Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma
Abstract:Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortu… Show more
“…The endothelin pathway (the ligands ET1-3 and their two receptors ETA-B) is associated with bone formation by targeting osteoblast differentiation and function [ 34 ]. Macitentan is an inhibitor of both ETA-B endothelin receptors [ 35 ]. Despite the absence of a direct effect on tumor growth, the combination of macitentan with RANKL blockade resulted in a decrease in lung metastases as well as a bone protective action in a preclinical OS murine model (Fig.…”
Section: Signaling Pathwaysmentioning
confidence: 99%
“…Despite the absence of a direct effect on tumor growth, the combination of macitentan with RANKL blockade resulted in a decrease in lung metastases as well as a bone protective action in a preclinical OS murine model (Fig. 1 ) [ 35 ]. Fig.…”
Purpose of Review
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
Recent Findings
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme.
Summary
The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.
“…The endothelin pathway (the ligands ET1-3 and their two receptors ETA-B) is associated with bone formation by targeting osteoblast differentiation and function [ 34 ]. Macitentan is an inhibitor of both ETA-B endothelin receptors [ 35 ]. Despite the absence of a direct effect on tumor growth, the combination of macitentan with RANKL blockade resulted in a decrease in lung metastases as well as a bone protective action in a preclinical OS murine model (Fig.…”
Section: Signaling Pathwaysmentioning
confidence: 99%
“…Despite the absence of a direct effect on tumor growth, the combination of macitentan with RANKL blockade resulted in a decrease in lung metastases as well as a bone protective action in a preclinical OS murine model (Fig. 1 ) [ 35 ]. Fig.…”
Purpose of Review
This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.
Recent Findings
Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme.
Summary
The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.
“…When considering the role of osteoclasts in the clinical treatment of osteosarcoma, two main aspects are important: inhibiting osteoclast formation induced by the tumor and inducing osteoclast-specific apoptosis in response to bone resorption. [74][75][76] Siglec-15, which is predominantly expressed in osteoclasts, can modulate the effect of RANKL on osteoclast cell lines. Anti-Siglec-15 antibodies can stimulate PDGF-BB secretion through various mechanisms.…”
Section: Osteoclasts In the Treatment Of Osteosarcomamentioning
Osteosarcoma is an extremely malignant tumor, and its pathogenesis is complex and remains incompletely understood. Most cases of osteosarcoma are accompanied by symptoms of bone loss or result in pathological fractures due to weakened bones. Enhancing the survival rate of osteosarcoma patients has proven to be a long-standing challenge. Numerous studies mentioned in this paper, including in-vitro, in-vivo, and in-situ studies have consistently indicated a close association between the symptoms of bone loss associated with osteosarcoma and the presence of osteoclasts. As the sole cells capable of bone resorption, osteoclasts participate in a malignant cycle within the osteosarcoma microenvironment. These cells interact with osteoblasts and osteosarcoma cells, secreting various factors that further influence these cells, disrupting bone homeostasis, and shifting the balance toward bone resorption, thereby promoting the onset and progression of osteosarcoma. Moreover, the interaction between osteoclasts and various other cells types, such as tumor-associated macrophages, myeloid-derived suppressor cells, DCs cells, T cells, and tumor-associated fibroblasts in the osteosarcoma microenvironment plays a crucial role in disease progression. Consequently, understanding the role of osteoclasts in osteosarcoma has sparked significant interest. This review primarily examines the physiological characteristics and functional mechanisms of osteoclasts in osteosarcoma, and briefly discusses potential therapies targeting osteoclasts for osteosarcoma treatment. These studies provide fresh ideas and directions for future research on the treatment of osteosarcoma.
“…The five-year survival rate of osteosarcoma patients with lung metastases was only 19% [3][4][5][6]. Although the diagnosis and treatment of osteosarcoma has made progress compared to the past few decades [7][8][9][10][11][12][13][14], the prognosis for patients with metastatic or recurrent cancer is still poor [15]. So, it is pivotal to study the mechanism underlying the progression of osteosarcoma and develop novel therapy targets of osteosarcoma.…”
Researchers have reported that zinc finger CCHC domain containing 12 gene (ZCCHC12) plays a role in the progression and tumorigenesis of papillary thyroid cancer. However, the biological role of ZCCHC12 in osteosarcoma (OS) remains unknown. ZCCHC12 was highly upregulated in OS cell lines according to our present study. Also, our subsequent assays demonstrated that ZCCHC12 enhanced the proliferation, tumor growth and migration of OS cells. Moreover, the epithelial-mesenchymal transition (EMT) of OS cells was also promoted by ZCCHC12. In addition, downregulation of ZCCHC12 induced apoptosis and S-phase arrest in OS cells. Then, our study indicated that ZCCHC12 exerts its oncogenic function in OS cells by activating the PI3K/AKT pathway. Inhibition of the PI3K/AKT pathway greatly limits the oncogenic function of ZCCHC12 in OS cells. Also, overexpression of ZCCHC12 promotes tumor growth in vivo. Altogether, our study suggests ZCCHC12 promotes OS cells progression by activating the PI3K/AKT pathway. The ZCCHC12 gene may be a novel diagnostic and therapeutic target for OS.
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