Zoledronic Acid as a New Adjuvant Therapeutic Strategy for Ewing's Sarcoma Patients

Abstract

Ewing's sarcoma (ES) is the second most frequent pediatric bone tumor also arising in soft tissues (15% of cases). The prognosis of patients with clinically detectable metastases at diagnosis, not responding to therapy or with disease relapse, is still very poor. Among new therapeutic approaches, bisphosphonates represent promising adjuvant molecules to chemotherapy to limit the osteolytic component of bone tumors and to protect from bone metastases. The combined effects of zoledronic acid and mafosfamide were investigated on cell proliferation, viability, apoptosis, and cell cycle distribution of human ES cell lines differing in their p53 and p16/ink4 status. ES models were developed to reproduce both soft tissue and intraosseous tumor development. Mice were treated with 100 μg/kg zoledronic acid (two or four times per week) and/or ifosfamide (30 mg/kg, one to three cycles of three injections). ES cell lines showed different sensitivities to zoledronic acid and mafosfamide at the cell proliferation level, with no correlation with their molecular status. Both drugs induced cell cycle arrest, but in the S or G 2 M phase, respectively. In vivo, zoledronic acid had no effect on soft tissue tumor progression, although it dramatically inhibited ES development in bone. When combined with ifosfamide, zoledronic acid exerted synergistic effects in the soft tissue model: Its combination with one cycle of ifosfamide resulted in an inhibitory effect similar to three cycles of ifosfamide alone. This very promising result could allow clinicians to diminish the doses of chemotherapy.

Zoledronic acid negatively affects the expansion of in vitro activated human NK cells and their cytolytic interactions with Ewing sarcoma cells

“…ZA has attracted recent interest as a non-cytotoxic anticancer drug and is under clinical investigation for use in various diseases, including primary bone tumors (3,4,(7)(8)(9). Promising features of ZA include the observed anticancer synergies between bisphosphonates and cytotoxic chemotherapies (4,30), the favorable toxicity profile, and the proposed effect on the tumor-promoting bone/bone marrow microenvironment to prevent dissemination.…”

“…Promising features of ZA include the observed anticancer synergies between bisphosphonates and cytotoxic chemotherapies (4,30), the favorable toxicity profile, and the proposed effect on the tumor-promoting bone/bone marrow microenvironment to prevent dissemination. However, drug therapy alone is unlikely to completely eliminate residual disease in patients with high-risk disseminated tumors.…”

“…Bisphosphonates are a class of drugs that inhibit osteoclast activity and bone resorption and are widely used in patients with osteolytic skeletal disorders (2). Based on the rationale that ZA may interfere with stimulatory interactions between the bone microenvironment and tumor cells and on observations of direct antiproliferative effects against tumor cells (3)(4)(5), the drug was also evaluated for the treatment of primary and metastatic bone tumors. As expected, ZA demonstrated clinical antitumor activity in multiple myeloma (6) and osteosarcoma (7) and against (micro)metastatic bone and/or bone marrow disease in solid tumors (8,9).…”

“…In preclinical studies in Ewing sarcoma, ZA was found to inhibit in vivo tumor growth both alone and in synergism with chemotherapies (4,5), and initial clinical reports suggest that ZA combined with chemotherapy may be effective in refractory disease (10). The drug has now entered randomized clinical evaluation to improve overall survival as an add-on therapy in localized disease (4).…”

Tissue-Engineered Model of Human Osteolytic Bone Tumor

“…43,44 Although no negative effect on osteoblasts has been reported yet, little is known about the role of ZA in regulating osteoblast functions. Interestingly, recent reports showed that ZA could induce BSP expression directly in osteoblast-like cells through inactivation of Rho GTPases 45,46 Although it was beyond the scope of this study, our model would also be useful for further characterization of the mechanism of action of ZA in osteoblasts and for studies of osteoporosis.…”