Abstract B40: Blocking Ras chaperons for cancer therapy

We have previously developed a new concept and a new class of Ras inhibitors that affect specifically the active forms of Ras. This concept is based on the knowledge that the farnesyl moiety common to all Ras proteins might not only serve as a lipophilic lipid anchor but also confer functional specificity on Ras. This raised the possibility that the farnesyl group may act as part of a recognition unit for specific anchorage lipids or protein(s) that interact with Ras in the cell membrane. Such binding partners of Ras have been identified where it was shown that galectin-1 and galectin-3 discovered first as lectin binding proteins, act respectively as specific binding partners of farnesylated active H-Ras and K-Ras. Recently Nucleoline was identified as a specific chaperon of active N-Ras. The galectins possess a putative hydrophobic binding pocket-the putative farnesyl binding site. Galectin-1 was shown to drive H-Ras.GTP nanocluster formation and to be an integral component of the H-Ras-GTP nanocluster, a site at which Raf is activated. Similarly, galectin-3 drives K-Ras.GTP nanoclustring and robust K-Ras signaling. Ras signaling to ERK is strongly diminished in Galectin -3 knockout MEFS and in thyroid cancer cells that lack Galectin - 3. Together these findings mark the farnesyl-binding pockets as outstanding targets for Ras directed therapy, assuming that compounds that would block such sites will act as Ras inhibitors. The Ras inhibitor, S-trans-trans farnesylthiosalicylic acid (Salirasib, FTS) was indeed designed to mimic the farnesyl moiety in the carboxy terminal of Ras and was found to induce accelerated dislodgement of Ras from the cell membrane and subsequently degradation of the protein. FTS was also found to be highly efficient in inhibiting growth of many types of cancer cell lines that exhibit high Ras.GTP levels both, in vitro and in vivo. More recent phase 2 clinical trials showed that oral Salirasib treatment of pancreatic and of non-small-lung cancer patients increased significantly survival of the patients with no toxic effects. We propose to use Salirasib for the treatment of pancreatic and of non-small-lung carcinoma. Note: This abstract was not presented at the conference. Citation Format: Yoel Kloog, Roni Haklai, Galit Elad-Sfadia. Blocking Ras chaperons for cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AA