312: Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts

Abstract

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment.

Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications

“…Zoledronic acid (ZA) is an eligible agent of this kind, which has been FDA-approved as the third generation of amino-bisphosphonate agent for treating skeletal-related events (SREs) and pain caused by bone metastasis. Beyond the skeleton, plenty of studies have generated new insights into its potent role in modulating macrophages phenotypes [147]. According to those studies, ZA was able to reverse the polarity of TAMs from M2-like to M1-like by attenuating IL-10, VEGF, and MMP-9 production and recovering iNOS expression [99, 148].…”

“…Based on this evidence, zoledronic acid has been added into the adjuvant endocrine therapy for premenopausal women with early-stage breast cancer in ABCSG-12 trial [125]. Data of 62 months’ follow-up [125] showed that the addition of ZA at clinically achievable doses delayed tumor recurrence and significantly prolonged disease-free survival, which provides a solid clinical evidence for ZA to be a promising agent for cancer prevention [147, 148]. Another agent capable of repolarizing TAMs to M1 phenotype is CP-870,893, which is an agonist monoclonal antibody (mAb) of CD40 [150, 151].…”

Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression

“…Interestingly, this antibody was tested in a phase II trial (NCT00072930) for patients with metastatic prostate cancer in combination with standard-of-care docetaxel, prednisone, and zoledronic acid. Notably, steroids such as prednisone have been associated with inferior immunotherapy responses (11), whereas zoledronic acid can block the activity of M2 macrophages (12). Similarly, etaracizumab was tested in a phase II trial for melanoma in combination with the standard-of-care dacarbazine (13).…”