The diagnosis of pancreatic cancer is devastating with mortality rates nearing its incidence rates. At present, surgical removal of the pancreas is the only treatment available for early-stage tumors in about 20% of patients, with the best clinical outcome of 2 years survival for just 8% of patients. Since early diagnosis is impossible, most pancreatic cancer patients are diagnosed with non-operable tumors and receive chemotherapy and radiotherapy treatments. Chemotherapy drugs approved for pancreatic cancer are not organ or tissue specific, have severe side effects and do not result in significant long-term survival. Thus, there is a desperate need for improved therapeutic options and effective pancreatic cancer drugs. Recent research has led to significant advances in understanding of the genetic changes and signaling pathways characteristic to pancreatic cancer. These studies already suggest targets for the development of novel cancer therapeutics whose anti-cancer effects would be based on selective inhibition of tumor-associated regulatory proteins. Targeted therapies disable specific molecular pathways that are absolutely required for survival of cancer cells but may be dispensable for normal cells. Since normal cells are left relatively unharmed, the targeted therapies would lead to less severe toxicities. Although several specific protein targets are currently in clinical studies, to date, there are no effective targeted anti pancreatic cancer therapeutics. We propose experiments that will explore function of an essential regulator of pancreatic development, the nuclear receptor LRH-1, in pancreatic cancer cells. This protein is already shown to play a critical role in triggering and progression of several types of cancers including gastrointestinal tumors. Recent structural studies of LRH-1 in complex with the potent oncoprotein, catenin, which promotes many metastatic cancers, make a compelling argument for discovery of antagonists of LRH-1 activity. As we rationalize in this proposal, we hypothesize that LRH-1 is a novel target for the discovery of pancreatic cancer therapeutics. In this work, we propose to discover compounds that inhibit the LRH-1 activity in pancreatic cancer cells. These novel regulatory compounds could be developed into a pharmaceutical that will inhibit proliferation of cancer cells in pancreatic tumors, advancing the existing pancreatic cancer therapies.
Determination of mechanisms that trigger and drive pancreatic cancer growth is urgently needed to pinpoint new targets and to develop novel therapeutics. The combined data that we describe in this grant application suggest that nuclear receptor LRH-1 is a novel target for the discovery of pancreatic cancer therapeutics.
The aim of this proposal is to find compounds that inhibit the LRH-1 activity in pancreatic tumors.
|Fletterick, Robert (2017) NR5A2 discovering compounds that block tumor growth in PDAC. J Surg Oncol 116:89-93|
|Benod, Cindy; Carlsson, Jens; Uthayaruban, Rubatharshini et al. (2013) Structure-based discovery of antagonists of nuclear receptor LRH-1. J Biol Chem 288:19830-44|
|Benod, Cindy; Vinogradova, Maia V; Jouravel, Natalia et al. (2011) Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation. Proc Natl Acad Sci U S A 108:16927-31|