A small molecule inhibitor of AXL is a novel therapeutic strategy in osteosarcoma

Despite aggressive surgical and chemotherapeutic approaches, the survival rate among osteosarcoma patients who present with metastasis is ~25% and is ~70% in those who present without metastasis. These survival rates have not improved in the last few decades. A better understanding of osteosarcoma pathophysiology is therefore needed to allow development of novel therapeutic approaches. RTK activation is responsible for progression of many forms of cancer, and inhibitors of these RTKs are a majority of the most promising anticancer drugs. Our recent phospho-proteomic and functional genomic screening showed that a RTK known as AXL contributes to the in vitro phenotype of highly metastatic human 143B osteosarcoma cells. Moreover, we also found that a relatively specific inhibitor of AXL that blocks metastasis of other types of cancer also reduces motility, invasion, and colony formation by the osteosarcoma cells. AXL will therefore be the focus of this proposal and our overall hypothesis is that AXL is a novel metabolic target in osteosarcoma. This hypothesis will be tested by the following Aims:

AIM 1: Determine the role of AXL in tumorigenesis and metastasis in murine xenograft models of osteosarcoma. This aim will measure the in vivo effects of shRNA-mediated knockdown of AXL on tumorigenesis and metastasis by 143B human osteosarcoma cells. Experiments will include both the orthotopic tibial implantation model and the tail vein injection model.

AIM 2: Determine the therapeutic effect of the AXL inhibitor on tumorigenesis and metastasis in murine xenograft models of osteosarcoma. This aim will measure the in vivo effects of the AXL inhibitor on tumorigenesis and metastasis in the same murine models used in Aim 1.

Successful completion of this project would determine whether AXL is a promising metabolic target, and whether the inhibitor is a promising therapeutic approach, for osteosarcoma that should be evaluated in future studies.