Targeting RAS Gene Pathways in Psoriatic Arthritis

? DESCRIPTION (provided by applicant): Psoriatic arthritis (PsA) is a chronic inflammatory condition that causes erosive joint damage. Although advances in treatments, including availability of new biologics, have improved outcomes, many patients still do not respond to available therapies and suffer significant joint damage with resultant disability. The pathogenesis of PsA remains poorly understood and this is an impediment to development of new and more effective therapeutics. We have generated preliminary data suggesting that genes in the RAS pathway are upregulated in patients with PsA. The RAS-related gene signature appears to be distinct for PsA compared to patients with other inflammatory conditions such as rheumatoid arthritis (RA), suggesting that there are unique targets in PsA which would be amenable to therapeutic blockade. Furthermore, activating RAS genes are known to be involved in some malignancies and are associated with enhanced production of inflammatory mediators including cytokines that are implicated in PsA pathogenesis. Targeting RAS in PsA is especially attractive because small molecule drugs that inhibit signaling in this pathway are in development for treatment of malignancies and other diseases. These might be repurposed to treat PsA patients. We propose to establish the correlations of the RAS signature with clinical features of PsA and to test ex vivo the effects of RAS inhibition on blood cells from PsA patients, examining effects on production of inflammatory cytokines. Results of this exploratory project will be used to determine feasibility of testing in vivo the effects of RAS inhibition in patients with PsA.