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.
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.
|Liou, Geou-Yarh; Döppler, Heike; Necela, Brian et al. (2015) Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5:52-63|
|Zhen, David B; Rabe, Kari G; Gallinger, Steven et al. (2015) BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 17:569-77|
|Delgiorno, Kathleen E; Hall, Jason C; Takeuchi, Kenneth K et al. (2014) Identification and manipulation of biliary metaplasia in pancreatic tumors. Gastroenterology 146:233-44.e5|
|Li, Liang; Fridley, Brooke L; Kalari, Krishna et al. (2014) Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines. BMC Genomics 15:93|
|Halfdanarson, Thorvardur R; Bamlet, William R; McWilliams, Robert R et al. (2014) Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study. Pancreas 43:1219-22|
|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|
|Chini, Claudia C S; Guerrico, Anatilde M Gonzalez; Nin, Veronica et al. (2014) Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors. Clin Cancer Res 20:120-30|
|Wu, Lang; Goldstein, Alisa M; Yu, Kai et al. (2014) Variants associated with susceptibility to pancreatic cancer and melanoma do not reciprocally affect risk. Cancer Epidemiol Biomarkers Prev 23:1121-4|
|Calvo, Ezequiel; Grzenda, Adrienne; Lomberk, Gwen et al. (2014) Single and combinatorial chromatin coupling events underlies the function of transcript factor Krüppel-like factor 11 in the regulation of gene networks. BMC Mol Biol 15:10|
|Urrutia, Raul; Velez, Gabriel; Lin, Marisa et al. (2014) Evidence supporting the existence of a NUPR1-like family of helix-loop-helix chromatin proteins related to, yet distinct from, AT hook-containing HMG proteins. J Mol Model 20:2357|
Showing the most recent 10 out of 152 publications