David McFadden, M.D., M.B.A.
Stanley S. Fieber Professor and Chair of Surgery
Physician Leader of Surgery, Fletcher Allen
Interim Associate Director for Clinical Cancer Care and Research, VCC
Research Program: Clinical Research
VCC Membership Level: Full Member
Contact Information
Fletcher House 301
ph: (802) 847-5354
f: (802) 847-5552
David.McFadden@vtmednet.org
Biography
Dr. McFadden is a general surgeon with a focus on surgical oncology. He joined UVM/Fletcher Allen earlier this year from West Virginia University, where he was Chair of the Department of Surgery, Surgeon-in-Chief and Chief of General Surgery, and also served on the leadership team at West Virginia University's Mary Babb Randolph Cancer Center.
McFadden's career includes: undergraduate and medical degrees from the University of Virginia, a surgical internship, residency, and faculty appointment at Johns Hopkins Hospital, five years at the University of Cincinnati Medical Center, leading the Division of General Surgery at the University of California Los Angeles, and most recently, Chairmanship of Surgery, Surgeon-in-Chief and Chief of General Surgery at West Virginia University. McFadden was also a member of the UCLA Jonsson Cancer Center and the West Virginia University Mary Babb Randolph Cancer Center.
McFadden, who has performed funded research for two decades in the areas of pancreatic oncology and physiology, holds a 1996 patent for a method of inhibiting the growth of pancreatic tumors. Notably, he has been named one of America's Top Doctors four times, is Co-Editor in Chief of the Journal of Surgical Research, and is the current President of the Society for Surgery of The Alimentary Tract.
Research
Much of Dr. McFadden's efforts over the past seven years have concerned Peptide YY (PYY). PYY orchestrates function of the gut and pancreas by regulating growth, digestion and absorption. In addition to its physiological role, PYY exhibits immune and antitrophic properties in the pancreas by decreasing cytokine and amylase release. Although the exact mechanism(s) of action are still incompletely understood, PYY interacts at the acinar level with numerous intracellular transcription factors. In addition to ameliorating pancreatic inflammation, novel synthetic analogs of PYY have been developed that are potent inhibitors in the proliferation of pancreatic cancer. He has received a U.S. Patent for this work.
His research shows that PYY offers promising potential as hormonal adjunct in the chemotherapy of pancreatic adenocarcinoma. When a synthetic analog (BIM-43004-1) to PYY was developed, his group tested its efficacy in reducing pancreatic cancer cell growth. Using two pancreatic ductal adenocarcinoma cell lines, PANC-1 and Mia PaCa-2, they found a significant reduction (25%) in growth with either PYY (22-36) or its analog. Consistent with this finding, PYY has been shown to reduce pancreatic tumor size by 27% in an orthotopic murine model (Fig. 2). When combined with adjuvant therapy, 5-fluorouracil or leucovorin, growth was further decreased when pretreated with PYY prior to chemotherapy. Epidermal growth factor receptor expression was also reduced. We have also observed the same inhibitory effects on cell proliferation after treatment with PYY in esophageal adenocarcinoma and breast cancer cells.
Research from cross-linking studies reveal a receptor on the cell membrane of human pancreatic ductal adenocarcinoma cells that could be instrumental in delivering avidin-dye complexes to cancer through biotinylated peptides. They tested biotinylated PYY analogs with lengths ranging from PYY (1-36), PYY (9-36), PYY (14-36), PYY (22-36), and PYY (27-36) in their binding to pancreatic cancer cells. Growth inhibition and specific binding was measured. They found PYY (14-36) had the highest potency against pancreatic cancer and provided the optimal binding for the delivery of fluorescent dyes for imaging and therapy.
Investigations into the reduced risk of cancer and vitamin intake are generating interest as a strategy for combinational therapy. Success with Vitamin E in inhibiting cancer call growth in the pancreas prompted us to test its efficacy in the presence of PYY. They observed an additive effect on growth inhibition when cells were treated with both vitamin E succinate (VES) and PYY(3-36). Similar results were obtained when PYY was combined with VES in either breast cancer cells or with RRR-α-tocopheryl succinate and the Y4 agonist BA-129 in prostate cancer cell growth studies.
Dr. McFadden and his colleagues have previously demonstrated the potent in vitro anti-proliferative effects of Keyhole Limpet Hemocyanin (KLH) against melanoma. Their prior studies directed them to hypothesize that KLH would be effective in vivo against melanoma, alone and in combination with conventional immunotherapy. In their most recent study (in Press, American Journal of Surgery, 2007) mice were inoculated with 2 x 107 HTB68 melanoma cells and randomized to 6 groups. Treatment groups consisted of Control, KLH 200µg, AIFN (alpha interferon) 1000 IU, IL2 (Interleukin-2) 5000 IU, KLH + AIFN, and KLH+IL2. Our resultsKLH+IL2 exhibited a 30% reduction in tumor volume as compared to control (P=0.014), followed by KLH+AIFN (28%, P=0.031). Singly treated animals had less tumor inhibition: IL2 (30%, P=0.022), KLH (18%, NS) and AIFN (16%, NS). They concluded that KLH augments the effects of standard immunotherapy against melanoma in vivo. Further in vivo and early clinical studies into the effects of KLH as both a single and combined agent are warranted.
Recent Publications
Bukreirat F, Ostrinsky Y, McFadden DW: The Use of GI Tumor Markers in Clinical Practice: A practical Interpretation. WVMJ 104:17-21, 2008.
Karimi KH, Rizvi IA, Cassim R, McNatt S, McFadden DW, Williams H: When Gastrointestinal stromal tumors (GIST) Can Cause Massive Hemorrhage. Contemporary Surgery, 64:315-320, 2008.
McFadden DW, Riggs DR, Jackson BJ, Cunningham C: Corn- derived IP6 inhibits Barrett's Adenocarcinoma growth by pro-apoptotic mechanisms. Oncology Reports 19: 563-566, 2008.
Karimi KH, Sundaram M, McFadden DW: Pancreatic resection for metastatic renal cell carcinoma. Am Surg 73: 1158-116, 2008
Karimi KH, Sundaram M, McFadden DW: Pancreatic resection for metastatic renal cell carcinoma. Am Surg 73: 1158-1160, 2007.
Vona-Davis L, McFadden DW: NPY family of hormones: clinical relevance and potential use in gastrointestinal disease. Curr Top Med Chem 1 Jan 2007 7(17): p. 1710-16.
Rizvi I, Riggs D, Jackson B, McFadden D: KLH is an effective adjunct against melanoma, in vivo. Am J Surg 194:628-632, 2007.
McMillan B, Riggs D, Jackson B, Cunningham C, McFadden DW: Dietary Influence on pancreatic growth by catechin and inositol hexaphosphate. J Surg Res 141: 115-119, 2007
Karimi KH, Sundaram M, McFadden DW: Pancreatic resection for metastatic renal cell carcinoma. Am Surg 73: 1158-1160, 2007
Vona-Davis L, McFadden DW: NPY family of hormones: clinical relevance and potential use in gastrointestinal disease. Curr Top Med Chem 1 Jan 2007 7(17): p. 1710-16.
Rizvi I, Riggs D, Jackson B, McFadden D: KLH is an effective adjunct against melanoma, in vivo. Am J Surg 194:628-632, 2007.
McMillan B, Riggs D, Jackson B, Cunningham C, McFadden DW: Dietary Influence on pancreatic growth by catechin and inositol hexaphosphate. J Surg Res 141: 115-119, 2007
Vona-Davis L, McFadden DW: NPY family of hormones: clinical relevance and potential use in gastrointestinal disease. Curr Top Med Chem 1 Jan 2007 7(17): p. 1710-16.
Rizvi I, Riggs D, Jackson B, McFadden D: KLH is an effective adjunct against melanoma, in vivo. Am J Surg 194:628-632, 2007.
Other Key Publications
Step Up to Surgery, Eds. McFadden, D.W., and Zaslau, S, WoltersKluwer, 2008
Roberts EG, Vona-Davis L, Riggs DR, Jackson BJ, Hohseni H, Kandzari SJ, McFadden DW. COX-2 inhibition and cancer: experimental findings and clinical correlates. W V Med J. 2004 May-Jun;100(3):96-101.
Vona-Davis L, Riggs DR, Jackson BJ, McFadden DW. Antiproliferative and apoptotic effects of rofecoxib on esophageal cancer in vitro. J Surg Res. 2004 Jun 15;119(2):143-8.
Somasundar P, Frankenberry KA, Skinner H, Vedula G, McFadden DW, Riggs D, Jackson B, Vangilder R, Hileman SM, Vona-Davis LC. Prostate cancer cell proliferation is influenced by leptin. J Surg Res. 2004 May 1;118(1):71-82.
Somasundar P, McFadden DW, Hileman SM, Vona-Davis L. Leptin is a growth factor in cancer. J Surg Res. 2004 Feb;116(2):337-49. Review.
Somasundar P, Riggs D, Jackson B, Vona-Davis L, McFadden DW. Leptin stimulates esophageal adenocarcinoma growth by nonapoptotic mechanisms.Am J Surg. 2003 Nov;186(5):575-8.
McFadden DW, Riggs DR, Jackson BJ, Vona-Davis L. Keyhole limpet hemocyanin, a novel immune stimulant with promising anticancer activity in Barrett's esophageal adenocarcinoma. Am J Surg. 2003 Nov;186(5):552-5.
Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res. 2003 Jul;113(1):50-5.
Yu A, Somasundar P, Povoski SP, McFadden DW. Pancreatic cancer in West Virginia: results from a rural academic medical center. W V Med J. 2002 Jul-Aug;98(4):146-8.
Yu A, Somasundar P, Balsubramaniam A, Rose AT, Vona-Davis L, McFadden DW. Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor. J Surg Res. 2002 Jun 1;105(1):65-8.
Yu A, Somasundar S, Povoski S, McFadden D. Pancreatic cancer in West Virginia: Results from a rural academic medical center. WVMJ 98:146-148, 2002.
Yu A, Somasundar S, Balasubramaniam A, Rose A, Vona-Davis L, McFadden D. Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and VEGF production. J Surg Res 105:65-68, 2002
Liu C, Tilch L, Kwan D, McFadden DW. VEGF is increased in ascites from metastatic pancreatic cancer. J. Surg. Res. 102:31-34, 2002
Rose A, McFadden DW. Alpha-tocopherol succinate inhibits growth of gastric cancer cells in vitro. J Surg Res 95: 19-22, 2001
Towfigh S, McFadden D, Cortina G, Thompson J, Tompkins R, Hines O. Porcelain gallbladder is not associated with gallbladder carcinoma. Am Surg 67:7-10, 2001.
Sebastian J, Rigberg D, Shrivatsan E, Revasova E, McFadden D, Livingston E. The use of large-scale cDNA analysis to profile differential gene expression in KYSE 410 human esophageal cancer cells after irradiation. Bul Exp Biol Med 130 (9):882-885, 2000
Liu C, Saxton R, McFadden D. Hypericin and photodynamic therapy decreases human pancreatic cancer growth in vivo and in vitro. J Surg Res 93:137-143, 2000.
Heisler T, Towfigh S, Simon N, McFadden D. Peptide YY and Vitamin E inhibit hormone sensitive and insensitive breast cancer cells. J Surg Res 91:9-14, 2000
Heisler T, Simon N, Liu C, McFadden D. Peptide YY augments growth inhibition by vitamin E succinate of human pancreatic cancer cell growth. J. Surg Res. 88:23-26, 2000.
Kling K, Kim F, Cole M, McFadden DW. Peptide YY and bcl-2: Clues to chemotherapy resistance in colon cancer. Am J Surg 178:411-414, 1999.
Rigberg D, Centeno J, Kim F, Ke B, Swenson K, Maggard M, McFadden DW. Irradation induced up regulation of FAS in esophageal squamous cell carcinoma is not accompanied by Fas ligand-induced apoptosis. Journal of Surgical Oncology 71:91-96, 1999.
Rigberg D, Kim F, Sebastian J, Kazanjian K, McFadden DW. Hypophosphorylated retinoblastoma protein is asociated with G2 arrest in esophageal squamous cell carcinoma. J. Surg Res 84:101-105, 1999.
Grise K, Rongione A, Laird E, McFadden DW. Peptide YY inhibits the growth of human breast carcinoma in vivo and in vitro. J Surg Research 82:151-155, 1999.
Rigberg DA, Blinman TA, Kim FS, Cole MA, McFadden DW. Antisense blockade of p21/waf 1 decreases radiation induced G2 arrest in esophageal squamous cell cancer. J. Surg Research. 81:6-10, 1999.
Grise K, McFadden D. Gastric cancer: three decades of management. Am. Surg. 64: 930-933, 1998.
Shaw J, Burt R, McFadden DW. Eccrine porocarcinoma: A rare malignancy that simulates common dermatologic diseases. Surg Rounds 21: 298-300, 1998.
Rigberg D, Kim F, Lee S, Cole M, McFadden DW. Differential expression of p53 and p21 in chemotherapeutic treatment of esophageal squamous cell carcinoma. Surgical Forum 48: 809-811, 1997.
Liu CD, Rongione AJ, Garvey L, Balasubramaniam A, McFadden DW. Adjuvant hormonal treatment with peptide YY or its analog decreases human pancreatic carcinoma growth. Am. J. Surg. 171:192-196, 1996.
Swisher SG, Holmes EC, Hunt KK, Zinner MJ, McFadden DW. Perioperative blood transfusions and decreased survival in esophageal cancer. J. Thor. Cardiovasc. Surg. 112:341-348, 1996
