Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma.

Abstract

Preclinical trials in mice represent a critical step in the evaluation of experimental therapeutics. Genetically engineered mouse models (GEMMs) represent a promising platform for the evaluation of drugs, particularly those targeting the tumor microenvironment. We evaluated sunitinib, an angiogenesis inhibitor that targets VEGF and PDGF receptor signaling, in two GEMMs of pancreatic cancer. Sunitinib did not reduce tumor burden in pancreatic ductal adenocarcinoma (PDAC), whereas tumor burden was reduced in the pancreatic neuroendocrine tumor (PNET) model, the latter results confirming and extending previous studies. To explore the basis for the lack of pathologic response in PDAC, we used noninvasive microbubble contrast-enhanced ultrasound imaging, which revealed that sunitinib reduced blood flow both in PDAC and in PNET, concomitant with a reduction in vessel density; nevertheless, PDAC tumors continued to grow, whereas PNET were growth impaired. These results parallel the response in humans, where sunitinib recently garnered FDA and European approval in PNET, whereas two antiangiogenic drugs failed to demonstrate efficacy in PDAC clinical trials. The demonstration of on-target activity but with discordant benefit in the PDAC and PNET GEMMs illustrates the potential value of linked preclinical and clinical trials.

• Authors: Peter Olson, Gerald C Chu, Samuel R Perry, Olivier Nolan-Stevaux, Douglas Hanahan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 49 Pg. E1275-84 (Dec 06 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 22084065 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antigens, CD34
• Contrast Media
• Indoles
• Platelet Endothelial Cell Adhesion Molecule-1
• Pyrroles
• Receptors, Platelet-Derived Growth Factor
• Sunitinib

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antigens, CD34 (metabolism)
• Blood Flow Velocity (drug effects)
• Carcinoma, Pancreatic Ductal (diagnostic imaging, drug therapy, genetics)
• Clinical Trials as Topic
• Contrast Media
• Drug Evaluation, Preclinical
• Humans
• Immunohistochemistry
• Indoles (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microbubbles
• Neuroendocrine Tumors (diagnostic imaging, drug therapy, genetics)
• Pancreas (blood supply, drug effects, metabolism)
• Pancreatic Neoplasms (diagnostic imaging, drug therapy, genetics)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Prognosis
• Pyrroles (therapeutic use)
• Receptors, Platelet-Derived Growth Factor (metabolism)
• Sunitinib
• Treatment Outcome
• Tumor Burden (drug effects)
• Ultrasonography