Daniel D. Von Hoff, M.D., is currently Professor of Medicine, Pathology, Molecular and Cellular Biology, Director of the Arizona Health Sciences Center's Cancer Therapeutics Program, Executive Vice President, Translational Genomics Research Institute (TGen), Director, TGen's Translational Drug Development Division and Head, Pancreatic Cancer Research Program. He is also Chief Scientific Officer for US Oncology.

Dr. Von Hoff's major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents we now use routinely, including: mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, CPT-11, and others. At present, he and his colleagues are concentrating on the development of molecularly targeted therapies.

Dr. Von Hoff's laboratory interests and contributions have been in the area of in vitro drug sensitivity testing to individualize treatment for the patient. He and his laboratory are now concentrating on discovery of new targets in pancreatic cancer. Dr. Von Hoff has published more than 515 papers, 127 book chapters, and more than 850 abstracts. Dr. Von Hoff was appointed to President Bush's National Cancer Advisory Board in June 2004 - March 2010. Dr. Von Hoff is the past President of the American Association for Cancer Research, a Fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology. He is a founder of ILEXTM Oncology, Inc. (recently acquired by Genzyme). He is founder and the Editor Emeritus of Investigational New Drugs - The Journal of New Anticancer Agents; and, Editor-in-Chief of Molecular Cancer Therapeutics.

He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows.

Wang,H., Han, H., Bearss, D., Von Hoff, D.D.. A pharmacological synthetic lethal screening system for the identification of new anti-pancreatic cancer agents specifically targeting DPC4 deficient cells. Proc Am Assoc Cancer Res, 44:5489. 2003.

Han, H., Munoz, R.M., Bearss, D.J., Vankayalapati, H., Nagle, R.B., Hurley, L.H., Von Hoff, D.D.. The urokinase-type plasminogen activator and its receptor as drug targets for pancreatic cancer. Proc Am Assoc Cancer Res, 44:5574. 2003.

Washingon, D., Miller, K., Budd, G.T., Taylor C., Von Hoff, D.D. , Brown, G.L., Parra, R., Jameson, A., Mascavage, J., Henner, W.D.. Phase 2 study of TLK286 (GST P1-1 activated glutathione analog) as > third-line therapy in patients with advanced metastatic breast cancer (MBC). Proc Am Soc Clin Oncol, 22:61. 2003.

Von Hoff, D.D. , Jolivet, J., Steward, W.. A dose-escalating phase I study of troxacitabine and gemcitabine in advanced solid malignancies. Proc Am Soc Clin Oncol, 22:566. 2003.

Garland, L.L., Gitlitz, B., Ebbinghaus, S., Gately, N., Trammell, J., Von Hoff, D.D. , Figlin, R.. Phase I trial of intravenous IL-4 pseudomonas exotoxin (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor. Proc Am Soc Clin Oncol, 22:911. 2003.

Papadimitrakopoulou, V., Figlin, R., Garland, L., Blumenschein, G., Fossella, F., Von Hoff, D.D. , King, L., Brown, G.L., Mascavage, J., Henner, W.D.. Phase 2 study of TLK286 (GST P1-1 activated glutathione analog) administered weekly in patients with non-small cell lung cancer (NSCLC) who failed prior platinum-based regimens. Proc Am Soc Clin Oncol, 22:2636. 2003.

Work in Dr. Trent's laboratory focuses on the study of genetic changes related to cancer predisposition and progression. Recently his research has focused on the genetic susceptibility to human prostate cancer. Other work in his laboratory has been focused upon relating the recent advances in both molecular biology and cancer genetics and the valuable tools of the Human Genome Project for the study of human oncogenesis. This has included the development of technologies for analyzing the expression patterns of genes using cDNA microarray technology.

Additionally, current research in his laboratory is focusing on the isolation and cloning of specific chromosomal breakpoints, coupled with the identification and study of the products of these genes, which is providing an exciting avenue for future research. The central viewpoint underlying research in this laboratory is that genetic abnormalities represent the critical events important to the genesis and progression of human neoplasia. In addition to prostate cancer, his laboratory does work in malignant melanoma, ovarian and breast carcinoma. Studies have ranged from the utilization of fluorescent genotyping for genome-wide scans, microcell-mediated chromosome transfer, genomic mapping using fluorescence in situ hybridization, numerous genomic strategies for positional cloning, and recently, the development of chromosome microdissection and cDNA microarray technology. Accordingly, the spectrum of activities in this laboratory ranges from chromosome-banding analysis of tumors through molecular studies of gene function.

Duggan, D., Bittner, M., Chen, Y., Meltzer, P., and Trent, J.M.. Expression profiling using cDNA microarrays. Nature Genetics, 21, 10-14. 1999.

Iyer V.R., Eisen M.B., Ross D.T., Schuler G., Moore T., Lee J.C.F., Trent J .M., Staudt L.M., Hudson J. Jr., Boguski M.S., Lashkari D., Shalon D., Botstein D., Brown P.O.. The transcriptional program in the response of human fibroblasts to serum. Science, 283(5398), 83-7. 1999.

Becker K.G., Simon R.M., Bailey-Wilson J.E., Freidlin B., Biddison W.E., McFarland H.F., Trent J .M. . Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci U S A, 18;95(17), 9979-84. 1998.

Ermolaeva O., Rastogi M., Pruitt K.D., Schuler G.D., Bittner M.L., Chen Y., Simon R., Meltzer P.,Trent J .M., Boguski M.S.. Data management and analysis for gene expression arrays. Nat Genet, 20(1), 19-23. 1998.

Khan J., Simon R., Bittner M., Chen Y., Leighton S.B., Pohida T., Smith P.D., Jiang Y., Gooden G.C., Trent J .M., Meltzer P.S..Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. Cancer Res, 15;58(22), 5009-13. 1998.

Adrenocortical carcinoma is a rare cancer, with an incidence of 1-2/million. Surgical resection is the only potential for a cure at this time. However, 40-70% of cases are metastatic at the time of diagnosis, preventing complete resection and leading to a 5 year survival rate of 25-30%. The only approved chemotherapy, mitotane, is not well-tolerated by patients and shows response in only a quarter of tumors. The ACC Program began in 2006 as a collaborative effort developed through a generous donation from the Advancing Treatments for Adrenocortical Carcinoma (ATAC) Fund (www.atac.org). The program has and continues to build a repository of ACC tumors from around the world. Multiple genetic and genomic technologies available at TGen (microarray expression profiling, single nucleotide polymorphism (SNP) analysis, comparative genomic hybridization (CGH), and tissue microarray (TMA), chemical synthetic lethal screening (RNAi)) generate data from the tumors that is being analyzed both separately and in combination to elucidate the acquired genomic changes that characterize this tumor type. These insights into the cellular processes of carcinogenesis in the adrenal cortex allow the identification of novel therapeutic targets necessary in the treatment of this rare, aggressive endocrine tumor. The program is translating our expanding knowledge of the particular cellular changes in ACC into in vitro and in vivo experiments as preliminary data for clinical trials.

Additionally, the ACC data sets represent an opportunity to test various methodologies geared toward using the NCI60 cell line panel as an initial step to identifying potential therapeutic targets in other rare tumor types. The NCI60 cell line panel was developed by the Developmental Therapeutics Program of the National Cancer Institute to screen compounds for anti-cancer activity. Over 100,000 compounds have been tested so far, and the cell lines have been extensively characterized at the DNA, RNA and protein levels. Combining this data can identify associations of drug response with sets of molecular parameters that can then be verified experimentally.

Dr. Bussey received her B.S. in general biology from the University of Arizona. She received her Ph.D. in Molecular and Medical Genetics from Oregon Health Sciences University where her dissertation research focused on the cytogenetic and molecular characterization of pediatric germ cell tumors, a group of rare tumors in children. Prior to comming to TGen as an Associate Investigator and Lead Investigator for the ACC Research Program, she did a post-doctoral fellowship and worked as a contract scientist with John Weinstein, M.D., Ph.D. and the Genomics and Bioinformatics lab in the Laboratory of Molecular Pharmacology at the NCI. Her work there focused on integrative analysis of array CGH data and expression data in the NCI60 and development of computational tools to facilitate such analyses.

Lorenzi PL, Reinhold WC, Rudelius M, Gunsior M, Shankavaram U, Bussey KJ, Scherf U, Eichler GS, Martin SE, Chin K, Gray JW, Kohn EC, Horak ID, Von Hoff DD, Raffeld M, Goldsmith PK, Caplen NJ, Weinstein JN. Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells. Molecular Cancer Therapeutics, 5(11):2613-23. 2006.

Bussey KJ, Chin K, Lababidi S, Reinhold WC, Kuo W-L, Gwadry F, Ajay, Kouros-Mehr H, Fridlyand J, Jain A, Collins C., Nishizuka S, Tonon G, Roschke A, Stover K, Kirsch I, Scudiero DA, Gray JW, Weinstein JN. Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 Cell Line Panel. Molecular Cancer Therapeutics, 5(4):853-67. 2006.

Bussey KJ, Kane D, Sunshine M, Narasimhan S, Nishizuka S, Reinhold WC, Zeeburg B, Ajay, Weinstein JN. MatchMiner: a tool for batch navigation among gene and gene product identifiers. Genome Biology, 4(4):R27. 2003.

Bussey KJ, Lawce HJ, Himoe E, Shu XO, Heerema NA, Perlman EJ, Olson SB, Magenis RE. SNRPN methylation patterns in germ cell tumors as a reflection of primordial germ cell development. Genes, Chromosomes, and Cancer, 32:342-352. 2001.

Bussey KJ, Lawce HJ, Himoe E, Shu XO, Suijerbuijk RF, Olson SB, Magenis RE. Chromosome 1 and chromosome 12 abnormalities in pediatric germ cell tumors by interphase FISH. Cancer Genetics and Cytogenetics, 125:112-118. 2001.

Bussey KJ, Lawce HJ, Olson SB, Arthur DC, Kalousek DK, Krailo M, Giller R, Heifetz S, Womer R, and Magenis RE. Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site-, and histopathology-related differences. A Children’s Cancer Group Study. Genes, Chromosomes, and Cancer, 25:134-146. 1999.

Dr. Demeure is a fellowship-trained endocrine surgeon who has been in academic surgical practice since 1991. He had maintained an active clinical and basic research program during this time focusing on the mechanisms of tumor metastases. Dr. Demeure went to medical school at Hahnemann University, and completed his surgical residency at the University of Arizona. His fellowship in endocrine surgery was in Perth, Australia and then at the University of California, San Francisco. Subsequently, Dr. Demeure took an academic appointment at the Medical College of Wisconsin where he practiced surgical oncology for 11 years before moving to the University of Arizona where he was a tenured professor of surgery and chief of general surgery. He then moved to the Phoenix area full time in 2008 in order to further the translational therapeutics program in ACC. He has published over 80 manuscripts and book chapters. Dr. Demeure served as the president of the American Association of Endocrine Surgeons from 2008 to 2009. He is also a member of many surgical societies including the American College of Surgeons and the Society of Surgical Oncology. Dr. Demeure is the Director of the Pancreatic Cancer Biospecimens Repository for a recently awarded pancreatic cancer program project grant from the NIH. His role in this project is to enroll and manage multiple institutions whose investigators submit cancer and blood specimens for researches involved in the study of the molecular genetics of pancreatic cancer. This role is similar to a key function of this adrenocortical cancer project. Dr. Demeure started the ACC project at TGen which, along with Dr. Kim Bussey, he now directs.

Dr. Demeure has been a Senior Investigator with TGen since 2005.

The ATAC Research Fund is a program designed to support adrenocortical carcinomas (ACC) research efforts. Working in collaboration with the Translational Genomics Research Institute (TGen) in Phoenix, AZ, the ATAC Fund is focused on collecting ACC tumor samples though a recently launched tissue bank.

The goal is to develop new, more effective treatments against ACC.

The ATAC Research Fund

Robert T. Dorr is a Professor of Pharmacology and Director of Pharmacology Research at the Arizona Cancer Center, The University of Arizona, Tucson, Arizona. He obtained his B.S. (with distinction) and M.S. degrees in Pharmacy at The University of Arizona in 1974 and 1978. He then taught in the Clinical Pharmacy Program at the Arizona Health Sciences Center before returning to graduate school at the College of Medicine, Pharmacology Program in 1981. He obtained a Ph.D. degree in Pharmacology and Toxicology in 1984 and established a drug development laboratory effort at the Arizona Cancer Center in 1985. Dr. Dorr also heads the Cancer Center Research Pharmacy.

He has conducted and participated in numerous Phase I, II, III clinical drug trials of new antitumor agents at The University of Arizona. He has been funded on several N.I.H. research grants since 1980. Current research interests include characterization and development of cyanoaziridines, such as imexon, for refractory myeloma, melanoma and pancreatic cancer, the development of novel DNA-binding agents for resistant tumors and the use of synthetic melanotropins for skin cancer chemoprevention. He has written over 200 peer-reviewed full-length scientific articles and numerous book chapters. He is the originator and co-author of The Cancer Chemotherapy Handbook (1980, 1994) and has received several patents for medical devices and new agents. Dr. Dorr consults on anticancer drug pharmacology for numerous pharmaceutical firms and is considered one of our country’s top cancer drug pharmacologists.

Pourpak A, Meyers RO, Samulitis BK, Chow H-H, Kepler CY, Raymond MA, Hersh E, Dorr RT. Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice. Anti-Cancer Drugs, 17:1179-1184, 2006.

Scott J, Dorr RT,Samulitis B, Landowski T. Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. Cancer Chemother Pharmaco l.,59(6);749-757, 2007.

Baker AF, Landowski T, Dorr R, Tate WR, Gard JMC, Tavenner BE, Dragovich T, Coon A, Powis G. The antitumor agent imexon activates antioxidant gene expression: Evidence for an oxidative stress response. Clin Cancer Res, 13(11):3388-3394, 2007.

Pourpak A, Dorr RT, Meyers RO,Powell MB, Stratton SP.Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line.Invest New Drugs 25(2):107-114,2007.

Dragovich T, Gordon M,Mendelson D, Wong L, Modiano M, Chow S, Samulitis B, O’Day S, Grenier K, Hersh E, Dorr RT. Phase I trial of imexon in patients with advanced malignancy. J Clin Oncol, 25(13):1779-84, 2007.

Piao WH, Wong R, Bai XF, Huang J, Campagnolo DI, Dorr RT, Vollmer TL, Shi FD. Therapeutic effect of anthracene-based anticancer agent ethonafide in an animal model of multiple sclerosis. J Immunol 179(11):7415-23,2007.

Congdon LM, Pourpak A, Escalante AM, Dorr RT, Landowski TH. Proteasomal inhibition stabilizes topoisomerase IIa protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethyoxyazonafide).Biochem Pharmacol. 75:883-90, 2008.

Stratton SP, Saboda KL, Myrdal PB, Gupta A, McKenzie NE, Brooks C, Salasche SJ, Warneke JA, Ranger-Moore J, Bozzo PD, Blanchard J, Einspahr JG, Dorr RT, Levine N, Alberts DS. Phase 1 study of topical perilly alcohol cream for chemoprevention of skin cancer.Nutr Cancer. 60(3):325-30, 2008.

Samulitis BK, Landowski TH, Dorr RT.Inhibition of protein synthesis by imexon reduces HIF-1alpha expression in normoxic and hypoxic pancreatic cancer cells. Invest New Drugs. 27(1):89-98, 2009.

Henderson MC, Shaw Y-J, Wang H, Han H, Hurley LH, Flynn G, Dorr RT, Von Hoff DD. UA62784, a novel inhibitor of centromere protein E kinesin-like protein. Mol Cancer Ther. 8(1):36-44, 2009.

Dr. Han’s research at TGen involves the identification of frequent alterations responsible for driving the onset and progression of pancreatic cancer and the development of new anti-pancreatic cancer agents that target these alterations.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and has the worst survival rates of any cancer (The 1-year and 5-year survival rates are approximately 19% and 4%, respectively). This dismal picture of pancreatic cancer is mainly due to the lack of early diagnosis and effective surgical or chemotherapeutic treatments. In order to make real progress against this devastating disease, we are involved in research to discover basic genetic, molecular, and biochemical abnormalities and help translate the findings into practical and effective therapies for patients with pancreatic cancer. The development of targeted therapies based on distinguishing characteristics of pancreatic cancer cells versus normal cells relies on our ability to identify alterations that are present at high frequencies in pancreatic cancer cells.

In collaboration with an interdisciplinary team, we have utilized several genomic and biochemical approaches including whole genome expression profiling (DNA microarrays), gene copy number analysis (CGH microarrays), and tissue array immunohistochemistry to identify alterations in pancreatic cancer cells. We have identified and validated a list of upregulated and downregualted gene targets in pancreatic cancer cells and are currently developing new agents against some of these targets.

One gene we are studying is the mitotic serine/threonine kinase Aurora A (STK15). We have shown that the STK15 gene is amplified in pancreatic cancers and this amplification leads to overexpression of the STK15 protein. STK15 regulates the duplication of the microtubule organizing centers of the cells called centrosomes, and overexpression of STK15 causes increased centrosome numbers in cells. Increases in centrosome numbers can in turn lead to genomic instability which is thought to be one of the underlying factors driving the progression of many cancers. We have previously developed several small molecular inhibitors of the STK15 protein. Currently, we are using high throughput siRNA screening to identify sensitizers and biomarkers for Aurora kinase inhibitors.

Other drug targets being pursued in the lab include tumor suppressor genes such as DPC4 and p16 that are frequently inactivated in pancreatic cancer. We use synthetic lethal screening approaches to identify small molecules that selectively kill pancreatic cancer cells that harbor inactivating mutations in these tumor suppressor genes.

Dr. Han’s lab is also investigating the molecular mechanism of perineural invasion in pancreatic cancer. Perineural invasion is one of the most common features of pancreatic cancer and it causes pain. This pain has a tremendous impact on the patient quality of life. By understanding the mechanism of perineural invasion, we hope to identify molecular targets for the development of therapeutics that may alleviate the pain suffered by pancreatic cancer patients

Henderson MC, Shaw YJ, Wang H, Han H, Hurley LH, Flynn G, Dorr RT, Von Hoff DD. UA62784, a novel inhibitor of centromere protein E kinesin-like protein Mol Cancer Ther, Jan;8(1):36-44. 2009.

Wang H, Stephens B, Von Hoff DD, Han H. Identification and characterization of a novel anticancer agent with selectivity against deleted in pancreatic cancer locus 4 (DPC4)-deficient pancreatic and colon cancer cells Pancreas, Jul;38(5):551-7. 2009.

Stephens B, Han H, Hostetter G, Demeure MJ, Von Hoff DD. Small interfering RNA-mediated knockdown of PRL phosphatases results in altered Akt phosphorylation and reduced clonogenicity of pancreatic cancer cells Mol Cancer Ther, Jan;7(1):202-10. 2008.

Baker AF, Koh MY, Williams RR, James B, Wang H, Tate WR, Gallegos A, Von Hoff DD, Han H, Powis G. Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1alpha-induced gene in pancreatic cancer Pancreas, Mar;36(2):178-86. 2008.

Balagurunathan Y, Morse DL, Hostetter G, Shanmugam V, Stafford P, Shack S, Pearson J, Trissal M, Demeure MJ, Von Hoff DD, Hruby VJ, Gillies RJ, Han H. Gene expression profiling-based identification of cell-surface targets for developing multimeric ligands in pancreatic cancer Mol Cancer Ther., Sep;7(9):3071-80. 2008.

Warner SL, Muñoz RM, Bearss DJ, Grippo P, Han H, Von Hoff DD. Pdx-1-driven overexpression of aurora a kinase induces mild ductal dysplasia of pancreatic ducts near islets in transgenic mice Pancreas, Oct;37(3):e39-44.. 2008.

Chen S, Auletta T, Dovirak O, Hutter C, Kuntz K, El-Ftesi S, Kendall J, Han H, Von Hoff DD, Ashfaq R, Maitra A, Iacobuzio-Donahue CA, Hruban RH, Lucito R. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification Cancer Biol Ther, Nov 21;7(11). 2008.

Zhu M, Gokhale VM, Szabo L, Munoz RM, Baek H, Bashyam S, Hurley LH, Von Hoff DD, Han H. Identification of a novel inhibitor of urokinase-type plasminogen activator Mol Cancer Ther, Apr;6(4):1348-56. 2007.

Wang H, Han H, Mousses S, Von Hoff DD. Targeting loss-of-function mutations in tumor-suppressor genes as a strategy for development of cancer therapeutic agents Semin Oncol, Aug;33(4):513-20. 2006.

Our laboratory has worked to develop animal models that faithfully mimic the clinical and histopathologic progression of human pancreatic ductal adenocarcinoma (PDA) from its earliest precursor lesions to invasive and metastatic disease. PDA is a nearly uniformly lethal disease that defies all forms of conventional chemotherapy and radiotherapy. The same factors that conspire to obscure the diagnosis of the disease in patients until very advanced stages also hinder the study of its pathogenesis. The murine models form the basis for our efforts to elucidate mechanisms of disease pathogenesis, to identify biomarkers associated with each stage of disease and potentially with disease response to specific therapies, and to develop and test strategies for chemoprevention and treatment. Our investigations have also helped identify unique genetic routes to PDA with distinct clinical and histopathologic features. Thus, the models should also provide more rigorous platforms for preclinical studies of disease-specific detection and treatment strategies that will be more predictive of efficacy in patients.

Izeradjene, K, Combs, C, Best, M, Gopinathan, A, Wagner, A, Grady, WM, Deng, C, Hruban, RH, Adsay, NV, Tuveson, DA, Hingorani, SR (2007) Oncogenic Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas, Cancer Cell, 11, 229-243

Izeradjene, K, Hingorani, SR (2007) Targets, Trials and Travails in Pancreas Cancer, JNCCN, 5(10)1042-1053

Thomas, RM, Toney, K, Fenoglio-Preiser, C, Revelo-Penafiel, M, Hingorani, SR, Tuveson, DA, Waltz, SE, Lowy, AM (2007) The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression, Cancer Research, 67, 6075-6082

Clark, CE, Hingorani, SR, Mick, R, Combs, C, Tuveson, DA, Vonderheide, RH (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion, Cancer Research, 67, 9518-9527

Hingorani, SR (2007) Location, location, location: precursors and prognoses for pancreatic cancer, Gastroenterology, 133, 345-350

Deramaudt, TB, Takaoka, M, Upadhyay, R, Bowser, MJ, Porter, J, Lee, A, Rhoades, B, Johnstone, CN, Weissleder, R, Hingorani, SR, Mahmood, U, Rustgi, AK (2006) N-cadherin and keratinocyte growth factor receptor mediate the functional interplay between Ki-RASG12V and p53V143A in promoting pancreatic cell migration, invasion, and tissue architecture disruption, Molecular Cell Biology, 26(11)4185-200

Hingorani, SR, Wang, L, Multani, AS, Combs, C, Deramaudt, TB, Hruban, RH, Rustgi, AK, Chang, S, Tuveson, DA (2005) Trp53(R172H) and Kras(G12D) cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice, Cancer Cell, 7, 469-483

Hatzivassiliou, G, Zhao, F, Bauer, DE, Andreadis, C, Shaw, AN, Dhanak, D, Hingorani, SR, Tuveson, DA, Thompson, CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth, Cancer Cell, 8, 311-321

Tuveson, D.A., Hingorani, S.R. (2005) , Ductal Pancreatic Cancer in Humans and Mice, Cold Spring Harbor Symposia on Quantitative Biology, Volute LXX, Woodbury, NY, Cold Spring Harbor Laboratory Press

Hingorani, S.R. (2005) , Modeling Pancreatic Ductal Adenocarcinoma in the Mouse, Exocrine Pancreas Cancer, Hannover, Felsenstein CCCP Publishing

The research activities of the Tissue Microarray Core (TMA) focus on applying highly sensitive and specific molecular assays to characterize biomarkers in clinical specimens. As a pathologist and Core Director at TGen, I play a critical role on the translational research team in the standardization of the clinical tissue collection process to ensure optimal detection and analysis of molecular biomarkers implicated in a given medical disease or cancer.

The tissue microarray (TMA) as introduced by Kononen, et al. (Nature Medicine, 1998) has widely advanced the clinical validation process of novel biomarkers identified in cancer. As a research fellow in the Kallioniemi and Trent laboratories at NIH, I developed novel TMA applications to characterize specific genetic alterations in archival clinical specimens. In collaboration with the Center for Information Technology at NIH, we developed a robotic tissue array with multiple software applications and demonstrated improved accuracy of tissue sampling in the construction of ‘specialty’ TMAs. I have used this technology to accurately target and sample tissues for TMA construction of intra-epithelial neoplasia (IEN) in breast and prostate specimens. Widespread applications of TMA technology in the field of cancer research has translated findings from genomic discovery-based assays to clinicopathologic correlates, permitting molecular analyses in the context of tissue morphology and clinical outcomes.

A primary focus of the TMA core service is the rapid analysis of immunohistochemical (IHC) staining patterns simultaneously on hundreds of tissues. Staining patterns of novel candidate biomarkers are first characterized in a carefully constructed panel of normal tissues. The TMA platform is well suited for automated image acquisition and the subsequent quantitative measure of biomarker(s). Active collaborations with imaging experts and computer programmers are an integral component of my efforts to extend TMA applications. Most notable was a two-year collaborative development of an automated fluorescence in situ hybridization (FISH) spot counting program. This highly interactive program was designed to enumerate probe signals after hybridization to specific DNA sequences. In situ hybridization (ISH) using DNA or RNA probes remains an active part of my research. The TMA format provides a useful tool for assessing tissue fixative alternatives for RNA ISH applications using non-radioactive probes.

Pollock, P.M., Harper, U.L., Hansen, K.S., Yudt, L.M., Stark, M., Robbins, C.M., Moses, T.Y., Hostetter, G., Wagner, U., Kakareka, J., Salem, G., Pohida, T., Heenan, P., Duray, P., Kallioniemi, O-P, Hayward N.K., Trent, J.M., Meltzer, P.S.. High Frequency of BRAF mutations in nevi. Nature Genetics, 33, 19-20. 2003.

Kononen, J., Hostetter, G., Sauter, G., and Kallioniemi, O-P.. Construction of tissue microarrays. In: "DNA Microarrays: A Molecular Cloning Manual" (eds. David Bowtell and Joe Sambrook). Cold Spring Harbor Laboratory Press, . 2002.

Weeraratna, A., Jiang, Y., Hostetter, G., Rosenblatt, K., Duray, P., Bittner, M., Trent, J.M.. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell, 1(3), 279-288. 2002.

Grigoryan, A.M., Dougherty, E. R., Kononen, J., Bubendorf, L., Hostetter, G., Kallioniemi, O-P.. Morphological spot counting from stacked images for automated analysis of gene copy numbers by fluorescence in situ hybridization. Journal Biomedical Optometry, 7(1), 109-22. 2002.

Mousses, S., Bubendorf,L., Wagner, U., Hostetter, G., Kononen, J., Corneilson, R., Goldberger, N., Elkahloun, A., Raffeld, M., Ferhle, W., Sauter, G., Kallioniemi, O-P.. Clinical Validation of Candidate Genes Associated with Prostate Cancer Progression in the CWR22 Model System using Tissue Microarrays. Cancer Research, 62, 1256-1260. 2002.

Andersen, C.L., Hostetter, G., Grigoryan, A., Sauter, G., Kallioniemi, A.. Improved protocol for Fluorescence In Situ Hybridization on Tissue Microarrays. Cytometry, 45, 83-86. 2001.

Allander, S.A., Nupponen, N.N., Ringnr, M., Hostetter, G., Maher, G.W., Goldberger, N., Chen, Y., Carpten, J., Elkahloun, A.G., and Meltzer, P.S.. Gastrointestinal stromal tumors with KIT mutations exhibit a remarkably homogeneous gene expression profile. Cancer Research, 61,8624-8628. 2001.

Dr. Hu's research in statistical methodology has been motivated by problems encountered in the analysis of medical data. His current interest, arising from HIV and cancer studies, is to develop innovative methods to investigate the relationship between high-dimensional genetic information and longitudinal markers or survival endpoints. Other areas of interest include the modeling of measurement error and missing data and the strategy of design and analysis of clinical trials.

Dr. Hu has extensive experience with collaborative medical research. For seven years he served as a senior statistician for the Pediatric AIDS Clinical Trials Group (PACTG) and the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT). He is now working on two cancer program project grants, the Chemoprevention of Skin Cancer Program Project and the Targets to Therapeutics in Pancreatic Cancer Program Project. In these areas Dr. Hu has provided statistical expertise and leadership in the design, conduct, and analysis of clinical trials of various phases and types.

Hu C and Lin DY. Cox regression with covariate measurement error. Scandinavian Journal of Statistics, 2002; 29:637-655.

Hu C and Lin DY. Semiparametric failure time regression with replicates of mismeasured covariates. Journal of the American Statistical Association, 2004; 99:105-118.

Best BM, Mirochnick M, Capparelli EV, Stek A, Burchett SK, Holland DT, Read JS, Smith E, Hu C, Spector SA, Connor JD, and the PACTG P1026s Study Team. Impact of pregnancy on abacavir pharmacokinetics. AIDS, 2006; 20: 553-560.

Wang KH, Majewska A, Schummers J, Farley B, Hu C, Sur M, and Tonegawa S. In vivo two-photon imaging reveals a role of Arc in enhancing orientation specificity in visual cortex. Cell, 2006; 126: 389-402.

Stek AM, Mirochnick M, Capparelli E, Best BM, Hu C, Burchett SK, Elgie C, Holland DT, Smith E, Tuomala R, Cotter A, Read JS, for the PACTG 1026s study team. Reduced lopinavir exposure during pregnancy. AIDS, 2006; 20: 1931-1939.

Chen YQ, Hu C, and Wang Y. Attributable risk function in the proportional hazards model for censored time-to-event. Biostatistics, 2006; 7: 515-529.

Hu C and De Gruttola V. Joint modeling of progression of HIV resistance mutations measured with uncertainty and time to virological failure. Biometrics, 2007; 63: 60-68.

McKinney RE, Rodman J, Hu C, Britto P, Hughes M, Smith ME, Serchuk LK, Kraimer J, Ortiz AA, Flynn P, Yogev R, Spector S, Draper L,Tran P, Scites M, Dickover R, Weinberg A, Cunningham C, Abrams E, Blum HR, Chittick GE, Reynolds L, Rathore M, and Pediatric AIDS Clinical Trials Group Protocol P1021 Study Team. Long term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents (Pediatric AIDS Clinical Trials Group protocol P1021), Pediatrics, 2007; 120: e416-e423.

Mirochnick M, Best BM, Stek AM, Capparelli E, Hu C, Burchett SK, Holland DT, Smith E, Gaddipati S, Read JS, for the PACTG 1026S Study Team (2008). Lopinavir exposure with an increased dose during pregnancy. Journal of Acquired Immune Deficiency Syndromes, 49(5): 485-491.

Weinberg A, Dickover R, Britto P, Hu C, Patterson-Bartlett J, Kraymer J, Gutzman H, Shearer W, Gelman R, Rathore M, McKinney R, and the PACTG 1021 Team (2008). Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy. AIDS, 22(17): 2267-2277.

Dr. Jeffrey Kiefer’s research is focused on leveraging high throughput genomic technologies with the goal of improving cancer therapy. There are currently two research projects in his laboratory conducted in collaboration with Dr. Spyro Mousses and additional faculty in the Pharmaceutical Genomics Division at TGen. The first research project involves applying high-throughput siRNA to evaluate the mechanism of rapamycin action in prostate cancer.

Specifically, we are using a large–scale siRNA library, targeting over 7000 genes, to identify contextual vulnerabilities that govern response to rapamycin. These particular gene targets, whose inhibition can increase the anti-cancer effects of rapamycin, can be directly applied towards drug development to produce combination therapy and serve as biomarkers in delineating patients who will respond to rapamycin therapy. A second research project is target-centric and focused on elucidating the role of S100P protein on prostate cancer growth and survival. S100P represents a unique target that was identified first by gene expression analysis and confirmed by tissue microarray to be overexpressed in androgen-independent prostate cancer.

Researchers within the Pharmaceutical Genomics Division, including Dr. Kiefer, applied classical cell biology techniques, coupled with gene expression and RNA interference, to identify S100P as a putative oncogene that regulates prostate cancer growth and survival. Continuing studies focused on S100P as a putative drug target for the treatment of advanced prostate cancer are ongoing.

Coleman IM, Kiefer JA, Brown LG, Pitts TE, Nelson PS, Brubaker KD, Vessella RL and Corey E.. Inhibition of androgen-independent prostate cancer by estrogenic compounds is associated with increased expression of immune-related genes. Neoplasia, Oct; 8(10):862-878. 2006.

Lugli A, Spichtin H, Maurer R, Mirlacher M, Kiefer J, Huusko P, Azorsa D, Terracciano L, Sauter G, Kallioniemi OP, Mousses S, and Tomillo L.. EphB2 expression across 138 human tumor types in a tissue microarray: high levels of expression in gastrointestinal cancers. Clinical Cancer Research, Sep; 15;11(18):6450-8. 2005.

Corey E, Brown LG, Kiefer JA, Quinn JE, Pitts TE, Blair JM and Vessella RL. Osteoprotegerin in prostate cancer bone metastasis. Cancer Research, Mar; 1:65(5):1710-8. 2005.

Huusko P, Ponciano-Jackson D, Wolf M, Kiefer JA, Azorsa DO, Tuzmen, S., Weaver D, Robbins C, Moses T, Allinen M, Hautaniemi S, Chen Y, Elkahloun A, Basik M, Bova GS, Bubendorf L, Lugli A, Sauter G, Schleutker J, Ozcelik H, Elowe S, Pawson T, Trent JM, Carpten JD, Kallioniemi OP, Mousses S. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nature Genetics, 36(9): 979-83. 2004.

Kiefer JA, Vessella RL, Quinn JE, Odman AM, Zhang J, Keller ET, Kostenuik PJ, Dunstan CR and Corey E.. The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft. Clinical and Experimental Metastasis, 21(5):381-7. 2004.

Kiefer JA and Farach-Carson MC. Type I collagen-mediated proliferation of PC3 prostate carcinoma cell line: implications of enhanced growth in the bone microenvironment. Matrix Biology, 20:429-437. 2001.

Thalmann GN, Sikes RA, Devoll RE, Kiefer JA, Markwalder R, Klima I, Farach-Carson CM, Studer UE, and Chung LW. Osteopontin: possible role in prostate cancer progression. Clinical Cancer Research, 5:2271-2277. 1999.

Kiefer J, Okret S, Jondal M, and McConkey DJ. Functional glucocorticoid receptor expression is required for cAMP- mediated apoptosis in a human leukemic T cell line. J Immunology, 155:4525-4528. 1995.

Fernandez A, Kiefer J, Fosdick L, and McConkey DJ. Oxygen radical production and thiol depletion are required for Ca(2+)- mediated endogenous endonuclease activation in apoptotic thymocytes. J Immunology, 155:5133-5139. 1995.

Neamati N, Fernandez A, Wright S, Kiefer J, and McConkey DJ. Degradation of lamin B1 precedes oligonucleosomal DNA fragmentation in apoptotic thymocytes and isolated thymocyte nuclei. J Immunology, 154:3788-3795. 1995.

Dr. Kim’s research at the TGen is to incorporate mathematical, statistical, computational and engineering tools into the study of biological systems, focusing on cancer biology and other biological systems. Currently, his research is focused on 1) the molecular classification of cancers and 2) understanding and mathematical modeling of genetic regulatory networks.

Mathematical modeling is to approximate a real world system, (i.e., cell), to an extent that the prediction can be tested against observable properties of the system. Therefore, the sophistication of the model is tied to that of techniques to make observations of the system. More sophisticated modeling may lead to the development of better measurement techniques and vice versa. Recently, new technologies that make possible genomic and proteomic profiling of cellular behavior have been developed, providing enormous amounts of information for cellular systems behavior. These genomic and proteomic observations could, and have successfully been used to, identify molecular markers for certain kinds of disease such as cancers. However, the monitoring and modeling of genetic regulatory behaviors of the cell could benefit most from the advancement of technology. Therefore, the need for mathematical models to better describe cellular behavior is critical as measurement technologies advance.

Classification of cancers or other genetic diseases at the molecular level and identifying those genes responsible for different phenotypes (molecular markers), may lead to the discovery of new drug targets. Various pattern classification algorithms have been developed and applied not only for the design of classifiers for cancers but also for the identification of novel genes that can discriminate different types of cancers. This will be extended and studied more extensively in the future for the improvement of integrating biological prior-knowledge with data analysis. The genes identified as molecular markers may also become important clue to the study of genetic regulatory mechanisms.

Learning causative relationships as well as predictive relationships among genes from steady-state observations are of great importance since many of biological measurements are from steady-state. We are exploring diverse mathematical and algorithmic approaches to attack this problem. Understanding a genetic regulatory network will require interdisciplinary collaboration and hopefully lead to the mathematical modeling of the system. Of many proposed approaches, the probabilistic Boolean network is promising for qualitative description of biological systems and can be extended in the perspective of biological context. However, it is also desirable to develop more biologically oriented mathematical models to describe biological systems in a more quantitative manner. This will require collaborative studies among biologists, mathematicians, computer scientists, and/or engineers.

Molecular Diagnostics and Target Validation Division and TGen provides a unique opportunity to achieve my research goals since the division has research units to develop various measurement (CGH and expression arrays) and perturbation (siRNA) technologies, to seek for molecular targets for cancer treatment (melanoma and breast cancers), and to utilize integrated diagnostic tools (Nanobiomics) for clinical uses.

Dr. Kim received his BS degree in Agricultural Engineering at the Seoul National University in Seoul, Korea in 1993. He received his MS in Agricultural Engineering in 1995 also from the Seoul National University. Dr. Kim received a PhD in Electrical Engineering from Texas A&M University in 2001.

Kim, S., Li, H., Dougherty, E.R., Cao, N., Chen, Y., Bittner, M.L., Suh, E. B.. Can Markov Chain Mimic Biological Regulation?. Journal of Biological Systems, 10(4), 337-358. 2002.

Kim, S., Dougherty, E.R., Barrera, J., Chen, Y., Bittner, M. L., Trent, J.M.. Strong Feature Sets from Small Samples. Journal of Computational Biology, 9(1), 127-146. 2002.

Shmulevich, I., Dougherty, E. R., Kim, S., Zhang, W.. Probabilistic Boolean Networks: A Rule-based Uncertainty Model for Gene Regulatory Networks. Bioinformatics, 18(2), 261-274. 2002.

Kim, S., Dougherty, E.R., Chen, Y., Sivakumar, K., Meltzer, P., Trent, J.M., Bittner, M.L.. Multivariate measurement of gene expression relationships. Genomics, 67(2), 201-9. 2000.

Dr. Kingsley's background and interest centers on the quantitative analysis of heterogeneous biological data sets using computational, statistical, and machine learning techniques.

Dr. Kingsley's research within the Diabetes, Cardiovascular and Metabolic (DCM) division focuses on the analysis of diabetes, cardiovascular disease, and associated conditions such as diabetic kidney disorders. Coronary heart disease (CHD) is the leading cause of death in the United States, while rates of obesity and type 2 diabetes have increased dramatically in recent decades. Both diseases can also increase susceptibility to a host of chronic disorders that are both costly to treat and have a profound negative impact on the quality of life of affected individuals. The DCM division focuses on identifying risk factors that increase risk of CHD, diabetes, and associated diseases through the use of genetic and genomic analyses.

Dr. Kingsley's research interests in the DCM division include:

Family based linkage and association analysis of lipid and lipoprotein levels in different ethnic populations from the GENNID (Genetics of Non-Insulin-Dependent Diabetes Mellitus) study
Family based linkage studies of Diabetic nephropathy in Pima Indians
Identification of functional variants in disease associated regions through computational annotation of published genomic sequence and direct analysis of high throughput sequencing data

In addition to his primary appointment in the DCM division, Dr. Kingsley has established several collaborations to provide computational and statistical support to oncology researchers at TGen, TD2, and the Mayo Clinic, Scottsdale. Research interests in oncology include:

• Meta Analysis of gene expression data in non-small cell lung cancer to identify pathways for therapeutic intervention
• Analysis of tissue microarray data from glioma tumor samples
• Generation of software applications for the automated identification of translocation events in comparative genomic hybridization data, and integration with mRNA gene expression data
• Analysis of comparative genomic hybridization data from flow sorted pancreatic tumor samples

Dr. Kingsley completed his PhD at the University of California, San Francisco in Biological and Medical informatics, his M.S. in Biomedical Sciences at UCSF and his B.S. in Molecular Biology at the University of California, Berkeley.

Weiss GJ, Kingsley C. Pathway targets to explore in the treatment of non-small cell lung cancer. J Thoracic Oncol , In Press. 2008.

Millis M, Bowen D, Kingsley C, Watanabe R, Wolford J. Variants in the plasmacytoma variant translocation gene (PVT1) are associated with end-stage renal disease attributed to type 1 diabetes. Diabetes, 56(12):3027-32. 2007.

Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung BM, Esserman L, Albertson DG, Waldman FM, Gray JW. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell, 10(6).529-41. 2006.

Kingsley C, Kuo W, Polikoff D, Berchuck A, Gray JW, Jain AN. Magellan. A Web Based System for the Integrated Analysis of Heterogeneous Biological Data and Annotations; Application to DNA Copy Number and Expression Data in Ovarian Cancer. Cancer Informatics, 2(1). 10–21. 2006.

Dr. Mount directs the Bioinformatics Shared Service facility at the Arizona Cancer Center at the University of Arizona Medical Center in Tucson. This position involves multiple interactions with the faculty and students of the Cancer Center. We try to utilize information from the human genome and SNP population studies to identify individuals at risk for cancer.

We develop sophisticated computational and statistical tools and data models in order to facilitate early identification of cancer and drugs that kill cancer cells. We provide the biologist with an answer to one of the most difficult questions that arise in the laboratory – what to obtain biologically useful information from a microarray, proteomics, or siRNA gene knockdown experiment. We are collaborating with colleagues at the Cancer Center to identify early markers of cancer progression in prostate and gastrointestinal cancer, and with Drs. Dan Von Hoff and Jeff Trent at the Translational Genomics Research Institute in Phoenix in a search for drugs to combat pancreatic and adrenocortical cancer. Our support system for cancer research also includes informatics and the integration of molecular, genetic, and clinical data as a means to assist in individual analysis and treatment.

Pandey R, Guru RK, Mount DW. 2004. Pathway Miner: extracting gene association networks from molecular pathways for predicting the biological significance of gene expression microarray data. Bioinformatics.20:2156-8.

Mount DW 2004 Text book. Bioinformatics: Sequence and Genome Analysis, Second Edition, 692 pp. Cold Spring Harbor Press, Cold Spring Harbor, NY.

Mount, DW and Pandey, R 2005 Using bioinformatics and genome analysis for new therapeutic interventions. Mol Cancer Ther. 4:1636-43.

Calaluce R, Beck SK, Bair EL, Pandey R, Greer KA, Hoying AM, Hoying JB, Mount D, Nagle RB. 2006. Human Laminin-5 and Laminin-10 Mediated Gene Expression of Prostate Carcinoma Cells. Prostate. 66:1381-90.

My laboratory, the Cancer Drug Development Laboratory (CDDL), is dedicated to accelerating the drug discovery process by developing new technologies and integrated systems biology approaches in order to translate genomic data rapidly to new anti-cancer drug compounds.

The discovery of curative drugs to battle cancer have eluded scientists for centuries. The promise of genomics is that it will invigorate the drug development process and produce effective and safe therapeutics. However, this dream has not yet been realized. In fact, lack of functional and causal information associated with genomics-based drug discovery has substantially increased the cost of pharmaceutical research, and delayed the translation of cancer targets to effective drugs. This is due in part to the fact that much of our current molecular and cancer biology research is not "genome-compatible". Although associative gene correlations are acquired by the thousands, we often perform experiments to distinguish causalities one gene at a time.

Our approach implements a three tier approach to accelerating drug discovery at CDDL.

• Data from several different microarray platforms (such as cDNA, CGH and NMD microarrays) are being integrated to better understand the molecular processes that play a key role in cancer and to prioritize the prime targets for drug development.


• Innovative technologies for miniaturized, highly parallel cell-based microarrays are being developed. Using the highly powerful RNA interference (RNAi) technology, it is possible to "knock-down" the function of specific gene in the human genome. By applying ultra high throughput (UHT) transfection of agents that trigger RNAi, genes can be screened at the genome scale using detailed analyses of the functional responses in living cells to determine which specific gene inhibitors produce anti-cancer effects and therefore have therapeutic utility as drug targets.


• CDDL will be used to develop and discover small molecule, antibody, and nucleic acid based agents to target the most promising gene and gene products for advancement to preclinical and clinical testing. This research is setting the stage for the ability to rapidly and effectively translate genomics into advances in anti-cancer drug development.

Mousses, S., Bubendorf,L., Wagner, U., Hostetter, G., Kononen, J., Corneilson, R., Goldberger, N., Elkahloun, A., Raffeld, M., Ferhle, W., Sauter, G., Kallioniemi, O-P.. Clinical Validation of Candidate Genes Associated with Prostate Cancer Progression in the CWR22 Model System using Tissue Microarrays. Cancer Research, 62, 1256-1260. 2002.

Hyman E., Kauraniemi, P., Hautaniemi, S., Wolf, M., Mousses, S., Rozenblum, E., Ringnr, M., Sauter, G., Monni, O., Elkahloun, A., Kallioniemi, A., Kallioniemi, O-P.. Impact of DNA amplification on gene expression patterns in breast cancer. Cancer Research, 62(21),6240-5. 2002.

Mousses, S., Wagner, U., Chen, Y., Kim, J.W., Bubendorf, L., Bittner, M., Pretlow, T., Elkahloun, A.G., Trepel, J., Kallioniemi O-P.. Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene, 20(46),6718-23. 2001.

Monni, O., Brlund, M., Mousses, S., Kononen, K., Sauter, G., Heiskanen, M., Paavola, P., Avela, K., Chen, Y., Bittner, M.L., & Kallioniemi, A.. Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer. PNAS, 98(10),5711-5716. 2001.

Mousses, S., Kallioniemi, A., Kauraniemi, P., Elkahloun, A., and Kallioniemi, O-P.. Clinical and functional target validation using tissue and cell microarrays. Current Opinion in Chemical Biology, 6,97101. 2001.

Dr. Richard Posner’s research is focused on the development of mechanistic computational models of cancer signaling pathways. For a given cancer phenotype, individual patients generally express a subset of a much larger set of genetic mutations found among the population of patients with this type of cancer. These mutations typically affect proteins of signal-transduction systems. It is clear that accumulation of molecular changes of signaling proteins (e.g., truncations, fusions, and point mutations) and changes in the expression levels of these proteins can be oncogenic, but what are the controlling principles that govern the transformation to malignancy? How is it that many different combinations of mutations (and/or protein expression levels) lead to the same disease phenotype? Because signaling networks are so highly interconnected and dynamic, it is difficult to use intuition or qualitative methods to predict how a cell will respond to perturbations, such as molecularly targeted drug therapy. We believe that the development of computational models for cancer pathways is essential for understanding the underlying reasons for the dysfunctional behaviors of cancer cells. Such models have the potential to guide rational drug discovery, clinical practice, and diagnosis.

We have recently developed a novel computational method for specifying and calculating the dynamics of large-scale signaling networks. With our software implementation of this new method (Colvin et al., 2009), it is now possible to contemplate building and analyzing models that include a significant fraction of the protein interactions that comprise a cancer pathway, with incorporation of the site-specific details of the interactions. We believe modeling at this level of detail will be important for understanding cancer pathways, because these pathways are affected by mutations of protein sites that subtly alter protein function. Our group is currently building mechanistic models of canonical cancer pathways (signaling via ErbB, TGF-beta and WNT receptors as well as the cell cycle).

Dr. Posner received his Ph.D. in biophysical chemistry from Cornell University in Ithaca NY. He completed his postdoctoral training in theoretical biology at Los Alamos National Laboratory. He has been a visiting Professor at the Weizmann Institute of Science, where he was a Fogarty Center Senior International Fellow and at the Ludwig Institute for Cancer Research (Melbourne). Dr. Posner currently holds an appointment as a Professor of Biological Sciences at Northern Arizona University.

W. S. Hlavacek, W, Fontana, M. Hucka, , M. Blinov, R. G. Posner and J R. Faeder Rules for Modeling Signal-transduction Systems, Science STKE (344) 2006.

Clayton AH, Orchard SG, Nice EC, Posner RG, Burgess AW. Predominance of activated EGFR higher-order oligomers on the cell surface. Growth Factors. 2008 Dec;26(6):316-24.

Colvin J, Monine MI, Faeder JR, Hlavacek WS, Von Hoff DD, Posner RG. Simulation of large-scale rule-based models. Bioinformatics. 2009 Apr 1;25(7) 910-917.

GetBonNie for building, analyzing and sharing rule-based models. Hu B, Fricke GM, Faeder JR, Posner RG, Hlavacek WS. Bioinformatics. 2009 Jun 1;25(11):1457-60

Dr. Garth Powis is leading the charge to coordinate all stages of the drug discovery and development process at The University of Texas M. D. Anderson Cancer Center. As director of the Center for Targeted Therapy and professor and chairman of the Department of Experimental Therapeutics, he believes that the academic environment is ideal for initiating and developing new therapies.

Since his recruitment to M. D. Anderson in 2005, Dr. Powis is steadily working to make the dream of personalized medicine a reality. The establishment of the Center for Targeted Therapy, a state-of-the-art facility slated for completion in 2010, will allow researchers and clinicians alike the ability to design new, specific and more effective drugs with less toxicity, targeted for individualized therapy. It is a mission that begins with a concept to identify molecular and genetic targets specific to each patient, continues with drug discovery and development and is followed by clinical trials. Bringing novel therapeutic and preventive drugs from the bench to the bedside, quicker than ever before, is his ultimate goal for the Center for Targeted Therapy.

A pioneer of the targeting of signaling pathways for cancer drug discovery, Dr. Powis is the author of four books. He has published more than 300 peer-reviewed articles and holds 11 patents in the area of cancer drug discovery and development. Dr. Powis is a member of the editorial board for several leading scientific publications including the Journals of Molecular Pharmacology, Molecular Cancer Therapeutics, Cancer Pharmacology and Therapeutics and Clinical Cancer Research. His research interests include mechanism of action of new anti-cancer drug, inhibition of P13K/AKT survival signaling and inhibition of redox and hypoxia signaling in cancer.  He has developed 3 cancer drugs, a thioredoxin inhibitor, a P13K inhibitor and a HIF-1alpha inhibitor that are currently in early clinical trial.

Exploiting Tumor Stress Response for Cancer Therapy

Solid tumors exist in a stressed environment for cell growth. In order to survive, cancer cells initiate specific adaptive and constitutive changes allowing them to adapt to the hostile hypoxic environment, escape cell death and increase formation of new blood vessels and metastasis. All of these responses lead to highly aggressive tumors that are resistant to therapy. In order to identify novel targets for therapeutic intervention that is applicable to a wide variety of tumor types, our lab studies the mechanisms that enable cancer cells to survive stress.

Powis G , Ihle N and Yung WKA. Inhibiting PI-3-K for glioma therapy. Cell Cycle:335-337, 2/2009.

Ihle NT and Powis G. Take your PIK: Phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy.Mol Cancer Ther(8):1-9, 1/2009.

Ihle NT, Lemos R, Schwartz D, Oh J, Halter R J, Wipf P, Kirkpatrick D L and Powis G. The PPAγ agonist pioglitazone prevents the hyperglycemia caused by phosphoinositide-3-kinase pathway inhibition by PX-866 without affecting antitumor activity.Mol Cancer Ther(8):94-100, 1/2009.

Mahadevan D, Powis G, Mash EA, George B, Gokhale VM, Zhang S, Shakalya K, Du-Cuny L, Berggren M, Ali MA, Jana U, Ihle N, Moses S, Franklin C, Narayan S,Shirahatti N, Meuillet EJ. Discovery of a novel class of AKT pleckstrin homology domain inhibitors. Mol Cancer Ther 7(9):2621-32, 9/2008. PMID: 18790745.

Koh MY, Spivak-Kroizman TR, Powis G.HIF-1 regulation: not so easy come easy go. Trends Biochem Sci 33(11):526-534, 9/2008. PMID: 18809331.

Koh MY, Darnay BG, Powis G.Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation.Mol Cell Biol 28(23):7081-95, 1/2008. PMCID: PMC2593390.

Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G. Molecular Mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia inducible factor-1 (alpha).Mol Cancer Ther 7(1):90-100, 2008. PMID: 18202012.

Dr. Ramesh K. Ramanathan is Medical Director of TGen Clinical Research Services in Scottsdale, Arizona and is Clinical Professor of Medicine at the College of Medicine, Phoenix Campus, University of Arizona. Prior to this appointment, Dr. Ramanathan was Associate Professor and Director of the GI Oncology Program at the University of Pittsburgh Cancer Institute from 1996-2007.

Dr. Ramanathan’s research interests are in new drug development, and he specializes in the treatment of GI cancers with an emphasis on colon and pancreatic cancer. Dr. Ramanathan has been involved in the development of a number of new drugs and treatments for colon and pancreatic cancers.

Dr. Ustach works on the synthetic lethal project, analyzing small molecules which selectively kill cancer cells carrying a SMAD4 deletion. Carolyn is very involved in the analysis of expression and genomic data from primary pancreas tumors, facilitating communication between a team of TGen scientists from the Clinical Translational Research Division, Computational Division, and the Pharmaceutical Genomics Division. This collaboration has yielded several potential “druggable” molecular targets, which she is currently investigating.

Carolyn holds a bachelor of science degree from University of California, San Diego and received her PhD in 2001 in Plant Molecular Biology from UC Berkeley, studying genetic based resistance to tobacco mosaic virus in Solanaceae. From 2001-2005, she focused her research on Platelet-Derived Growth Factor D involvement in the progression of Prostate Cancer as a post-doctoral fellow at Wayne State University, Detroit, MI. In 2005, she moved on to a Staff Scientist position at the Cole Eye Institute at the Cleveland Clinic in Ohio, where she investigated PDGF-D involvement in retinal vasculature development, working extensively with mouse models. She joined Dr. Von Hoff’s discovery research team in 2007.

Chial HJ, Wu R, Ustach CV, McPhail LC, Mobley WC, Chen YQ. Membrane targeting by APPL1 and APPL2: dynamic scaffolds that oligomerize and bind phosphoinositides. Traffic. 2008 Feb;9(2):215-29. Epub 2007 Dec 18. Erratum in: Traffic. 2008 Apr;9(4):623-4.

Ustach CV, Kim HR. Platelet-derived growth factor D is activated by urokinase plasminogen activator in prostate carcinoma cells. Mol Cell Biol. 2005 Jul;25(14):6279-88.

Hu G, deHart AK, Li Y, Ustach C, Handley V, Navarre R, Hwang CF, Aegerter BJ, Williamson VM, Baker B. EDS1 in tomato is required for resistance mediated by TIR-class R genes and the receptor-like R gene Ve. Plant J. 2005 May;42(3):376-91.

Ustach CV, Taube ME, Hurst NJ Jr, Bhagat S, Bonfil RD, Cher ML, Schuger L, Kim HR. A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. Cancer Res. 2004 Mar 1;64(5):1722-9.

Yu J, Ustach C, Kim HR. Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 2003 Jan 31;36(1):49-59. Review.

Dr. Whatcott is interested in identifying novel therapeutic targets involved in the metabolic or molecular signaling events altered in cancer. Utilizing the various genetic analysis platforms available at TGen, he is working to understand some of the changes that originate specifically within the tumor stroma that contribute to tumorigenesis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) currently stands as the fourth leading cause of cancer-related death in the US. A key feature of PDAC and PDAC tumor progression is the formation of significant tumor fibroses, termed the ‘desmoplastic reaction.’ The desmoplastic reaction is not the product of cancerous epithelial cells themselves, but is rather a product of the stromal myofibroblasts that secrete large quantities of extracellular matrix (ECM) proteins. The role of the desmoplastic reaction and the ECM proteins in PDAC are an area of intense study as we now know that they contribute to the growth of tumor cells. Recent studies have revealed that specific signaling by both stromal and tumor cells contribute to the tumorigenic characteristics of PDAC, including the desmoplastic reaction.

The stroma is comprised of multiple cell types, including fibroblasts, immune cells, endothelial cells, and nerve cells. It is now believed that this microenvironment is vital to and selects for the highly tumorigenic characteristics seen in PDAC. Of the many tumor types, PDAC is also one of the most poorly vascularized tumor types, due in large part to fibrosis and the development of abnormal vasculature. The design of his project includes the identification of new therapeutic targets found within the stroma of which inhibition may capitalize on the dependence of cancer cells on the tumor-stroma interaction. With further study of the tumor vascularization and with the use of a mouse model system, his project seeks to target the stroma in an effort to augment current therapies for PDAC.

Dr. Whatcott received his bachelor’s degree in microbiology from Brigham Young University, and his Ph.D. from the University of Arizona, under the direction of Dr. Myron Jacobson. He dissertation studies included the identification of a novel isoform of the poly(ADP-ribose) glycohydrolase, a protein important in the cellular metabolic response to DNA damage, and in the mitochondrial signaling for cell death. He is currently employed as a post-doctoral fellow at TGen, working under the direction of Drs. Haiyong Han and Daniel Von Hoff.

Whatcott, C.J., Meyer, R.G., Meyer-Ficca, M.L., Jacobson, M.K. 2009. A specific isoform of poly(ADP-ribose) glycohydrolase is targeted to the mitochondrial matrix by a N-terminal mitochondrial targeting sequence. Exp Cell Res. April 21. Epub ahead of print.

Meyer, R.G., Meyer-Ficca, M.L., Whatcott, C.J., Jacobson, E.L., and Jacobson, M.K. 2007. Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity. Exp Cell Res. 313:2920-36.

Ambrus, A., Chen, D., Whatcott, C.J., Somogyi, A., and Yang, D. 2005. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry protocol for monitoring the progress of enzymatic (13)C/(15)N-labeled DNA syntheses. Anal. Biochem. 342:246-53.