Douglas Wilmot Ball, MD

Research Summary

Dr. Ball is an endocrinologist whose lab studies mechanisms underlying the neuroendocrine phenotype seen in some human cancers. The neuroendocrine phenotype is especially relevant for understanding the origins and evolution of small-cell lung carcinoma (SCLC), a common and highly lethal smoking-related cancer. Dr. Ball and colleagues discovered several years ago that the basic helix-loop-helix transcription factor achaete-scute like-1 (ASCL1) is essential during embryonic development for the appearance of the lung neuroendocrine cells that are likely to be the normal progenitors of SCLC. In Drosophila, the family of achaete-scute proteins is responsible for primitive ectodermal cells to establish a neural fate during early embryogenesis. ASCL1 is highly expressed in human SCLC and is essential for maintenance of the neuroendocrine properties of the tumor cell. Dr. Ball and colleagues have established a transgenic mouse that over-expresses ASCL1 in developing lung epithelium. In combination with the SV40 Large T antigen, ASCL1 promotes formation of aggressive lung cancers with neuroendocrine features. Thus, in the proper setting, ASCL1 appears to behave as an oncogene. In Drosophila, the actions of achaete-scute genes are counteracted by expression of the Notch signal transduction pathway that steers cells away from a neural fate and results in down-regulation of the achaete-scute genes. In collaboration with other Hopkins investigators, Dr. Ball has revealed unique mechanisms underlying Notch down-regulation of ASCL1 and explored contributions of Notch signaling to a variety of tumor types.

Dr. Ball also is active in developing new therapies for a type of thyroid cancer closely related to SCLC, medullary thyroid cancer. This active translational research program, in collaboration with other Kimmel Cancer Center investigators, has led to a phase II clinical trial and further promising therapeutic approaches to follow.


Journal Citations

Gallia, G.L.; Rand, V.; Siu, I.M.; Eberhart, C.G.; James, C.D.; Marie, S.K.; Oba-Shinjo, S.M.; Carlotti, C.G.; Caballero, O.L.; Simpson, A.J.; Brock, M.V.; Massion, P.P.; Carson, B.S., Sr.; Riggins, G.J. PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res. 2006 Oct;4(10):709-714.

Huang, H.Y.; Caballero, B.; Chang, S.; Alberg, A.J.; Semba, R.D.; Schneyer, C.R.; Wilson, R.F.; Cheng, T.Y.; Vassy, J.; Prokopowicz, G.; Barnes, G.J., 2nd; Bass, E.B. The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference. Ann Intern Med. 2006 Sep 5;145(5):372-385.

Strock, C.J.; Park, J.I.; Nakakura, E.K.; Bova, G.S.; Isaacs, J.T.; Ball, D.W.; Nelkin, B.D. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 2006 Aug 1;66(15):7509-7515.

Strock, C.J.; Park, J.I.; Rosen, D.M.; Ruggeri, B.; Denmeade, S.R.; Ball, D.W.; Nelkin, B.D. Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. J Clin Endocrinol Metab. 2006 Jan;91(1):79-84.

Ball, D.W.; Jin, N.; Rosen, D.M.; Dackiw, A.; Sidransky, D.; Xing, M.; Nelkin, B.D. Selective Growth Inhibition in BRAF Mutant Thyroid Cancer by the Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244. J Clin Endocrinol Metab. 2007 Dec;92(12):4712-4718.

Mas, S.; Crescenti, A.; Gasso, P.; Deulofeu, R.; Molina, R.; Ballesta, A.; Kensler, T.W.; Lafuente, A. Induction of apoptosis in HT-29 cells by extracts from isothiocyanates-rich varieties of Brassica oleracea. Nutr Cancer. 2007;58(1):107-114.

Smith, I.M.; Mydlarz, W.K.; Mithani, S.K.; Califano, J.A. DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage. Int J Cancer. 2007 Oct 15;121(8):1724-1728.

Wood, L.D.; Parsons, D.W.; Jones, S.; Lin, J.; Sjoblom, T.; Leary, R.J.; Shen, D.; Boca, S.M.; Barber, T.; Ptak, J.; Silliman, N.; Szabo, S.; Dezso, Z.; Ustyanksky, V.; Nikolskaya, T.; Nikolsky, Y.; Karchin, R.; Wilson, P.A.; Kaminker, J.S.; Zhang, Z.; Croshaw, R.; Willis, J.; Dawson, D.; Shipitsin, M.; Willson, J.K.; Sukumar, S.; Polyak, K.; Park, B.H.; Pethiyagoda, C.L.; Pant, P.V.; Ballinger, D.G.; Sparks, A.B.; Hartigan, J.; Smith, D.R.; Suh, E.; Papadopoulos, N.; Buckhaults, P.; Markowitz, S.D.; Parmigiani, G.; Kinzler, K.W.; Velculescu, V.E.; Vogelstein, B. The genomic landscapes of human breast and colorectal cancers. Science. 2007 Nov 16;318(5853):1108-1113.

Yang, M.; Culhane, J.C.; Szewczuk, L.M.; Jalili, P.; Ball, H.L.; Machius, M.; Cole, P.A.; Yu, H. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry. 2007 Jul 10;46(27):8058-8065.

Brait, M.; Begum, S.; Carvalho, A.L.; Dasgupta, S.; Vettore, A.L.; Czerniak, B.; Caballero, O.L.; Westra, W.H.; Sidransky, D.; Hoque, M.O. Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer. Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2786-2794.

Brandes, J.C.; Schmidt, E.; Yung, R. Occlusive endobronchial stent placement as a novel management approach to massive hemoptysis from lung cancer. J Thorac Oncol. 2008 Sep;3(9):1071-1072.

McGarvey, K.M.; Van Neste, L.; Cope, L.; Ohm, J.E.; Herman, J.G.; Van Criekinge, W.; Schuebel, K.E.; Baylin, S.B. Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells. Cancer Res. 2008 Jul 15;68(14):5753-5759.

Schroder, F.H.; Carter, H.B.; Wolters, T.; van den Bergh, R.C.; Gosselaar, C.; Bangma, C.H.; Roobol, M.J. Early detection of prostate cancer in 2007. Part 1: PSA and PSA kinetics. Eur Urol. 2008 Mar;53(3):468-477.

Vendt, B.A.; McKinstry, R.C.; Ball, W.S.; Kraut, M.A.; Prior, F.W.; Barton, B.; Casella, J.F.; Debaun, M.R. Silent Cerebral Infarct Transfusion (SIT) Trial Imaging Core: Application of Novel Imaging Information Technology for Rapid and Central Review of MRI of the Brain. Journal of digital imaging : the official journal of the Society for Computer Applications in Radiology. 2008 Apr 9;22:326-343.

Wolfl, M.; Rutebemberwa, A.; Mosbruger, T.; Mao, Q.; Li, H.M.; Netski, D.; Ray, S.C.; Pardoll, D.; Sidney, J.; Sette, A.; Allen, T.; Kuntzen, T.; Kavanagh, D.G.; Kuball, J.; Greenberg, P.D.; Cox, A.L. Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire. J Immunol. 2008 Nov 1;181(9):6435-6446.

Yoon, H.H.; Forastiere, A.A. Locally advanced esophageal adenocarcinoma: current standards and molecular predictors of outcome. Future oncology (London, England). 2008 Jun;4(3):413-425.

Jiang, T.; Collins, B.J.; Jin, N.; Watkins, D.N.; Brock, M.V.; Matsui, W.; Nelkin, B.D.; Ball, D.W. Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res. 2009 Feb 1;69(3):845-854.

Jin, N.; Jiang, T.; Rosen, D.M.; Nelkin, B.D.; Ball, D.W. Dual inhibition of mitogen-activated protein kinase kinase and mammalian target of rapamycin in differentiated and anaplastic thyroid cancer. J Clin Endocrinol Metab. 2009 Oct;94(10):4107-4112.

Karanam, B.; Jagu, S.; Huh, W.K.; Roden, R.B. Developing vaccines against minor capsid antigen L2 to prevent papillomavirus infection. Immunol Cell Biol. 2009 May-Jun;87(4):287-299.

Kramer, B.S.; Hagerty, K.L.; Justman, S.; Somerfield, M.R.; Albertsen, P.C.; Blot, W.J.; Ballentine Carter, H.; Costantino, J.P.; Epstein, J.I.; Godley, P.A.; Harris, R.P.; Wilt, T.J.; Wittes, J.; Zon, R.; Schellhammer, P. Use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Clin Oncol. 2009 Mar 20;27(9):1502-1516.

Kung, L.A.; Tao, S.C.; Qian, J.; Smith, M.G.; Snyder, M.; Zhu, H. Global analysis of the glycoproteome in Saccharomyces cerevisiae reveals new roles for protein glycosylation in eukaryotes. Mol Syst Biol. 2009;5:308.

Penet, M.F.; Pathak, A.P.; Raman, V.; Ballesteros, P.; Artemov, D.; Bhujwalla, Z.M. Noninvasive multiparametric imaging of metastasis-permissive microenvironments in a human prostate cancer xenograft. Cancer Res. 2009 Nov 15;69(22):8822-8829.

Tjiang, T.; B.J., C.; Jin, N.; Brock, M.V.; Watkins, D.N.; Matsui, W.; Nelkin, B.D.; Ball, D.W. ASCL1 regulates CD133 and tumor-initiating capacity of SCLC. Cancer Research. 2009 (In Press).

Torio, C.M.; Klassen, A.C.; Curriero, F.C.; Caballero, B.; Helzlsouer, K. The Modifying Effect of Social Class on the Relationship Between Body Mass Index and Breast Cancer Incidence. Am J Public Health. 2009 Jan 15.
Ball, D.W. Selectively targeting mutant BRAF in thyroid cancer. J Clin Endocrinol Metab. 2010 Jan;95(1):60-61.

Cho, Y.J.; Tsherniak, A.; Tamayo, P.; Santagata, S.; Ligon, A.; Greulich, H.; Berhoukim, R.; Amani, V.; Goumnerova, L.; Eberhart, C.G.; Lau, C.C.; Olson, J.M.; Gilbertson, R.J.; Gajjar, A.; Delattre, O.; Kool, M.; Ligon, K.; Meyerson, M.; Mesirov, J.P.; Pomeroy, S.L. Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome. J Clin Oncol. 2010 Dec 6.

Crawford, S.O.; Hoogeveen, R.C.; Brancati, F.L.; Astor, B.C.; Ballantyne, C.M.; Schmidt, M.I.; Young, J.H. Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. Int J Epidemiol. 2010 Dec;39(6):1647-1655.

Feldmann, G.; Mishra, A.; Hong, S.M.; Bisht, S.; Strock, C.J.; Ball, D.W.; Goggins, M.; Maitra, A.; Nelkin, B.D. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res. 2010 Jun 1;70(11):4460-4469.

Hida, K.; Won, S.Y.; Di Pasquale, G.; Hanes, J.; Chiorini, J.A.; Ostermeier, M. Sites in the AAV5 capsid tolerant to deletions and tandem duplications. Arch Biochem Biophys. 2010 Apr 1;496(1):1-8.

Hudson, T.J.; Anderson, W.; Artez, A.; Barker, A.D.; Bell, C.; Bernabe, R.R.; Bhan, M.K.; Calvo, F.; Eerola, I.; Gerhard, D.S.; Guttmacher, A.; Guyer, M.; Hemsley, F.M.; Jennings, J.L.; Kerr, D.; Klatt, P.; Kolar, P.; Kusada, J.; Lane, D.P.; Laplace, F.; Youyong, L.; Nettekoven, G.; Ozenberger, B.; Peterson, J.; Rao, T.S.; Remacle, J.; Schafer, A.J.; Shibata, T.; Stratton, M.R.; Vockley, J.G.; Watanabe, K.; Yang, H.; Yuen, M.M.; Knoppers, B.M.; Bobrow, M.; Cambon-Thomsen, A.; Dressler, L.G.; Dyke, S.O.; Joly, Y.; Kato, K.; Kennedy, K.L.; Nicolas, P.; Parker, M.J.; Rial-Sebbag, E.; Romeo-Casabona, C.M.; Shaw, K.M.; Wallace, S.; Wiesner, G.L.; Zeps, N.; Lichter, P.; Biankin, A.V.; Chabannon, C.; Chin, L.; Clement, B.; de Alava, E.; Degos, F.; Ferguson, M.L.; Geary, P.; Hayes, D.N.; Johns, A.L.; Kasprzyk, A.; Nakagawa, H.; Penny, R.; Piris, M.A.; Sarin, R.; Scarpa, A.; van de Vijver, M.; Futreal, P.A.; Aburatani, H.; Bayes, M.; Botwell, D.D.; Campbell, P.J.; Estivill, X.; Grimmond, S.M.; Gut, I.; Hirst, M.; Lopez-Otin, C.; Majumder, P.; Marra, M.; McPherson, J.D.; Ning, Z.; Puente, X.S.; Ruan, Y.; Stunnenberg, H.G.; Swerdlow, H.; Velculescu, V.E.; Wilson, R.K.; Xue, H.H.; Yang, L.; Spellman, P.T.; Bader, G.D.; Boutros, P.C.; Flicek, P.; Getz, G.; Guigo, R.; Guo, G.; Haussler, D.; Heath, S.; Hubbard, T.J.; Jiang, T.; Jones, S.M.; Li, Q.; Lopez-Bigas, N.; Luo, R.; Muthuswamy, L.; Ouellette, B.F.; Pearson, J.V.; Quesada, V.; Raphael, B.J.; Sander, C.; Speed, T.P.; Stein, L.D.; Stuart, J.M.; Teague, J.W.; Totoki, Y.; Tsunoda, T.; Valencia, A.; Wheeler, D.A.; Wu, H.; Zhao, S.; Zhou, G.; Lathrop, M.; Thomas, G.; Yoshida, T.; Axton, M.; Gunter, C.; Miller, L.J.; Zhang, J.; Haider, S.A.; Wang, J.; Yung, C.K.; Cross, A.; Liang, Y.; Gnaneshan, S.; Guberman, J.; Hsu, J.; Chalmers, D.R.; Hasel, K.W.; Kaan, T.S.; Lowrance, W.W.; Masui, T.; Rodriguez, L.L.; Vergely, C.; Bowtell, D.D.; Cloonan, N.; deFazio, A.; Eshleman, J.R.; Etemadmoghadam, D.; Gardiner, B.A.; Kench, J.G.; Sutherland, R.L.; Tempero, M.A.; Waddell, N.J.; Wilson, P.J.; Gallinger, S.; Tsao, M.S.; Shaw, P.A.; Petersen, G.M.; Mukhopadhyay, D.; DePinho, R.A.; Thayer, S.; Shazand, K.; Beck, T.; Sam, M.; Timms, L.; Ballin, V.; Lu, Y.; Ji, J.; Zhang, X.; Chen, F.; Hu, X.; Yang, Q.; Tian, G.; Zhang, L.; Xing, X.; Li, X.; Zhu, Z.; Yu, Y.; Yu, J.; Tost, J.; Brennan, P.; Holcatova, I.; Zaridze, D.; Brazma, A.; Egevard, L.; Prokhortchouk, E.; Banks, R.E.; Uhlen, M.; Viksna, J.; Ponten, F.; Skryabin, K.; Birney, E.; Borg, A.; Borresen-Dale, A.L.; Caldas, C.; Foekens, J.A.; Martin, S.; Reis-Filho, J.S.; Richardson, A.L.; Sotiriou, C.; Thoms, G.; van't Veer, L.; Birnbaum, D.; Blanche, H.; Boucher, P.; Boyault, S.; Masson-Jacquemier, J.D.; Pauporte, I.; Pivot, X.; Vincent-Salomon, A.; Tabone, E.; Theillet, C.; Treilleux, I.; Bioulac-Sage, P.; Decaens, T.; Franco, D.; Gut, M.; Samuel, D.; Zucman-Rossi, J.; Eils, R.; Brors, B.; Korbel, J.O.; Korshunov, A.; Landgraf, P.; Lehrach, H.; Pfister, S.; Radlwimmer, B.; Reifenberger, G.; Taylor, M.D.; von Kalle, C.; Majumder, P.P.; Pederzoli, P.; Lawlor, R.A.; Delledonne, M.; Bardelli, A.; Gress, T.; Klimstra, D.; Zamboni, G.; Nakamura, Y.; Miyano, S.; Fujimoto, A.; Campo, E.; de Sanjose, S.; Montserrat, E.; Gonzalez-Diaz, M.; Jares, P.; Himmelbaue, H.; Bea, S.; Aparicio, S.; Easton, D.F.; Collins, F.S.; Compton, C.C.; Lander, E.S.; Burke, W.; Green, A.R.; Hamilton, S.R.; Kallioniemi, O.P.; Ley, T.J.; Liu, E.T.; Wainwright, B.J. International network of cancer genome projects. Nature. 2010 Apr 15;464(7291):993-998.

Tuttle, R.M.; Ball, D.W.; Byrd, D.; Daniels, G.H.; Dilawari, R.A.; Doherty, G.M.; Duh, Q.Y.; Ehya, H.; Farrar, W.B.; Haddad, R.I.; Kandeel, F.; Kloos, R.T.; Kopp, P.; Lamonica, D.M.; Loree, T.R.; Lydiatt, W.M.; McCaffrey, J.; Olson, J.A., Jr.; Parks, L.; Ridge, J.A.; Shah, J.P.; Sherman, S.I.; Sturgeon, C.; Waguespack, S.G.; Wang, T.N.; Wirth, L.J. Medullary carcinoma. J Natl Compr Canc Netw. 2010 May;8(5):512-530

Tuttle, R.M.; Ball, D.W.; Byrd, D.; Dilawari, R.A.; Doherty, G.M.; Duh, Q.Y.; Ehya, H.; Farrar, W.B.; Haddad, R.I.; Kandeel, F.; Kloos, R.T.; Kopp, P.; Lamonica, D.M.; Loree, T.R.; Lydiatt, W.M.; McCaffrey, J.C.; Olson, J.A., Jr.; Parks, L.; Ridge, J.A.; Shah, J.P.; Sherman, S.I.; Sturgeon, C.; Waguespack, S.G.; Wang, T.N.; Wirth, L.J. Thyroid carcinoma. J Natl Compr Canc Netw. 2010 Nov;8(11):1228-1274

Yan, Y.; Klein, R.; Heiss, G.; Girman, C.J.; Lange, E.M.; Klein, B.E.; Rose, K.M.; Boerwinkle, E.; Pankow, J.S.; Brancati, F.L.; Ballantyne, C.M.; Kottgen, A.; North, K.E. The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study. BMC Endocr Disord. 2010;10:9.