We hypothesize that developing pancreas cancer can be detected at its earliest stage by positron emission tomography (PET) scanning after intravenous administration of our unique nuclear medicine diagnostics that detect overproduction of mutant cancer-causing messenger RNAs (mRNA). Pancreas cancer will kill over 30,000 US men and women in 2006. Even before an enlarged mass can be seen by MRI or CT, early stage pancreas cancer cells contain high levels of mRNAs from the mutant cancer-causing genes KRAS, HER2, KSR1, and MYC.
     We already know that we can see high levels of mutant KRAS mRNA in human pancreas cancer cells growing in a mouse (xenografts). The ability to see KRAS, HER2, KSR1, and MYC mRNAs being overproduced in an early stage malignancy without biopsy provides a powerful tool to diagnose pancreas cancer at its earliest stage. Surgical removal of developing pancreas cancer at this stage might enable longterm survival.
     We have demonstrated the feasibility of radioimaging mutant KRAS mRNA overexpressed in human pancreas cancer xenografts by the binding of our nuclear medicine diagnostics to mutant KRAS mRNAs. Our KRAS peptide nucleic acid (PNA) diagnostic agents, bound to the radionuclides Tc-99m, In-111, or Cu-64, form Watson-Crick basepairs with complementary bases in the mutated region of KRAS mRNA. A change of one base in the PNA diagnostic back to the natural sequence reduces PNA binding to background levels. We have also succeeded in radioimaging CCND1 and MYC mRNA overexpressed in human breast cancer xenografts upon administration of Tc-99m or Cu-64 chelated to CCND1 and MYC PNA hybridization probes.
     We will test our hypothesis that cancer gene activity in developing pancreas cancer can be detected at its earliest stage by synthesizing HER2, KSR1, and MYC chelator-PNA-peptide hybridization probes, labeling them with positron-emitting Cu-64, and determining their stability, pharmacokinetics, and sensitivity for PET imaging of mRNAs of HER2, KSR1, and MYC cancer genes in pancreas cancer xenografts in immunocompromised mice.
     Detection of pancreas cancer at the earliest stage might permit life-saving intervention. We propose to look for a glowing image in the pancreas after administration of our unique nuclear medicine gene diagnostics. In the future, we will test the most sensitive PET imaging agents, most likely for the KRAS and HER2 pancreas cancer genes, in phase I clinical trials in participants with family histories of pancreas cancer, and with participants showing symptoms that do not exclude pancreas cancer.