Clear cell renal cell carcinomas (ccRCC), the most common kidney cancers, are highly vascularized tumors that initially respond to antiangiogenic therapies. However, in the majority of patients treated with these agents, the tumor becomes resistant and progresses. Thus, therapies that inhibit additional molecular targets are needed to improve the overall survival rate of patients with metastatic ccRCC patients. We recently discovered that the receptor tyrosine kinase, AXL, is in part regulated by the von Hippel Lindau (VHL) tumor suppressor in ccRCC cell lines. Most importantly, AXL expression in ccRCC patients correlates with the lethal phenotype, strongly indicating an important role for AXL in the pathogenesis of ccRCC. In addition, AXL is an upstream regulator of both SRC and cMET signaling which are independent prognostic factors for poor survival in ccRCC patients. Genetic and pharmacologic inhibition of AXL signaling is sufficient to inhibit ccRCC tumor invasion and metastasis. While these findings establish an important biologic role for AXL in renal metastasis, there is a significant deficit of therapeutic agents that specifically target AXL signaling in the clinic. For this purpose, we produced an ultra-high-affinity soluble AXL (sAXL) FC-fusion protein. In our preclinical studies, we demonstrated that sAXL is a potent and selective inhibitor of GAS6 and is safe in mice. Furthermore, sAXL blocked GAS6 mediated signaling and tumor cell invasion and produced antitumor efficacy in multiple tumor models. We hypothesize that sAXL, an anti-metastatic agent, will be effective in treating sunitinib sensitive and resistant ccRCC and work in combination with antiangiogenic agents to enhance antitumor efficacy in ccRCC. The proposed studies will investigate the efficacy, survival benefit, and safety of sAXL alone or in combination with antiangiogenic agents to support its clinical development for the treatment of advanced ccRCC. To achieve this goal, we will determine the efficacy of our sAXL receptor in sunitinib resistant and sensitive preclinical models and patient derived grafts of kidney cancer (Specific Aim 1). We will also elucidate the mechanisms by which sAXL therapy inhibits the invasive phenotype of ccRCC tumor epithelial cells (Specific Aim 2). In addition, our preliminary data indicate that AXL signaling contributes to VEGF production and the angiogenic phenotype in sunitinib resistant cells. Therefore, we will also determine the role of sAXL therapy on ccRCC tumor angiogenesis (Specific Aim 3).
Our final aim will test the hypothesis that, in comparison to the broad acting tyrosine kinase inhibitor cabozantinib, the combination of sAXL and axitinib, an approved second line tyrosine kinase inhibitor for advanced ccRCC, will be safer and more effective in blocking AXL activity in advanced ccRCC tumor growth and progression (Specific Aim 4). We believe that our novel strategy, an engineered form of AXL with enhanced GAS6-binding affinity, specificity, and safety represents a new and therapeutically robust clinical candidate for the treatment of advanced ccRCC.
Despite recent advances in kidney cancer therapy, it is estimated that only 11% of patients with metastatic kidney cancer will survive past five years. The future of kidney cancer treatment lies in development of new therapies that target critical signaling pathways in the tumor cells in combination with small molecules that target the formation of new blood vessels. In this proposal, we will evaluate the efficacy, safety and mechanisms of action of targeted sAXL therapy in the treatment of advanced renal cancer in the clinic.
| Tandon, Neha; Thakkar, Kaushik N; LaGory, Edward L et al. (2018) Generation of Stable Expression Mammalian Cell Lines Using Lentivirus. Bio Protoc 8: |
| Sinha, Subarna; Thomas, Daniel; Chan, Steven et al. (2017) Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. Nat Commun 8:15580 |
| Aguilera, Todd A; Giaccia, Amato J (2017) Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion-A New Role for the AXL Receptor Tyrosine Kinase. Clin Cancer Res 23:2928-2933 |
| Johnson, Rachelle W; Sowder, Miranda E; Giaccia, Amato J (2017) Hypoxia and Bone Metastatic Disease. Curr Osteoporos Rep 15:231-238 |
| Kariolis, Mihalis S; Miao, Yu Rebecca; Diep, Anh et al. (2017) Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. J Clin Invest 127:183-198 |
| Chiou, Shin-Heng; Risca, Viviana I; Wang, Gordon X et al. (2017) BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer. Cancer Discov 7:1184-1199 |
| Zhao, Hongjuan; Nolley, Rosalie; Chan, Andy M W et al. (2017) Cabozantinib inhibits tumor growth and metastasis of a patient-derived xenograft model of papillary renal cell carcinoma with MET mutation. Cancer Biol Ther 18:863-871 |
| Castellini, Laura; Moon, Eui Jung; Razorenova, Olga V et al. (2017) KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic Acids Res 45:3674-3692 |
| Giaccia, Amato J (2016) A New Chromatin-Cytoskeleton Link in Cancer. Mol Cancer Res 14:1173-1175 |
| Rankin, Erinn B; Giaccia, Amato J (2016) Hypoxic control of metastasis. Science 352:175-80 |
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