Busby, Robert W.

Abstract Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and continues to be a disease with few options for treatment. Current therapeutic regimens for pancreatic cancer often include the nucleoside analog gemcitabine (GEM), but while it has been in use for many years, the overall five year survival rate continues to be about 5%. New therapies are urgently needed to treat this disease. The nutritional supplement gamma-linolenic acid (GLA) is a poly-unsaturated fatty acid (PUFA) of the n-6 PUFA family, and has garnered attention for its cytotoxic effects against tumor cell lines while not affecting normal cells. In this study we look at the effect GLA has on Panc-1 cells and its ability to increase the sensitivity of these cells to treatment with GEM. Through the use of cell viability assays, immunofluorescence, 3-D growth assays, and western blotting, our results show that GLA alone will inhibit growth and induce apoptosis in Panc-1 cells. When GLA is combined with GEM, the results are synergistically enhanced. In addition, our results show that GLA may act through disruption of lipid rafts in the cellular membrane and may activate the extrinsic apoptotic pathway causing cell death. These results suggest that the nutritional supplement GLA could be used in combination with GEM to increase the therapeutic effectiveness of GEM while treating pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3854. doi:1538-7445.AM2012-3854

Abstract PG545 is a synthetic heparan sulfate (HS) mimetic purported to inhibit angiogenesis via the blockade of VEGF and FGF-2 signaling, and block the enzymatic activity of heparanase - a molecule closely associated with metastatic dissemination. The attenuation of VEGF and FGF-2 signaling is supported by recent clinical data from the first four advanced cancer patients with multiple tumor types treated with PG545 which exhibited increases in plasma VEGF and FGF-2 levels, often in close association with the drug treatments/exposure profile during the first treatment cycle over 4 weeks. Unfortunately, due to local injection site reactions associated with subcutaneous (SC) administration, the trial was recently terminated. However, to support a re-entry to the clinic using the intravenous route, we tested PG545 in a preclinical model of ovarian cancer.The rationale to investigate PG545 in ovarian cancer is derived from recently generated data which found PG545 (5 µM) almost completely inhibited migration of SKOV3 ovarian carcinoma cells stimulated by each of the following HS binding growth factors: VEGF, HGF, FGF-2, SDF-1 and HB-EGF. Because HB-EGF is thought to play a major role in the spread of this cancer, PG545 was also tested against HB-EGF dependant SKOV3 cell invasion and was found to be a potent inhibitor of this process. The effect of PG545 on HB-EGF signaling pathways in these experiments were investigated and the results indicated that PG545 reduces activation of the HB-EGF receptor (EGFR) and, consequently, both AKTand MAPK signaling are also reduced. Given the strong mechanism of action data for ovarian carcinoma, PG545 was next tested in the A2780 ovarian xenograft model. The signficant antitumor activity using PG545 at 7.5 mg/kg twice weekly intravenous (IV) and 15 mg/kg once weekly IV was similar to a 20 mg/kg once weekly SC dose. Pharmacokinetic analysis confirmed that drug exposure (AUC) over the course of a week was consistent between groups. PG545 significantly reduced tumor burden in a cisplatin resistant ovarian tumor model (C200) when given intraperitoneally at the dose of 20mg/kg, once a week until the end of the study. Most importantly, PG545 completely reduced tumor mass and reduced ascites accumulation in a syngeneic immunocompetent mouse model of ovarian cancer (ID8). Given the known effects of PG545 on heparanase and in metastatic models, these emerging data on growth factors in the clinic and HB-EGF in preclinical models provide a strong rationale to re-enter the clinic using the IV route and to focus on ovarian cancer as the clinical indication. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-309. doi:1538-7445.AM2012-LB-309

Abstract In pancreatic cancer both chemotherapy and radiotherapy have shown deficient results in treating the disease, indicating a fundamental need for more efficient therapies. Most pancreatic cancer patients present with an advanced form of the disease that is incurable by surgery, and will receive palliative treatment in the form of surgery, chemotherapy, radiotherapy and symptom control. There are few standard chemotherapeutics for the treatment of pancreatic cancer, although Gemcitabine and 5-Fluorouracil (5-FU) are the most widely used. In search for specific nutritional, and/or pharmacological agents to target pancreatic cancer cells/tissues we identified a series of nutritional supplements known as polyunsaturated fatty acids (PUFAs) that have an inhibitory effect on cancer cells. However, Gamma-Linolenic-Acid (GLA), a member of the ω-6 family of PUFAs exerts selective cytotoxic effects on pancreatic cancer cells without affecting normal epithelial cells. The goal of our study was to determine whether GLA could sensitize the targeted pancreatic cancer cells to chemotherapeutic agents (Gemcitabine or 5-FU). Therefore, pancreatic cancer cells were treated initially with GLA followed by each of the chemotherapeutic agents separately: Our results demonstrated that: 1) GLA induced growth inhibition and apoptosis of pancreatic cancer cells (Panc-1 and BxPC3); 2) the combination of GLA and Gemcitabine or GLA and 5-FU: a) promote a synergistic inhibitory effect on the growth of pancreatic cancer cells; b) inhibition of anchorage-independent growth; and 4) inhibition of morphogenesis in 3-D matrigel culture. These results show that GLA increases the sensitivity of pancreatic cancer cells to chemotherapy through a synergistic effect with Gemcitabine or 5-FU, implying that GLA could be used as a supportive drug for the pancreatic cancer patients receiving the current chemotherapeutic regimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 209.