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Osteosarcoma: Individualized Precision Treatment and Effective Drug Discovery
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Osteosarcoma: Individualized Precision Treatment and Effective Drug Discovery

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Drug Development".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 5535

Special Issue Editor

Dr. Margherita Cortini

E-Mail Website
Guest Editor
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
Interests: osteosarcoma; bone cancer; tumor microenvironment; tumor acidosis; lipid metabolism; targeted therapies; precision medicine; microfluidics; 3D tumor models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Osteosarcoma is a highly aggressive cancer of mesenchymal origin that develops in bone. Despite decades of research, the survival rates for patients with osteosarcoma have remained largely unchanged. While surgery and conventional therapies remain the cornerstone of treatment, they offer limited benefits for patients with metastatic disease. This underscores the urgent need for innovative therapies to improve survival rates and reduce metastatic spread.

This Special Issue seeks to explore the latest advancements and future directions in understanding the molecular mechanisms underlying bone and soft tissue sarcomas. By delving into the molecular landscape of these tumors, we aim to highlight novel therapeutic strategies and their potential to transform the treatment of these challenging diseases.

Recent years have witnessed remarkable progress in targeted therapies and drug discovery for osteosarcoma. Advances in the molecular characterization of the disease have unveiled promising new targets and treatment avenues.

In this Special Issue, we bring together cutting-edge research and insights to summarize recent breakthroughs in precision medicine and innovative drug discovery for osteosarcoma, offering hope for improved patient outcomes and a brighter future in the fight against this formidable malignancy.

Dr. Margherita Cortini
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • osteosarcoma
  • bone cancer
  • tumor microenvironment
  • targeted therapies
  • precision medicine
  • 3D tumor models
  • drug screening

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Published Papers (4 papers)

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Research

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14 pages, 3005 KB  
Article
Prognostic Analysis of Endoprosthetic Reconstruction Versus Biological Reconstruction in the Treatment of Extremity Osteosarcoma
by Guoxin Qu, Shengbiao Ma, Zhehuang Li, Zhichao Tian, Jiaqiang Wang, Xin Wang, Peng Zhang, Xiaohui Niu and Weitao Yao
Cancers 2026, 18(4), 610; https://doi.org/10.3390/cancers18040610 - 13 Feb 2026
Cited by 1 | Viewed by 505
Abstract
Objective: To compare the clinical prognosis of metal endoprosthetic reconstruction versus biological reconstruction in the treatment of limb osteosarcoma and to analyze associated prognostic factors. Methods: From October 2014 to October 2021, a retrospective study was carried out of patients with [...] Read more.
Objective: To compare the clinical prognosis of metal endoprosthetic reconstruction versus biological reconstruction in the treatment of limb osteosarcoma and to analyze associated prognostic factors. Methods: From October 2014 to October 2021, a retrospective study was carried out of patients with high-grade extremity osteosarcoma. Patients were categorized into two groups based on the type of reconstruction: endoprosthetic reconstruction and biological reconstruction. Demographic data and prognosis were systematically compared between the two groups. Furthermore, a Cox proportional hazards model was employed to evaluate the risk factors associated with recurrence and survival outcomes. Results: A total of 133 patients were enrolled in the study, comprising 88 patients in the endoprosthetic reconstruction group and 45 patients in the biological reconstruction group. The 5-year overall survival (OS) and disease-free survival (DFS) rates for the endoprosthetic reconstruction group were 76.2% and 70.5%, respectively, which were higher than those observed in the biological reconstruction group (64.3% and 60%). Additionally, the local recurrence rate was significantly higher in the biological reconstruction group compared to the endoprosthetic reconstruction group (17.8% vs. 2.3%, p = 0.004). Cox regression analysis revealed that pathological fracture (p = 0.034) and the biological reconstruction (p = 0.007) were independent risk factors for local recurrence. Conclusions: Endoprosthetic reconstruction may be preferable for patients requiring early functional recovery or presenting with pathological fractures. Biological reconstruction may be considered for younger patients with diaphyseal defects and demanding long-term functional requirements, albeit with elevated local recurrence risk. Individualized decision-making incorporating tumor location, patient age, and functional goals is essential. Full article
(This article belongs to the Special Issue Osteosarcoma: Individualized Precision Treatment and Effective Drug Discovery)
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Review

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32 pages, 1446 KB  
Review
From Bench to Bedside: Advancements in Precision Oncology and Drug Discovery for Osteosarcoma
by Luca Giacchi, Elisa Pucci and Nadia Rucci
Cancers 2026, 18(4), 561; https://doi.org/10.3390/cancers18040561 - 9 Feb 2026
Cited by 1 | Viewed by 829
Abstract
Osteosarcoma remains a highly aggressive malignancy with limited therapeutic progress and poor outcomes, particularly in metastatic or recurrent cases. Conventional treatment approaches, primarily based on surgery and high-dose chemotherapy, are hindered by significant drawbacks, including severe toxicity, high relapse rates, and drug resistance, [...] Read more.
Osteosarcoma remains a highly aggressive malignancy with limited therapeutic progress and poor outcomes, particularly in metastatic or recurrent cases. Conventional treatment approaches, primarily based on surgery and high-dose chemotherapy, are hindered by significant drawbacks, including severe toxicity, high relapse rates, and drug resistance, underscoring the inadequacy of current standard approaches. This review examines emerging advances in precision medicine and drug discovery, including targeted inhibitors, immunomodulatory agents, combination treatments, and advanced biomaterials, that promise to transform osteosarcoma care. Recent advances, such as combinations of immune checkpoint inhibitors with novel agents or nanoparticle-based drug delivery systems, as well as CRISPR-Cas9 gene-editing applications, offer new strategies to overcome the inherent challenges of conventional therapies. In addition, cutting-edge research leveraging multi-omics analyses and digital pathology is refining our understanding of the tumour microenvironment, paving the way for more individualised treatment strategies. Full article
(This article belongs to the Special Issue Osteosarcoma: Individualized Precision Treatment and Effective Drug Discovery)
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31 pages, 1304 KB  
Review
Exploring Emerging Therapeutic Targets in Osteosarcoma by Revisiting the Immune and Cancer-Intrinsic Hallmarks of Cancer
by Lidia Tarone, Antonella Iacoviello, Antonino Di Lorenzo, Roberta Verta, Chiara Cossu, Laura Conti, Federica Cavallo and Federica Riccardo
Cancers 2025, 17(23), 3846; https://doi.org/10.3390/cancers17233846 - 30 Nov 2025
Cited by 2 | Viewed by 1745
Abstract
Osteosarcoma (OSA) is an aggressive primary bone cancer mainly affecting the pediatric population. Despite intensive multimodal treatments, therapeutic progress has remained limited for decades, resulting in high recurrence rates, poor prognosis driven by metastatic progression, and severe chemotherapy-associated toxicities. To advance the development [...] Read more.
Osteosarcoma (OSA) is an aggressive primary bone cancer mainly affecting the pediatric population. Despite intensive multimodal treatments, therapeutic progress has remained limited for decades, resulting in high recurrence rates, poor prognosis driven by metastatic progression, and severe chemotherapy-associated toxicities. To advance the development of more effective and safer therapeutic strategies, our recent studies identified Chondroitin Sulfate Proteoglycan (CSPG)4 as a relevant mediator of the malignant behavior of OSA cells. Targeting CSPG4 DNA-based vaccine demonstrated encouraging antitumor activity against OSA. Nevertheless, since single-agent immunotherapies are often constrained by tumor immune escape, the need for rational combinatorial strategies is of utmost importance. In this perspective, we broaden our analysis to include other potentially complementary targets beyond CSPG4, which may contribute to OSA pathogenesis. Among these, the cystine/glutamate antiporter xCT and Toll-like Receptor 2 (TLR2) emerge as particularly promising due to their established role in tumor progression, therapy resistance, and immune modulation. We discuss the contribution of all these molecules in major hallmarks of OSA—(1) proliferative and survival advantages, (2) metastasis and angiogenesis, and (3) immune evasion—and examine potential strategies for their combined targeting. By leveraging knowledge gained from other cancer models and integrating it with the distinct biological and clinical features of OSA, this perspective seeks to outline rational and innovative combinatorial strategies that may overcome current therapeutic limitations and ultimately improve patient outcomes. Full article
(This article belongs to the Special Issue Osteosarcoma: Individualized Precision Treatment and Effective Drug Discovery)
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24 pages, 3626 KB  
Review
The Unfolded Protein Response in Sarcomas: From Proteostasis to Therapy Resistance
by Elizabeta Ilieva, Sofia Avnet, Nicola Baldini and Margherita Cortini
Cancers 2025, 17(21), 3489; https://doi.org/10.3390/cancers17213489 - 30 Oct 2025
Cited by 1 | Viewed by 1905
Abstract
Sarcomas are a rare and heterogeneous group of malignant tumors that pose significant clinical challenges, including delayed diagnosis, therapeutic resistance, and lack of reliable biomarkers. Despite advances in surgery and chemotherapy, effective treatment options for advanced disease remain limited, underscoring the urgent need [...] Read more.
Sarcomas are a rare and heterogeneous group of malignant tumors that pose significant clinical challenges, including delayed diagnosis, therapeutic resistance, and lack of reliable biomarkers. Despite advances in surgery and chemotherapy, effective treatment options for advanced disease remain limited, underscoring the urgent need to identify novel therapeutic vulnerabilities. The unfolded protein response (UPR), a conserved cellular stress pathway that maintains proteostasis under conditions of endoplasmic reticulum stress, has emerged as a critical modulator of cancer cell fate. By regulating protein folding, redox balance, and survival pathways, the UPR exerts a dual role in tumor biology, supporting tumor growth under stress while triggering apoptosis when stress becomes sustained or severe. In sarcomas, accumulating evidence indicates that UPR activation contributes to metabolic adaptation, angiogenesis, immune evasion, and chemoresistance. Drawing on the current literature encompassing preclinical models, recent translational research (PubMed from 2000 to 2025), and registered clinical trials, this narrative review synthesizes current knowledge on the multifaceted role of the UPR in sarcoma pathogenesis, with a particular focus on osteosarcoma. Furthermore, it explores the feasibility of UPR-targeted strategies as adjuvant or combinatorial approaches. In conclusion, this review provides an integrated and in-depth analysis of UPR-mediated mechanisms in sarcomas, offering perspectives on how targeting this pathway could accelerate the development of more effective and personalized treatments. Full article
(This article belongs to the Special Issue Osteosarcoma: Individualized Precision Treatment and Effective Drug Discovery)
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