The goal of this proposal is to provide Christine lacobuzio-Donahue with a period of mentorship in the proper academic environment so that she can develop the necessary skills to become an independent clinician-scientist. In addition to her specialized training in gastrointestinal pathology, Dr. lacobuzio has a strong commitment to the study of pancreatic cancer metastasis. Pancreatic cancers are an almost universally fatal disease, with a 5 yr survival rate of 4%. This dismal prognosis is largely due to the fact that most patients are diagnosed with metastatic disease and all will die of metastatic disease within one year. Current surgical and chemotherapeutic approaches are beneficial only in the minority of patients who present with localized disease. The overall goal of this proposal is to provide a comprehensive understanding of metastatic pancreatic ductal adenocarcinomas that will form the basis for novel therapies designed with respect to the unique features of metastatic disease. To accomplish this goal, Dr. lacobuzio has already taken the unique and innovative approach to the study of pancreatic cancer metastasis by establishment of a rapid (""""""""warm"""""""") autopsy protocol for procurement of high quality samples for study. These samples will be used for the generation of xenografted tumors and short-term cell cultures to provide an unparalleled resource for the planned studies. Next, Dr. lacobuzio will perform gene expression profiling of matched primary and metastatic pancreatic cancers to confirm potential biological markers identified in her prior studies of primary pancreatic cancers and to identify novel markers specific to metastatic disease. This approach will also aid Dr. lacobuzio in defining the """"""""gene expression architecture"""""""" of metastatic pancreatic cancers with a particular focus on those cellular signaling pathways related to tumor-stromal interactions of the proliferating metastases within target organ sites. Finally, the potential markers identified will form the basis for creation of novel therapies specific to metastatic disease through Dr. lacobuzio's ongoing collaboration with the Drug Development Program at Johns Hopkins Medical Institutions. In summary, this proposal will provide the first in depth understanding of metastatic pancreatic cancer to form the basis for more focused studies aimed at the therapeutic development with immediate translational potential to pre-clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA106610-01
Application #
6761278
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2004-09-27
Project End
2009-08-31
Budget Start
2004-09-27
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$140,130
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Haeno, Hiroshi; Gonen, Mithat; Davis, Meghan B et al. (2012) Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies. Cell 148:362-75
Zhong, Yi; Wang, Zheng; Fu, Baojin et al. (2011) GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS One 6:e22129
Yachida, Shinichi; Zhong, Yi; Patrascu, Raul et al. (2011) Establishment and characterization of a new cell line, A99, from a primary small cell carcinoma of the pancreas. Pancreas 40:905-10
DeNicola, Gina M; Karreth, Florian A; Humpton, Timothy J et al. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106-9
Campbell, Peter J; Yachida, Shinichi; Mudie, Laura J et al. (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467:1109-13
Yachida, Shinichi; Jones, Siân; Bozic, Ivana et al. (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467:1114-7
Stratford, Jeran K; Bentrem, David J; Anderson, Judy M et al. (2010) A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma. PLoS Med 7:e1000307
Iacobuzio-Donahue, Christine A; Fu, Baojin; Yachida, Shinichi et al. (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27:1806-13
Karafin, Matthew S; Cummings, Christopher T; Fu, Baojin et al. (2009) The developmental transcription factor Gata4 is overexpressed in pancreatic ductal adenocarcinoma. Int J Clin Exp Pathol 3:47-55

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