Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

Targeting the HIF/VHL pathway therapeutically to treat metastatic disease (#2)

Amato Giaccia 1 , Yu Maio 1 , Errin Rankin 1 , Katherin Fuh 2 , Mihalis Kariolis 3 , Jennifer Cochrane 3
  1. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States
  2. Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, United States
  3. Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, United States

The receptor tyrosine kinase AXL has recently been identified as a critical factor driving tumor cell invasion and migration. AXL is the founding member of the TAM family of receptor tyrosine kinases, which include Tyro3 (or SKY), AXL, and MER. The ligand growth arrest specific gene-6 (GAS6) is the common ligand for all three receptors. We recently discovered that AXL is a hypoxia inducible gene and a HIF target gene. In addition, it is both a biomarker and genetic driver for several types of metastatic cancer. While AXL plays an important biologic role in metastasis, there are currently no therapeutic agents directed against GAS6/AXL signaling available that can be used to inhibit tumor progression and/or metastasis in clinical trials. We have developed a novel screening strategy to identify inhibitors of the GAS/AXL signaling axis. This strategy takes advantage of the fact that unlike other proto-oncogenic receptor tyrosine kinases (RTKs), AXL appears to be a suitable target for inhibition through modulation of ligand binding, given the lack of compelling data for ligand independent activation in cancer. We have engineered and produced wild type and ultra-high affinity soluble AXL FC-fusion proteins. In our studies, we demonstrate increased thermostability, affinity for GAS6, and therapeutic efficacy in vivo of the engineered AXL-S-1 soluble receptor compared to the wild type soluble AXL receptor. Furthermore, soluble AXL therapy has an added benefit over AXL monoclonal antibodies in being able to block GAS6 activation of the AXL family receptor tyrosine kinases MER and TYRO3, and can be engineered to increase its affinity and stability.