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 #
5P50CA102701-10
Application #
8380763
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$278,115
Indirect Cost
$71,855
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Orozco, Carlos A; Martinez-Bosch, Neus; Guerrero, Pedro E et al. (2018) Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc Natl Acad Sci U S A 115:E3769-E3778
Radecki Breitkopf, Carmen; Wolf, Susan M; Chaffee, Kari G et al. (2018) Attitudes Toward Return of Genetic Research Results to Relatives, Including After Death: Comparison of Cancer Probands, Blood Relatives, and Spouse/Partners. J Empir Res Hum Res Ethics 13:295-304
Antwi, Samuel O; Fagan, Sarah E; Chaffee, Kari G et al. (2018) Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status. J Natl Cancer Inst :
Cobo, Isidoro; Martinelli, Paola; Flández, Marta et al. (2018) Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554:533-537
Razidlo, Gina L; Burton, Kevin M; McNiven, Mark A (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293:11143-11153
Chaker, Mahmoud; Minden, Audrey; Chen, Suzie et al. (2018) Rho GTPase effectors and NAD metabolism in cancer immune suppression. Expert Opin Ther Targets 22:9-17
Sugimoto, Motokazu; Farnell, Michael B; Nagorney, David M et al. (2018) Decreased Skeletal Muscle Volume Is a Predictive Factor for Poorer Survival in Patients Undergoing Surgical Resection for Pancreatic Ductal Adenocarcinoma. J Gastrointest Surg 22:831-839
Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604
Paradise, Brooke D; Barham, Whitney; Fernandez-Zapico, Martín E (2018) Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes? Cancers (Basel) 10:
Hogan, Kelly A; Cho, Dong Seong; Arneson, Paige C et al. (2018) Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment. Cytokine 107:9-17

Showing the most recent 10 out of 336 publications