Neuroendocrine tumors (NETs) constitute an unrecognized health threat to children and adults. The incidence and prevalence of NETs is rising in the United States; yet, there is very little research on NETs, and no effective treatment for patients with metastatic disease, over half of whom die within five years of diagnosis according to latest SEER data. These tumors do not respond to conventional chemotherapy or external beam radiation, making development of new diagnostic and therapeutic options imperative. We hypothesize that theranostics, use of a single compound as both a therapeutic and a diagnostic agent, will meet this critical need for children and adults with NETs. The translational component of this proposal will identify new theranostic targets, design and synthesize new targeting agents, and test their efficacy in vivo. Lead compounds that meet strict criteria as high affinity PET tracers and molecularly targeted therapeutic agents in pre-clinical models of bronchial, small bowel, or pancreatic neuroendocrine tumors will be brought forward to first in human PET imaging trials through an Exploratory IND mechanisms.
Specific aims are: 1. Design and synthesize unique, high-affinity, stable ligands for use in GPCR targeted theranostics. Expression data from Project 3 has identified three GPCR (OXTR, VPAC1, MC1R) as new targets in NETs. Theranostic radiopharmaceuticals will be designed and synthesized using NMR and 3-D modeling to guide chemical modifications that enhance affinity, specificity and stability of candidate ligands. Peptide libraries incorporating D- and unnatural amino acids, cyclization strategies, and lysine substitutions for DOTA conjugation will be synthesized; binding affinity, specificity and stability will be determined in vitro. 2. Characterize in vivo specificity, stability, pharmacokinetics, and cytotoxicity of new GPCR targeted theranostic compounds in mouse models of neuroendocrine tumors. We will conduct theranostic pre- clinical in vitro and in vivo testing of lead GPCR targeted ligands in mouse models of NETs with the goal of having at least two analogs ready to test as PET tracers in humans by year 5. 3. Examine safety and efficacy of new GPCR targeted PET tracers in humans using exploratory IND. Agents that pass rigorous pre-clinical testing will then be synthesized under GMP conditions. An exploratory IND will be obtained to examine the ability of lead candidates to localize to neuroendocrine tumors in first in human trials. Successful tracers that meet the strict theranostic criteria and demonstrate safety, specificity, and reproducibility as a PET tracer in patients with NETs, will be further developed through a full IND. Successful completion of these pre-clinical theranostic trials and first in human molecularly targeted PET imaging trials will pave the way for development of new radiotherapeutics with the ultimate goal of providing dual-target, dual-radionuclide therapy for patients with neuroendocrine tumors.
We have identified oxytocin, vasoactive intestinal peptide, melanocortin and glucose-dependent insulinotropic peptide receptors as prime new targets in small bowel and pancreatic neuroendocrine tumors. We will develop PET tracers for each receptor and examine their affinity and specificity for the GPCR of interest as well as their stability and targeted cytotoxicity in pre-clinical models of bronchial, small bowel and pancreatic NETs. An exploratory IND will be obtained to conduct first in human PET imaging with candidate tracers. Successful completion of these pre-clinical and first in human imaging trials will pave the way for development of new radiotherapeutics with the ultimate goal of providing dual-target, dual-therapy options for patients with neuroendocrine tumors.
Showing the most recent 10 out of 24 publications
