Background: Pancreatic cancer exhibits almost 100% morbidity and is almost 100% associated with activation of the Ras oncoprotein. Therefore, targeting Ras is the most logical approach to developing enhanced therapy for this disease. So far, all attempts at inhibiting Ras directly have failed in the clinic. Ras acts in large part by binding and activating the oncogenic effectors Raf, PI3 Kinase and RalGEFs. Inhibitors for Raf and PI3 kinase have been developed but have yet to show efficacy in the clinic against pancreatic cancer. To date, no inhibitors of the third arm of the Ras effector system, the RalGEFs have been described in the literature. We have developed what appears to be the first pan-RalGEF inhibitor.
Specific Aims : 1. To characterize the binding and action of novel, specific inhibitors of RalGEFs. 2. To determine if suppression of the RalGEF pathway prevents tumorigenesis and metastasis in pdx and transgenic models of cancer in vivo. Objective: To define the mechanism of action on suppression of the tumorigenic phenotype in vitro of novel small molecules that inhibit the Ras/RalGEF pathway. To determine if the molecule/s exhibit anti-tumor effects in an in vivo model of pancreatic cancer. Hypotheses: Targeting multiple RalGEFs will be an effective strategy for inhibiting Pancreatic cancer. Significance: There is no effective treatment for pancreatic cancer. Pancreatic cancer is driven by Ras activation. Ras driven cancers are highly dependent upon the Ras/RalGEF pathway. We describe the first inhibitor of this pathway. Relevance to public health: Pancreatic cancer has no effective therapies. This proposal seeks to develop a novel therapeutic small molecule for Pancreatic cancer. Unique features and innovation: The project used a combination of in silico and in vitro assays to identify and optimize novel inhibitors of RalGEF. As no such inhibitors have yet been reported, the project is intrinsically innovative. Methodology: In silico computer screens of large molecular libraries were used to identify potential RalGEF binding compounds based on the known structure of the Ras binding domain of RalGDS. The compounds were bioassayed to identify those that act as anticipated. The interaction of the compounds with their target will be defined by NMR and bioassays perfomed to determine their main biological modes of action in vitro. They will then tested in highly physiological animal models of human pancreatic cancer. Expected results: We will identify the first pan-RalGEF inhibitor and it will inhibit pancreatic cancer. Affects on other research areas: The molecules we identify may serve as powerful scientific tools to investigate Ras/RalGEF function in vivo and may lead to novel therapeutics for Ras driven cancer.
Ras is the most frequently activated oncoprotein found in human cancer. No effective anti-Ras drugs are yet available in the clinic. This proposal seeks to validate novel small molecules that block the ability of Ras to promote cancer/metastasis by inhibiting its ability to interact with the RalGEF class of Ras effector proteins.
