Studies Identify New Targets to Improve Survival in Pancreatic Cancer

Murray Korc, MD

Murray Korc, MD

Target: Angiogenic Gene Signature

Two recently published studies have reported discoveries that could eventually lead to improved outcomes in patients with pancreatic cancer. The first study, by researchers from Indiana University, has identified a new angiogenic gene signature that can be targeted to thwart tumor growth.¹The second study, by researchers from Taiwan, found a particular secreted immune protein and its receptors to be prevalent in pancreatic cancer.²When this protein and its receptors were targeted with a newly derived monoclonal antibody, metastasis was prevented and survival increased.The Indiana University researchers assessed data from the Cancer Genome Atlas and found overexpression of pro-angiogenic factors in some pancreatic ductal adenocarcinomas (PDACs). These factors facilitated tumor growth by enabling abnormal blood vessels to form in PDACs. The researchers also found, for the first time, that endothelial cells can produce molecules that directly stimulate the growth of pancreatic cancer cells. According to a press release announcing these discoveries, the researchers’ findings have the potential to benefit approximately 15% of people with pancreatic cancer by enabling them to receive therapies targeting this newly identified gene signature.³

“We showed that endothelial cells can stimulate the growth of pancreatic cancer cells and that by silencing or inhibiting certain pathways — JAK1–2 and STAT3 – we can alter that effect,” said Murray Korc, MD, the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine and a researcher at the Indiana University Melvin & Bren Simon Cancer Center.³“We demonstrated that it is possible to target these pathways and prolong the survival of genetically modified mice whose pancreatic cancers also have a strong pro-angiogenic gene signature.”

Target: Overexpression of Interleukin-17B Receptors

Another important feature of Korc et al study was that it demonstrated the feasibility of generating human tumors in mice by implanting them with small biopsy samples obtained from patients undergoing endoscopic procedures. The researchers found that when the original human tumor exhibited evidence for angiogenesis, the implanted tumor in the mouse also exhibited angiogenesis. This approach to studying tumors could potentially guide the design of precision medicine using targeted therapies, but confirmatory studies are necessary, noted Korc.³The secreted immune protein interleukin (IL)-17 has been associated with cancer progression, and receptors for IL-17 are expressed in the pancreas. Now, researchers from the Academia Sinica in Taiwan have shown that overexpression of the IL-17B receptor (IL-17RB) strongly correlates with postoperative metastasis and inversely correlates with progression-free survival in patients with pancreatic cancer.

The researchers’ ex vivo experiments consistently validated that IL-17RB and its ligand, IL-17B play an essential role in pancreatic cancer metastasis and malignancy. Signals from IL-17B and IL-17RB activated CCL20/CXCL1/IL-8/TFF1 chemokine expressions via the ERK1/2 pathway, promoting cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival at distant organs. When mouse xenograft models were treated with a newly derived monoclonal antibody against IL-17RB, tumor metastasis was blocked and survival improved.

The researchers conclude that their findings “not only illustrate a key mechanism underlying the highly aggressive characteristics of pancreatic cancer, but also provide a practical approach to tackle this disease.”

References

1. Gore J, Craven KE, Wilson JL, et al. TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=3233. Published February 25, 2015. Accessed March 2, 2015.
2. Wu HH, Hwang-Verslues WW, Lee WH, et al. Targeting IL-17B—IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. http://jem.rupress.org/content/early/2015/02/24/jem.20141702.abstract. Published March 2, 2015. Accessed March 2, 2015.
3. Pancreatic cancer patients with particular gene signature may benefit from personalized treatment [press release]. http://www.newswise.com/articles/view/630309/?sc=dwhr&xy=10013055. Indianapolis, IN: Indiana University; February 26, 2015. Accessed March 2, 2015