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.
|Kim, Jungsun; Bamlet, William R; Oberg, Ann L et al. (2017) Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med 9:|
|Espindola-Netto, Jair Machado; Chini, Claudia C S; Tarragó, Mariana et al. (2017) Preclinical efficacy of the novel competitive NAMPT inhibitor STF-118804 in pancreatic cancer. Oncotarget 8:85054-85067|
|Pathangey, Latha B; McCurry, Dustin B; Gendler, Sandra J et al. (2017) Surrogate in vitro activation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T-cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens. Oncotarget 8:10785-10808|
|Javeed, Naureen; Mukhopadhyay, Debabrata (2017) Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res 31:386-394|
|Blackburn, Patrick R; Tischer, Alexander; Zimmermann, Michael T et al. (2017) A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. J Biol Chem 292:3866-3876|
|Walz, Amy; Ugolkov, Andrey; Chandra, Sunandana et al. (2017) Molecular Pathways: Revisiting Glycogen Synthase Kinase-3? as a Target for the Treatment of Cancer. Clin Cancer Res 23:1891-1897|
|Yellow, Winta; Bamlet, William R; Oberg, Ann L et al. (2017) Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study. Nutrients 9:|
|Luo, Kuntian; Li, Yunhui; Yin, Yujiao et al. (2017) USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. EMBO J 36:1434-1446|
|Liou, Geou-Yarh; Bastea, Ligia; Fleming, Alicia et al. (2017) The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. Cell Rep 19:1322-1333|
|Cho, Dong Seong; Doles, Jason D (2017) Single cell transcriptome analysis of muscle satellite cells reveals widespread transcriptional heterogeneity. Gene 636:54-63|
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