Development of a PET CCR2 Imaging Agent to Profile PDAC Microenvironment

Emory University, Atlanta GA

Investigators

Abstract

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. PDAC is the 4th leading cause of cancer related death with a 5-year survival rate <12%, resulting in 200,000 deaths per year. Early detection of tumor size one inch or less with surgical resection of pre-metastatic disease has the best survival benefit. Clinical imaging is important in the early detection of small tumors. Unfortunately, no individual diagnostic imaging technique is sufficiently accurate for the detection of small, potentially curable PDAC. PDAC has a profuse extracellular matrix which can constitute 90% of tumor volume. A dominant cellular component of this matrix is infiltrating immune monocytes including myeloid-derived suppressor cells (MDSCs). MDSCs contribute to tumor progression and treatment resistance through a variety of mechanisms, ultimately culminating in failed antitumor immune responses. As a clinical imaging modality, positron emission tomography (PET) is capable of quantitating molecular features of MDSCs present in the PDAC that drive tumorigenesis, progression and treatment resistance. Mechanistically, the chemokine receptor 2, CCR2, expressed on monocytes may be instrumental in securing residence of these CCR2 positive monocytes in PDAC tumors. The monocyte chemoattractant protein-1 (MCP-1) is a specific ligand to CCR2 and induces migration by binding to components of the TME where MCP-1 expression is elevated. The central hypothesis of this proposal is that a 18F-CCR2 PET imaging agent can enable functional imaging of MDSC or other monocytic cells, thereby providing valuable insight into their role during tumorigenesis, progression or response to therapy. This hypothesis will be tested by completing the following specific aims: 1 Synthesis of CCR2 PET imaging tracers. SA1a. Synthesis of 18F-CCR2-1 and syntheses of three backup candidates. 2. In vitro characterization of 18F-CCR2 ligands. SA2a. In PANC-1 and MIAPaCa2 cell lines. SA2b. In mouse bone marrow derived monocytes (BMDM) and human monocytes. 3. To test and evaluate PET imaging capability of developed 18F-CCR2 candidates. SA3a. Selective uptake of the 18F-CCR2 probes in tumors in immune compromised rodent orthotopic models of pancreatic cancer determined by microPET and MR imaging. SA3b. CCR2 PET ligand specificity determined by blocking with non- radiolabeled CCR2-1 ligand followed by microPET and MR imaging. SA3c. The sensitivity and the ability to delineate tumor margins by PET will be evaluated in comparison to histo-pathology and autoradiography to demonstrate that a 18F-CCR2 probe specifically binds to regions associated with CCR2+ macrophage abundance. Overall, this project will enable development of an innovative, non-invasive imaging tool that acts as a CCR2 antagonist.