Pancreatic cancer is a deadly disease in which the dismal outcome is primarily attributed to the lack of aneffective treatment. Therefore, the need of translational researchers, such as our laboratory, to developtherapies targeting novel biochemical pathways relevant to the pathobiology of pancreatic cancer hasnever been greater. Our GOAL is to design studies that are both mechanistic and translational, takingadvantage of the knowledge recently generated in our laboratory with the support of the CareerDevelopment Award from the Mayo Clinic Pancreatic SPORE awarded to the PI. This data reports, for thefirst time, a novel pathway that identifies the transcription factor GLH as a shared effector for bothpancreatic 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 theSPORE 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 preclinicaland clinical testing of its targeted inhibition. Our CENTRAL HYPOTHESIS is that a novel functionalinteraction between the HH and EGF pathways regulates cell survival via a GLI 1-mediated anti-apoptoticresponse and targeting of this pathway by a combination therapy will positively impact on the treatment ofpancreatic 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 cancercell survival via a novel HH-EGF-GLI1 pathway;
AIM 2 : To characterize the translational implications oftargeting this novel HH-EGF-GLI1 survival pathway, with a combination therapy in pancreatic cancerxenografts, 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 throughcombination therapy using a multi-target approach with the HH inhibitor, GDC-0449, combined with EGFRinhibitor, Erlotinib (Phase I Trial). Thus, the knowledge derived from these studies will further ourunderstanding of the complex network implicated in pancreatic carcinogenesis, as well as serve as afoundation for the development of new therapeutic approaches for pancreatic cancer.
Showing the most recent 10 out of 336 publications
