Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Because of the poor therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy, survival beyond five years is rare with median survival less than six months. Thus, novel and effective therapies directed against pancreatic cancer are needed to control progression and metastatic disease. Our studies have shown that scavenging superoxide with the antioxidant enzyme extracellular superoxide dismutase (EcSOD) or pharmacologically with the nitroxide compound tempol, have a strong tumor-suppressive effect in pancreatic cancer both in vitro and in vivo. New data presented in this proposal shows that overexpression of EcSOD leads to suppression of hypoxia inducible factor- 1a (HIF-1a). HIF-1a responds to reduced O2 availability by regulating crucial homeostatic processes such as angiogenesis, glycolysis, and erythropoiesis and has been suggested to be an important regulator of pancreatic cancer cell progression and survival. As a transcription factor, HIF-1 has more than 80 known target genes and the number continues 1. Determine whether the effects of EcSOD overexpression on pancreatic cancer cell growth inhibition are due to HIF-1a suppression by manipulating HIF-1a levels genetically and pharmaceutically. to increase. The current proposal will test the hypothesis that themechanism for the tumor suppressive effect of EcSOD and/or tempol is caused inlarge part due to the suppression of HIF-1 in pancreatic cancer and that this suppression is due to the removal of superoxide. In order to examine this hypothesis, we will address the following three Specific Aims: 2. Determine if pharmacological scavenging of superoxide in human pancreatic cancer cells with Tempol mimics the effects observed with EcSOD on HIF-1a. 3. Determine if Tempol-induced growth inhibition can be enhanced by chemotherapeutic agents (gemcitabine, 5-FU) in human pancreatic cancer. As reported in a recent NCI cancer bulletin article on pancreatic cancer, ?the slow but steady march toward more individualized care in cancer medicine has left pancreatic cancer behind. Patients diagnosed with this disease live no longer today than patients diagnosed two decades ago, despite more than a dozen large clinical trials. Even as many patients with other cancers have benefited from targeted drugs, pancreatic cancer remains as deadly as ever? (www.cancer.gov/ncicancerbulletin/110309/page1). If we can rigorously demonstrate that the tumor suppressive effect of EcSOD and/or tempol is caused in large part by the suppression of HIF-1 in pancreatic cancer then the results of this proposed research program will provide a foundation for the rational design of a combined modality cancer therapy.
to VA patient care mission: Pancreatic cancer is the fourth most common cause of cancer death in the United States with over 44,000 fatal cases annually in the United States. The incidence increases with age and the 5-year survival is <3%. Surgery, radiation therapy and chemotherapy have not improved long-term survival. Thus, novel treatment strategies directed against this devastating malignancy are greatly needed. Because the incidence is increasing, the age of the VA population is increasing, and the disease is so deadly, this proposal is central to the mission of the Veterans Affairs patient care mission by facilitating the discovery and development of targeted therapeutics, and developing and validating preclinical models of human cancer.
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|Wilkes, Justin G; O'Leary, Brianne R; Du, Juan et al. (2018) Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1? (HIF-1?) in pancreatic adenocarcinoma. Clin Exp Metastasis 35:37-51|
|Cieslak, John A; Sibenaller, Zita A; Walsh, Susan A et al. (2016) Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an Index of Cell Proliferation after Pharmacological Ascorbate-Based Therapy. Radiat Res 185:31-8|
|Du, Juan; Cieslak 3rd, John A; Welsh, Jessemae L et al. (2015) Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. Cancer Res 75:3314-26|
|Cieslak, John A; Cullen, Joseph J (2015) Treatment of Pancreatic Cancer with Pharmacological Ascorbate. Curr Pharm Biotechnol 16:759-70|
|Matsumura, Jon S; Stroupe, Kevin T; Lederle, Frank A et al. (2015) Costs of repair of abdominal aortic aneurysm with different devices in a multicenter randomized trial. J Vasc Surg 61:59-65|
|Cieslak, John A; Strother, Robert K; Rawal, Malvika et al. (2015) Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer. Free Radic Biol Med 83:227-37|
|Sibenaller, Zita A; Welsh, Jessemae L; Du, Changbin et al. (2014) Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1? in pancreatic cancer. Free Radic Biol Med 69:357-66|
|Schweizer, Marin L; Cullen, Joseph J; Perencevich, Eli N et al. (2014) Costs Associated With Surgical Site Infections in Veterans Affairs Hospitals. JAMA Surg 149:575-81|
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