Pancreatic cancer is a uniformly lethal disease, and there is an urgent need for potent, mechanism-based therapies to improve survival, especially in patients with metastatic, inoperable tumors. Hedgehog (Hh) pathway activation is seen in the majority of pancreatic cancer cell lines, and in vitro growth can be profoundly inhibited by the Hh small molecule antagonist cyclopamine. A comprehensive preclinical analysis of Hh inhibitors in pancreatic cancer is proposed, using in vivo models that recapitulate the complexities of human pancreatic cancer progression. Low-passage cell lines have been established from resected human pancreatic cancers, and will be used for generating orthotropic xenografts in pancreata of athymic mice. Either cyclopamine or an orally bioavailable synthetic Hh inhibitor (Genentech, Inc.) will be administered as monotherapy for 28 days. Treatment efficacy versus control mice will be assessed at necropsy by objective gross and histopathologic parameters, including development of intra-abdominal metastases, and by survival analysis. Synergism between the Hh antagonists and an anti-metabolite (gemcitabine) will be assessed in a subset of xenografted cancers. A transgenic mouse model of pancreatic intraepithelial neoplasia and invasive pancreatic cancer has been developed by misexpression of oncogenic KRAS in the pancreas. The role of Hh signaling, including effects of inhibiting pathway during the multistage progression to invasive cancer, will be studied in this model. As a prelude to clinical trials, biomarkers that predict responsiveness to Hh antagonists will be defined by correlating in vitro therapeutic response with the expression of Hh pathway genes and to global expression profiles determined using oligonucleotide microarrays, in a panel of 50 pancreatic cancer cell lines. Based on the efficacy of Hh inhibitors in the preclinical studies and the identification of predictive biomarkers for response, Phase II clinical trials will be initiated in patients with unresectable pancreatic cancers using the orally bioavailable synthetic Hh inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113669-04
Application #
7363634
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (03))
Program Officer
Thurin, Magdalena
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$307,115
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
San Lucas, F A; Allenson, K; Bernard, V et al. (2016) Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes. Ann Oncol 27:635-41
Takano, Shigetsugu; Reichert, Maximilian; Bakir, Basil et al. (2016) Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. Genes Dev 30:233-47
Rajeshkumar, N V; Dutta, Prasanta; Yabuuchi, Shinichi et al. (2015) Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function. Cancer Res 75:3355-64
Hu, Chaoxin; Dadon, Tikva; Chenna, Venugopal et al. (2015) Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models. Mol Cancer Ther 14:1532-9
Ă–zdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L et al. (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719-34
Agarwal, Jasmin R; Wang, Qiuju; Tanno, Toshihiko et al. (2014) Activation of liver X receptors inhibits hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma. Mol Cancer Ther 13:1873-81
Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala et al. (2014) Imaging Axl expression in pancreatic and prostate cancer xenografts. Biochem Biophys Res Commun 443:635-40
Streppel, M M; Lata, S; DelaBastide, M et al. (2014) Next-generation sequencing of endoscopic biopsies identifies ARID1A as a tumor-suppressor gene in Barrett's esophagus. Oncogene 33:347-57
Cowan, Robert W; Maitra, Anirban (2014) Genetic progression of pancreatic cancer. Cancer J 20:80-4
Streppel, Mirte Mayke; Pai, Shweta; Campbell, Nathaniel R et al. (2013) MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1. Clin Cancer Res 19:4067-78

Showing the most recent 10 out of 79 publications