Abstract 3053: Receptor tyrosine kinase AXL as a new target for prostate cancer therapy

Abstract

Abstract Axl is a receptor tyrosine kinase of the family of TAM receptors (which includes TYRO3 and MER) and plays roles in different types of cancer. It is highly expressed in metastatic colon carcinoma, gastric, uterine endometrial and certain types of breast cancer, and sarcoma. As Axl is upregulated in several metastatic cell types it may play a role during invasion and metastasis. Tyrosine kinases (TKs) represent a major class of proto-oncogenes and are involved in tumor growth as well as progression and metastasis of cancer cells. TKs are being actively studied as targets for therapeutic intervention and several of this tyrosine kinase have shown efficacy in clinical trials. Prostate cancer has become the most common solid cancer in older men and is one of the most frequent causes of cancer deaths. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer, there is no effective treatment available for patients with the metastatic androgen-independent disease. In this work we demonstrated the role of Axl in prostate cancer progression. Using real time PCR to access the level of several tyrosine kinase receptors expression in prostate cancer cell and human tissue, we have identified the tyrosine kinase receptor Axl as a potential target for prostate cancer therapy. Axl has consistent overexpression across prostate cancer cell lines and human prostate tumor tissue providing a model for testing the targeting of Axl. Preliminary data shows a significant increase of Axl expression was found in metastatic PCa cells and clinical samples (48% of adenocarcinomas of prostate when compared with normal prostate tissue). Interestingly, microarray analysis in addition to pathway analysis of PCa cells infected with lentivirus encoding siRNA against Axl revealed that some survival pathways are inhibited, but strikingly all members of the NF-κB pathway are down regulated. Furthermore, the blockage of Axl gene expression strongly inhibits proliferation, migration and invasion of PCa cells. Pilot studies in animal models demonstrate that inhibition of Axl reduces dramatically tumor formation. since our xenograft subcutaneous model in MF5 nude mice demonstrate that blockage of Axl reduces tumor formation by 49.5%. Taken together these data demonstrated that Axl plays role for migration, invasion and tumor development and can be used as marker for invasive and metastatic tumors. Our data also indicates that Axl can be used as a target for drug therapies since its inhibition leads to induction of apoptosis and blocks cell proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3053. doi:10.1158/1538-7445.AM2011-3053