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, such as our laboratory, 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 with the support of the Career Development Award from the Mayo Clinic Pancreatic SPORE awarded to the PI. This data reports, for the first time, a novel pathway that identifies the transcription factor GLH as a shared effector for both pancreatic oncogenic pathways, Hedgehog (HH) and Epidermal Growth Factor (EGF), engendering a prosurvival/ anti-apoptotic function in pancreatic cancer cells. Thus, congruent with the major objective of the SPORE grant, our proposal utilizes a comprehensive translational approach (from molecules-to-cells-toanimals- to-human) for the molecular and cellular characterization of this pathway as well as the preclinical and clinical 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 GLI 1-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, vet interrelated.
aims :
AIM 1 : To characterize both, the molecular and cellular mechanism(s) underlying pancreatic cancer cell survival via a novel HH-EGF-GLI1 pathway;
AIM 2 : 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 (Preclinical Trial);
and AIM 3 : To characterize, in humans, the translational implications of HH-EGF-GLI1 survival pathway through combination therapy using a multi-target approach with the HH inhibitor, GDC-0449, combined with EGFR inhibitor, Erlotinib (Phase I Trial). 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA102701-10W1
Application #
8719562
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
2013-09-12
Project End
2014-08-31
Budget Start
2013-09-12
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$212,888
Indirect Cost
$71,544
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Chini, Claudia C S; Espindola-Netto, Jair M; Mondal, Gourish et al. (2016) SIRT1-Activating Compounds (STAC) Negatively Regulate Pancreatic Cancer Cell Growth and Viability Through a SIRT1 Lysosomal-Dependent Pathway. Clin Cancer Res 22:2496-507
Murphy, Stephen J; Hart, Steven N; Halling, Geoffrey C et al. (2016) Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease. Cancer Res 76:749-61
Chaiteerakij, Roongruedee; Petersen, Gloria M; Bamlet, William R et al. (2016) Metformin Use and Survival of Patients With Pancreatic Cancer: A Cautionary Lesson. J Clin Oncol 34:1898-904
Cao, H; Eppinga, R D; Razidlo, G L et al. (2016) Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. Oncogene 35:1099-110
Hu, Chunling; Hart, Steven N; Bamlet, William R et al. (2016) Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol Biomarkers Prev 25:207-11
McWilliams, Robert R; Maisonneuve, Patrick; Bamlet, William R et al. (2016) Risk Factors for Early-Onset and Very-Early-Onset Pancreatic Adenocarcinoma: A Pancreatic Cancer Case-Control Consortium (PanC4) Analysis. Pancreas 45:311-6
Carr, Ryan M; Fernandez-Zapico, Martin E (2016) Pancreatic cancer microenvironment, to target or not to target? EMBO Mol Med 8:80-2
Wang, Jianbo; Galvao, Joana; Beach, Krista M et al. (2016) Novel Roles and Mechanism for Krüppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells. J Biol Chem 291:18084-95
Lopez, Angelica P; Kugelman, Jeffrey R; Garcia-Rivera, Jose et al. (2016) The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication. J Mol Biol 428:2814-31
Lakshminarayanan, Vani; Supekar, Nitin T; Wei, Jie et al. (2016) MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice. PLoS One 11:e0145920

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