|Nathan Wall, PhD|
|Assistant Professor, Biochemistry and Microbiology|
|School of Medicine|
|University Faculty Profile|
Pancreatic cancer is the fourth most common cause of cancer death (~30,000 deaths annually) in men and women in the United States, with five-year survival for all stages of disease less than 5 percent. Despite several phase II trials of chemo-radiotherapy regimens, no clinically meaningful gains have been made in the treatment of pancreatic cancer. There is an urgent need for more effective therapy for patients with advanced disease. Potential approaches might include genetic-based therapies that attempt to eradicate cancer cells by manipulating their intracellular genetic material with strategies ranging from restoring the function of mutated or missing tumor suppressor genes to inhibiting the function of activated oncogenes.
One such strategy is to utilize the inhibitor of apoptosis (IAP), survivin, as a therapeutic target as it is overexpressed in cancer but undetectable in normal differentiated adult tissues. Survivin expression in cancer appears to be associated with unfavorable clinicopathological parameters, such as poor prognosis with progressive disease and shorter patient survival rates. Survivin is also expressed in the majority of pancreatic adenocarcinomas and correlates with cellular proliferation and apoptosis. My laboratory seeks to further elucidate the cellular pathways and molecular interactions taking place between survivin and members of the apoptosome and to evaluate whether pancreatic cancer can be treated by targeting survivin both in vitro and in vivo.
1. Galloway NR, Aspe JR, Sellers C, Wall NR. Enhanced antitumor effect of combined gemcitabine and proton radiation in the treatment of pancreatic cancer. Accepted-Pancreas.
2. Neidigh J, Darwanto A, Williams A, Wall NR, Sowers L. Cloning and characterization of Rhodotorula glutinis thymine hydroxylase. Accepted-Chemical Research in Toxicology.
3. Khan S, Aspe JR, Asumen MG, Almaguel F, Odumosu O, Acevedo-Martinez S, De Leon M, Langridge W, Wall NR. Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential. British Journal of Cancer 100(7):1073-1086, 2009.
4. Parrish YK, Baez I, Milford TA, Benitez A, Galloway N, Rogerio JW, Sahakian E, Kagoda M, Huang G, Hao Q, Sevilla Y, Barsky LW, Zielinska E, Price MA, Wall NR, Dovat S, Payne KJ. IL-7 Dependence in Human B Lymphopoiesis Increases During Progression of Ontogeny from Cord Blood to Bone Marrow. The Journal of Immunology 182(7): 4255-4266, 2009.
5. Kalla-Singh S, Moretta D, Almaguel F, Wall NR, De Leon M, De Leon D. Differential effect of ProIGF-II and IGF-II on Resveratrol Induced Cell Death by Regulating Survivin Cellular Localization and Mitochondrial Depolarization in Breast Cancer Cells. Growth Factors, 25(6):363-372, 2007.
6. Dohi T, Beltrami E, Wall NR, Plescia J, Altieri DC. Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J Clin Invest., 114(8):1117-1127, 2004.
7. Sui G, Affar EB, Shi Y, Brignone C, Wall NR, Yin P, Donohoe M, Calvo D, Luke MP, Grossman SR, Shi Y. Yin Yang 1 is a negative regulator of p53 in vivo. Cell, 117(7):859-872, 2004.
8. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, deCabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing SIRT1 deacetylase. Science. 305(5682):390-392, 2004. Epub Science Express 2004 Jun 17.
9. Chen J, Wall NR, Kocher K, Duclos N, Shi Y, Gilliland DG. Stable expression of small interfering RNA sensitizes TEL-PDGF'R to inhibition with imatinib or rapamycin. J Clin Invest., 113(12):1784-1791, 2004.
10. Wall NR, Shi Y. Small RNA: can RNA interference be exploited for therapy? Lancet, 362(9393): 1401-1403, 2003.
11. Blanc-Brude OP, Mesri M, Wall NR, Plescia J, Dohi T, Altieri DC. Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin Cancer Res., 9(7):2683-2692, 2003.
12. Wall NR, O'Connor DS, Plescia J, Pommier Y, Altieri DC. Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. Cancer Res., 63(1):230-235, 2003.
13. O'Connor DS, Wall NR, Plescia J, Porter ACG, Altieri DC. A p34cdc2 survival checkpoint in cancer. Cancer Cell, 2(1):43-54, 2002.
14. Griffith TS, Fialkov JM, Scott DL, Azuhata T, Williams RD, Wall NR, Altieri DC, Sandler AD. Induction and regulation of Tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma. Cancer Res., 62(11):3093-3099, 2002.
15. Giodini A, Kallio MJ, Wall NR, Gorbsky GJ, Tognin S, Marchisio PC, Symons M, Altieri DC. Regulation of microtubule stability and mitotic timing by survivin. Cancer Res., 62(9):2462-2467, 2002.