Pancreatic Cancer Therapy with GRP Receptor-Targeted Imageable Diphenyl difluorok

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，并且对于改善胰腺癌患者的预后大多无效。抗癌药物是治疗胰腺癌的基石，但它们在治疗剂量下可能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，而外周毒性不会平行增加。因此，不仅开发新的化疗分子，而且确保在癌组织中优先递送药物也很重要。该策略还应包括体内测定，以监测癌症中药物积累的充分性和选择性。我们的目标是针对胰腺癌中最近开发的抗增殖剂，并通过核技术对活体动物中靶向剂的分布进行分子成像。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 对多种癌症形式具有强效细胞毒性；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度表达的胃泌素释放肽受体（GRPrs）来靶向DPDK。我们将修饰 DPDK 分子以携带炸弹素 7-14 肽，该肽是 GRPr 的配体。该肽还含有 Tc-99m 放射性核素的螯合剂。 Tc-99m 放射性标记将允许对给药后铃蟾素-DPDK 的分布进行无创成像。我们的零假设是靶向 DPDK 并不比非靶向 DPDK 具有更强的抗增殖作用。为了拒绝这个零假设，具体目标是：1.合成适合用99mTc放射性核素进行放射性标记的铃蟾肽-DPDK缀合物，以及2.在胰腺癌小鼠模型中评价铃蟾肽-DPDK的抗癌活性。实现这些特定目标的实验旨在从基于实验室的合成工作进行到细胞培养条件下合成化合物的体外测试，最后到异种移植胰腺肿瘤小鼠模型的体内研究。我们预计靶向给药将有助于在胰腺癌中局部提高 DPDK 浓度，从而达到与大剂量非靶向药物相当的疗效。开发可通过非侵入性成像监测的双功能分子的策略是铃蟾肽-GRPr相互作用的新颖应用。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：需要有效的非手术疗法来改变胰腺癌患者的结局和黯淡的预后。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，并且可以通过非侵入性成像监测这种优先药物递送。

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.