr相互作用的新应用。成像将有助于评估药物在原发性/转移性胰腺癌组织中的可用性。NCI和FDA最近对成像生物标志物的重视为成像在药物开发中的应用提供了支持。公共卫生相关性：需要有效的非手术治疗来改变胰腺癌患者的结局和暗淡的预后。拟议的研究涉及开发一种新型抗癌药物，该药物可以靶向方式递送至胰腺癌组织，并且这种优先药物递送可以通过非侵入性成像进行监测。