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Pancreatic Cancer Therapy with GRP Receptor-Targeted Imageable Diphenyl difluorok

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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.

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