Without question, Ras is the primary oncoprotein that drives human pancreatic cancer. Ras exerts its oncogenic effects in rodents primarily by activating Rafs and correspondingly the MAPK pathway, although Ras also activates the PI3K and RalGEFs pathways, which in turn provide a secondary role in promoting Raf-induced transformation. Correspondingly, there has been much effort focused on inhibiting Ras, the MAPK pathway, and more recently the PI3K pathway as a means to treat cancers driven by Ras mutations. Unfortunately, inhibitors of Ras itself, or the downstream effector pathways of PI3K and MAPK, have not been particularly promising to date, spurring us to explore whether RalGEFs may be important targets in pancreatic cancer. RalGEFs were not deemed major effectors of Ras, in large part, because these proteins are only weakly transforming in murine cells. However, in a side-by- side comparison of Ras transformation between identically treated mouse and human cells, we found that RalGEFs play a key role only in the transformation of human cells, suggesting that this pathway may indeed be targeted as a means to inhibit Ras oncogenic signaling. RalGEFs activate two proteins, RalA and RalB, although only RalA is oncogenic. RalA is commonly activated in pancreatic tumor specimens and inhibiting this protein in pancreatic cancer cell lines curbs their tumor growth. Therefore, we propose to capitalize on a Small Molecule Screening Facility to screen for inhibitors of RalA activity, and validate candidate inhibitors for anti-transforming activity in easily scored soft agar assays and then anti-tumor activity in xenograft models of human pancreatic cancer. Identification of compounds that inhibit the growth of human pancreatic tumor xenografts will lay the groundwork to inhibit RalA in a clinical setting. Pancreatic cancer is a deadly disease that is highly refractory to current therapeutic modalities. 30,000 people per year are predicted to be inflicted by this disease with a five-year survival rate of only 4%. It is thus imperative that new strategies to target this cancer are developed. Without question, the molecular hallmark of pancreatic cancer is an activating mutation K-Ras. Since inhibiting Ras has been difficult in the clinic, we now propose to screen for inhibitors of a protein Ras ultimately activates that is critical for pancreatic cancer growth, RalA. Identification of compounds that inhibit RalA and pancreatic tumor growth could have therapeutic value in the treatment of this deadly disease. ? ? ? ?
| Lim, Kian-Huat; Brady, Donita C; Kashatus, David F et al. (2010) Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Mol Cell Biol 30:508-23 |
| Lee, Yi-Shan; Lim, Kian-Huat; Guo, Xing et al. (2008) The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis. Cancer Res 68:7561-9 |
