Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis
Abstract
Ras GTPases are molecular switches that regulate key cellular processes and in T cells they are necessary for proper TCR-dependent activation following antigen recognition. Reduced Ras signaling has been associated with T cell anergy and defective IL-2 production (1, 2). Importantly, synovial T cells from patients with RA display augmented activation of the Ras/Raf/ ERK pathway (3, 4). Thus, Ras GTPases appear to be a promising molecular target for inhibiting T cell activation in RA. Based on an innovative concept Kloog (the partnering PI) and colleagues discovered a potent non-toxic inhibitor of Ras, Farnesylthiosalicylic acid (FTS). In collaboration with Concordia Pharmaceuticals Inc., FTS was developed into and oral drug, Salirasib. The drug has been already tested in the clinic for the treatment of cancers with oncogenic mutations in KRAS and NRAS. No dose-limiting toxicities or major adverse events were reported during Salirasib treatment, in phase I clinical trials of patients with advanced solid cancer. Thus, Salirasib is the only available successful Ras GTPases inhibitor that reached clinical trials, and moreover received an orphan drug designation by the FDA for the treatment of pancreatic cancer (5,6). In the first year our aim was to complete Major Task 1: "Test in the rat AIA model of RA (rheumatoid arthritis) the prophylactic and therapeutic efficacy of FTS (a targeted synthetic DMARD) on relevant clinical outcomes and immunological parameters".
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1004128
Entities
People
- Itamar Goldstein
Organizations
- Tel Aviv University