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

Abstract

Abstract 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, and were able to show the significant spheroid production by these cells as a result on intratumoral hypoxia and HIF. Further we were able to test the HIF activity/Hypoxia response element ( HRE), after exposure to two synergistic compounds. It was shown that HIF activity significantly reduces by such combination, as a result of sensitization of cells to the subsequent exposure. Clinical application of such method showed significant clinical superiority to the standard of care alone. We will review a case series of patients with advanced disease, and their clinical outcome in summary. Conclusions: HIF-1alpha is a dominant factor driving the metastatic progression of pancreatic cancer is a potent therapeutic target for the disease. Here we were able to show synergism in combining epigenetic modifiers to inhibit HIF both invitro and in human, with relevant and significant outcome. We conclude that a multitargeted epigenetic therapy ( MTET) using combination of drugs modifying the HIF activity is clinically relevant and we further suggest large clinical trials to optimize the response in clinic. Citation Format: M. A. Nezami, Steve Hager.{Authors}. Invitro and invivo proof of concept for an effective antineoplastic combination of novel anti HIF therapy in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B22.