AH 7614 sale Prostate cancer is the second leading cause of

Prostate cancer is the second leading cause of cancer-related death in men in the United States [25]. Similar to pancreatic cancer, prostate cancer has few diagnostic options available, particularly to differentiate indolent from aggressive disease. Axl is also overexpressed in ∼50% of prostate cancers [13], [14]. Inhibition or blockade of Axl overexpression in prostate cancer cell lines inhibits proliferation, migration and invasion suggesting that Axl may contribute to the metastatic potential of prostate tumors [10], [13], [29]. Furthermore, phosphorylation of Axl leads to activation of the NF-kB pathway, which plays a critical role in cancer cell survival and metastasis [14]. In our studies [125I]Axl mAb showed high accumulation in the metastatic and Axlhigh DU145 tumors compared to the 22Rv1 Axllow tumors. Although we have used subcutaneous tumor models, Axl specific accumulation supports the feasibility of imaging Axl in tumors that derive from a variety of tissues of origin. The DU145 cell line showed highest Axl AH 7614 sale of the cell lines tested and the highest binding and uptake of the [125I]Axl mAb in vitro. However, the in vivo uptake in DU145 tumors, although higher than for 22Rv1 tumors, was not significantly different from that of pancreatic CFPAC tumors. High Axl expression led to increased vascularity, while inhibition of Axl reduced vessel density and diameter [15], [16]. We speculate that changes in tumor vascular properties due to elevated Axl expression levels, although not validated in the current study, could contribute to accumulation of antibody within tumor [30]. Axl also exists in cleavable, soluble form and the concentration and variability of soluble Axl in tumors is not known [31]. Another possibility for differences in radiolabeled antibody uptake is that freely available soluble Axl within plasma may bind to the radiolabeled antibody and reduce the availability and accumulation of the radiolabeled antibody in the tumors [31]. Also, it is not known whether the antibody we have used for imaging also binds to the soluble form of Axl. Further studies are warranted to investigate the role soluble Axl may play in imaging Axl expression in tumors. In conclusion, we have imaged pancreatic and prostate tumors with graded levels of Axl expression, with the degree of radio-antibody uptake correlating with this expression. Because of the importance of Axl to invasion and metastasis, quantitative imaging of this target provides a new way to visualize and measure this important cancer target in vivo.
Acknowledgments
Introduction As the most common extracranial solid tumor, neuroblastoma (NB) is most commonly diagnosed in early childhood, accounting for 10% of all pediatric oncology deaths [1]. Increasing evidences have showed that activating mutations in the anaplastic lymphoma kinase (ALK) gene are considered to be the leading cause for most cases of hereditary neuroblastoma [2]. Activated ALK caused by ALK rearrangements, such as NPM-ALK, has been shown to influence several main signaling pathways, thus promoting cell growth and survival [3]. However, the situation appears to be more complex in neuroblastoma as mutations and amplification in ALK gene both result in constitutive phosphorylation, leading to oncogenic effects [4]. NB with ALK aberration (mutation or amplification) have been implied significantly more sensitive to ALK inhibitors than that with wild-type ALK. ALK is mutated in 8% of diagnostic tumor samples [5], and amplification of the ALK gene has only been described in 1.2–4.4% of NB patients [2], [6]. In this study, we focused on the therapeutic effect of ALK-targeted therapy in ALK-mutated neuroblastoma. Growing evidences suggest that patients with ALK-mutated neuroblastoma might benefit from treatment with ALK tyrosine kinase inhibitors (TKIs), such as crizotinib and ceritinib, which have been approved by the US Food and Drug Administration (FDA) in 2011 and April this year [7], [8].