The applicant is a general surgeon whose clinical and research focus is pancreatic cancer. She plans to study the role of the developmental signaling factor Sonic hedgehog in pancreatic tumorigenesis. The career development plan focuses on acquiring basic knowledge and experimental skills in pancreatic cancer/pathology and development. Drs. Andrew Warshaw, mentor, internationally known for his work in pancreatic cancer, and Drucilla Roberts, co-mentor, an accomplished independent investigator in GI development and hedgehog signaling, have committed their expertise and resources to guiding her program. An informal advisory committee, consisting of the pancreatic developmental biologist Dr. Douglas Melton and pancreatic/ GI pathologist Dr. Gregory Lauwers, will augment the candidate's training in mouse modeling and pancreatic development and pathology. The combined resources of the Massachusetts General Hospital and Harvard Medical School provide a rich research environment for this young investigator's development. Hedgehog (Hh) signaling, an essential pathway during embryonic pancreatic development whose misregulation has been implicated in several forms of cancer, may also be an important mediator in human pancreatic carcinoma. SHH is abnormally expressed in pancreatic cancer and its precursor lesions, pancreatic intra-epithelial neoplasia (PanlN). Pancreata of mice in which Shh is misexpressed in the pancreatic endoderm develop abnormal tubular structures, a phenocopy of human PanlN-1 and -2. Furthermore, Hedgehog signaling remains active in cell lines from primary and metastatic pancreatic adenocarcinomas, and inhibition of Hh signaling induces apoptosis and blocks proliferation both in vitro and in vivo. Thus, the Hh pathway may be important in both initiation and maintenance of pancreatic cancer. The candidate's proposed aims are: 1) to develop a Tet conditional mouse model to determine whether misexpression of Shh in the adult pancreas is sufficient to cause pancreatic neoplasia; 2) to determine the prevalence of expression of Shh and pathway members in human cancer by real-time PCR; and 3) to determine whether inactivation of the HH pathway can influence the biologic behavior of pancreatic cancer in a murine xenograft model using fresh surgical explants. This will allow us to better understand the role of this pathway in human pancreatic cancer, so that it may be exploited for new diagnostic and therapeutic modalities. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK071329-04
Application #
7273561
Study Section
Subcommittee G - Education (NCI)
Program Officer
Podskalny, Judith M,
Project Start
2004-09-10
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2007
Total Cost
$131,693
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Rosow, David E; Liss, Andrew S; Strobel, Oliver et al. (2012) Sonic Hedgehog in pancreatic cancer: from bench to bedside, then back to the bench. Surgery 152:S19-32
Mino-Kenudson, Mari; Fernández-del Castillo, Carlos; Baba, Yoshifumi et al. (2011) Prognosis of invasive intraductal papillary mucinous neoplasm depends on histological and precursor epithelial subtypes. Gut 60:1712-20
Bausch, Dirk; Pausch, Thomas; Krauss, Tobias et al. (2011) Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma. Angiogenesis 14:235-43
Haynes, Alex B; Deshpande, Vikram; Ingkakul, Thun et al. (2011) Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg 146:534-8
Partelli, Stefano; Fernandez-Del Castillo, Carlos; Bassi, Claudio et al. (2010) Invasive intraductal papillary mucinous carcinomas of the pancreas: predictors of survival and the role of lymph node ratio. Ann Surg 251:477-82
Iyer, Veena R; Hahn, Peter F; Blaszkowsky, Lawrence S et al. (2010) Added value of selected images embedded into radiology reports to referring clinicians. J Am Coll Radiol 7:205-10
Rovira, Meritxell; Scott, Sherri-Gae; Liss, Andrew S et al. (2010) Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A 107:75-80
Konstantinidis, Ioannis T; Dursun, Abdulmetin; Zheng, Hui et al. (2010) Metastatic tumors in the pancreas in the modern era. J Am Coll Surg 211:749-53
Fritz, Stefan; Fernández-del Castillo, Carlos; Iafrate, A John et al. (2010) Novel xenograft and cell line derived from an invasive intraductal papillary mucinous neoplasm of the pancreas give new insights into molecular mechanisms. Pancreas 39:308-14
Kang, DongKyun; Suter, Melissa J; Boudoux, Caroline et al. (2010) Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy. Gastrointest Endosc 71:35-43

Showing the most recent 10 out of 23 publications