Cabozantinib Inhibits Growth of Androgen-Sensitive and Castration-Resistant Prostate Cancer and Affects Bone Remodeling

Holly M Nguyen,Ted S Gross,Robert L Vessella,Dana T Aftab,Roman Gulati,Eva Corey,Nazanin Ruppender,Colm Morrissey,Lisha G Brown,Frauke Schimmoller,Xiaotun Zhang

doi:10.1371/journal.pone.0078881

Holly M Nguyen, Ted S Gross + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0078881

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Abstract

Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.

Highlights

Metastases remain the major cause of morbidity and mortality in men suffering from advanced prostate cancer (PCa)
To address whether cabozantinib targets are expressed in PCa, we evaluated the levels of MET, P-MET, and VEGF receptor 2 (VEGFR2) in tissues representing normal prostate and different stages of PCa progression
MET and P-MET: Our results showed that MET is present at high levels in the NP and primary PCa cells, but there was only marginal evidence of differences between these tissues; see Figure S1

Summary

Introduction

Metastases remain the major cause of morbidity and mortality in men suffering from advanced prostate cancer (PCa). The effects of cabozantinib have been evaluated in the preclinical setting in multiple cancers, including glioma, breast, lung, and pancreatic cancers. In these studies, cabozantinib reduced tumor invasiveness, proliferation, and angiogenesis while increasing apoptosis [1,2]. Given the roles of these kinases in tumor biology, cabozantinib inhibition of any or all of these targets may be beneficial for the treatment of PCa by attacking tumor cells on multiple fronts. This type of attack could potentially target effectively heterogeneous cell populations, such as those of PCa

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