Pancreatic cancer is a deadly disease in which the dismal outcome is primarily attributed to the lack of an effective treatment. Therefore, the need of translational researchers to develop therapies targeting novel biochemical pathways relevant to the pathobiology of pancreatic cancer has never been greater. Our GOAL is to design studies that are both mechanistic and translational, taking advantage of the knowledge recently generated in our laboratory. This data reports, for the first time, a novel pathway that identifies the transcription factor GLI1 as a shared effector for both pancreatic oncogenic pathways, Hedgehog (HH) and Epidermal Growth Factor (EGF), engendering a pro-survival/anti-apoptotic function in pancreatic cancer cells. Thus, our proposal utilizes a comprehensive translational approach for the molecular and cellular characterization of this pathway interaction as well as the preclinical testing of its targeted inhibition. Our CENTRAL HYPOTHESIS is that a novel functional interaction between the HH and EGF pathways regulates cell survival via a GLI1- mediated anti-apoptotic response and targeting of this pathway by a combination therapy will positively impact on the treatment of pancreatic cancer. To address this hypothesis we propose the following independent, yet interrelated, aims:
AIM 1 : To characterize the molecular mechanism(s) underlying the HH-EGF pathway. We will test the hypothesis that the PI3K-AKT axis links the HH and EGF cascades via specific modulation of GLI1 activity. Specifically, we will determine the effect of AKT phosphorylation on GLI1-mediated transcription in pancreatic cancer cells.
AIM 2 : To characterize the role of the HH-EGF pathway interaction in pancreatic cancer cell survival. We will address the hypothesis that the HH-EGF-GLI1 pathway requires an active PI3K- AKT axis to modulate pancreatic cancer survival. We will examine the role of this pathway interaction on the modulation of GLI1-mediated activation of specific anti-apoptotic molecules in pancreatic cancer cells.
AIM 3 : To characterize the translational implications of targeting this novel HH-EGF-GLI1 survival pathway, with a combination therapy in pancreatic cancer xenografts, by assessing treatment response using molecular and imaging markers. Thus, the knowledge derived from these studies will further our understanding of the complex network implicated in pancreatic carcinogenesis, as well as serve as a foundation for the development of new therapeutic approaches for pancreatic cancer. These investigations represent a defined strategy to discover novel therapeutic strategies for pancreatic cancer, a painful and deadly disease that ranks 4th as the cause of death by cancer in USA. Patients affected by this cancer die within 3 to 6 months after the diagnosis, and currently, no effective treatment exists for this disease. However, we are optimistic that our studies will build the foundation for future treatment of this dismal disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136526-04
Application #
8206776
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Salnikow, Konstantin
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$273,714
Indirect Cost
$92,566
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Mills, Lisa D; Zhang, Lizhi; Marler, Ronald et al. (2014) Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. J Biol Chem 289:16516-25
Mathew, Esha; Collins, Meredith A; Fernandez-Barrena, Maite G et al. (2014) The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling. J Biol Chem 289:27727-43
Rhim, Andrew D; Oberstein, Paul E; Thomas, Dafydd H et al. (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735-47
Nye, Monica D; Almada, Luciana L; Fernandez-Barrena, Maite G et al. (2014) The transcription factor GLI1 interacts with SMAD proteins to modulate transforming growth factor ?-induced gene expression in a p300/CREB-binding protein-associated factor (PCAF)-dependent manner. J Biol Chem 289:15495-506
McCleary-Wheeler, Angela L; Lomberk, Gwen A; Weiss, Frank U et al. (2013) Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett 328:212-21
Weber, Georg F (2013) Why does cancer therapy lack effective anti-metastasis drugs? Cancer Lett 328:207-11
Mills, Lisa D; Zhang, Yaqing; Marler, Ronald J et al. (2013) Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem 288:11786-94
Baumgart, Sandra; Ellenrieder, Volker; Fernandez-Zapico, Martin E (2013) Oncogenic transcription factors: cornerstones of inflammation-linked pancreatic carcinogenesis. Gut 62:310-6
Iovanna, Juan L; Marks, David L; Fernandez-Zapico, Martin E et al. (2013) Mechanistic insights into self-reinforcing processes driving abnormal histogenesis during the development of pancreatic cancer. Am J Pathol 182:1078-86
Fernandez-Zapico, Martin E (2013) GLI1 finds a new role in cancer stem cell biology. EMBO Mol Med 5:483-5

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