Mifamurtide for the treatment of nonmetastatic osteosarcoma

Lezot

2019

Cellular Immunology

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171

183

Section: Developed Liposome-encapsulated Muramyl Tripeptide (L-mtp-pmentioning

confidence: 99%

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

Lezot

2019

Cellular Immunology

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171

183

Clinical Cancer Research

“…The standard treatment of osteosarcoma consists of complete surgical resection associated with neoadjuvant and adjuvant chemotherapy composed of 4 agents: doxorubicin, cisplatin, methotrexate or ifosfamide (6). These combined treatment protocols have significantly improved survival of the nonmetastatic patients over the past several decades (7,8). Unfortunately, such therapeutic strategies have a limited efficacy in the treatment of metastatic disease, and the metastatic relapse or recurrent conditions have remained unchanged over the last 3 decades (8).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma

Lamora

Talbot

Bougras

et al. 2014

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Purpose: Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastasis is present at diagnosis. Because transforming growth factor-b (TGFb) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFb/Smad signaling inhibitor Smad7 and the TbRI inhibitor SD-208 on osteosarcoma behavior.Experimental Design: By using a mouse model of osteosarcoma induced by paratibial injection of cells, we assessed the impact of Smad7 overexpression or SD-208 on tumor growth, tumor microenvironment, bone remodeling, and metastasis development.Results: First, we demonstrated that TGFb levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFb/Smad3 signaling pathway is activated in clinical samples. Second, we showed that Smad7 slows the growth of the primary tumor and increases mice survival. We furthermore demonstrated that Smad7 expression does not affect in vitro osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factors such as RANKL, suggesting that Smad7 overexpression affects the "vicious cycle" established between tumor cells and bone cells by its ability to decrease osteoclast activity. Finally, we showed that Smad7 overexpression in osteosarcoma cells and the treatment of mice with SD208 inhibit the development of lung metastasis.Conclusion: Taken together, these results demonstrate that the inhibition of the TGFb/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis.

“…Recently, mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine [L-MTP-PE]) a new therapeutic agent, has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. 3,4 L-MTP-PE is a nonspecific immunomodulator that is a synthetic analog of a component of bacterial cell walls. However, despite these therapeutic advances, limited improvement in survival has been achieved since the mid-1980s.…”

mentioning

confidence: 99%

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Moriceau

Roelofs

Brion

et al. 2011

Cancer

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BACKGROUND: Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis. METHODS: The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines. RESULTS: Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used. CONCLUSIONS: The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma. Cancer 2012;118:750-