Inhibition of CCL2 Signaling in Combination with Docetaxel Treatment Has Profound Inhibitory Effects on Prostate Cancer Growth in Bone

Peter Kirk,Holly Nguyen,Linda Snyder,Lisha Brown,Eva Corey,Theodore Koreckij,Robert Vessella

doi:10.3390/ijms140510483

Abstract

The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an area of intense research. The objective of our study was to investigate the efficacy of CCL2 blockade by neutralizing antibodies to inhibit the growth of PCa in bone. We used a preclinical model of cancer growth in the bone in which PCa C4-2B cells were injected directly into murine tibiae. Animals were treated for ten weeks with neutralizing anti-CCL2 antibodies, docetaxel, or a combination of both, and then followed an additional nine weeks. CCL2 blockade inhibited the growth of PCa in bone, with even more pronounced inhibition in combination with docetaxel. CCL2 blockade also resulted in increases in bone mineral density. Furthermore, our results showed that the tumor inhibition lasted even after discontinuation of the treatment. Our data provide compelling evidence that CCL2 blockade slows PCa growth in bone, both alone and in combination with docetaxel. These results support the continued investigations of CCL2 blockade as a treatment for advanced metastatic PCa.

Highlights

Death rates for prostate cancer (PCa) have been in decline since the mid-1990s, PCa remains the second most common cause of cancer-related death in American men [1]
C chemokine ligand 2 (CCL2) blockade resulted in significant decreases in serum prostate-specific antigen (PSA) levels over the control animals at weeks 7–10 after the beginning of the treatment, lowering PSA levels in the treated animals at week 10 to 28.9% ± 2.6% (p = 0.0038) of control animals (Figure 1A,B)
CCL2 blockade combined with docetaxel treatment resulted in significantly lowered PSA levels throughout the treatment period, with decreases in PSA levels at week 10 to 18.2% ± 2.1% of the control group (p = 0.0010)

Summary

Introduction

Death rates for prostate cancer (PCa) have been in decline since the mid-1990s, PCa remains the second most common cause of cancer-related death in American men [1]. The current standard of care for CRPC, docetaxel, offers a survival benefit of 2–3 months [2,3,4,5] and a great deal of emphasis continues to be placed on finding new improved therapies. Multiple new treatments of advanced CRPC have been approved by the FDA that result in increased survival, but these treatments are not yet considered standard (e.g., abiraterone, sipuleucel-t, and MDV3100). Previous strategies seeking improved therapies against advanced PCa focused on targeting the tumor cell, current research is placing an emphasis on targeting the tumor microenvironment in addition to tumor cells. Inhibition of chemokine signaling, which will affect tumor growth and alter the bone microenvironment, is a promising prospective target for treatment of PCa bone metastases

Objectives

Results

Conclusion