Abstract B22: Invitro and invivo proof of concept for an effective antineoplastic combination of novel anti HIF therapy in pancreatic cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-12, Vol.76 (24_Supplement), p.B22-B22
• Main Authors: Nezami, M. A., Hager, Steve
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PANCA16-B22

New therapeutic approaches for pancreatic cancer are needed owing to the extremely poor prognosis, in large part as a consequence of high rates of metastasis. Hypoxia plays a crucial role in carcinogenesis, and metastasis. We also know that HIF plays a significant role in tumor resistance to cytotoxic therapies, and further explains the pancreatic cancer lack of response in clinic. Unfortunately to our knowledge there has been no effective therapy to this date to overcome such cellular pathology. To address this shortcoming, we used both in vitro and in vivo approaches to evaluate the overall effects of anti HIF-1alpha protocol in pancreatic cancer. Here we used a novel combination of two epigenetic modifiers that were investigated in 2 and 3 dimentional cell cultures to synergistically inhibit HIF, migration and invasion of pancreatic cancer cell lines, and further were able to show significant clinical application of such therapy in a series of metastatic or refractory disease in human. Background: Hypoxia-inducible factor-1alpha (HIF-1alpha) is essential for the pancreatic cancer progression and metastasis, and has been suggested to be a target for cancer therapy, as the result, there has been tremendous efforts in recent years to target HIF, as a dominant factor driving the metastatic progression of pancreatic cancer, a meaningful therapeutic approach, both independently as well as in combination with current standard of care. Both in vitro and in vivo analysis has suggested that hypoxia significantly promotes cell proliferation and migration, resulting in metastasis. Pancreatic cancer cells in which HIF-1alpha expression was inhibited were less invasive, with reduced resistance to hypoxia, impaired migration, and reduced capacity to cause metastasis. It is also suggested by our colleagues as well as our own published data, that epigenetic modifiers are able to improve the degradation of HIF through VHL. We were convinced that such approach we would be able to reduce the activity of HIF or hypoxia response elements ( HRE). We tested this hypothesis by application of a combination of epigenetic modifiers in laboratory and further in human, successfully. Methods: To illustrate the role of hypoxia-inducible factor-1alpha in pancreatic cancer metastasis and the value of the molecule as a target for pancreatic cancer therapy, we tested the pancreatic cell lines ( Panc 1) in the experimental therapeutic laboratory using a 3 dimentional cell culture model, an