Osteosarcoma in the Post Genome Era: Preclinical Models and Approaches to Identify Tractable Therapeutic Targets

AbstractPurpose of ReviewOsteosarcoma (OS) is the most common cancer of bone, yet is classified as a rare cancer. Treatment and outcomes for OS have not substantively changed in several decades. While the decoding of the OS genome greatly advanced the understanding of the mutational landscape of OS, immediately actionable therapeutic targets were not apparent. Here we describe recent preclinical models that can be leveraged to identify, test, and prioritize therapeutic candidates.Recent FindingsThe generation of multiple high fidelity murine models of OS, the spontaneous disease that arises in pet dogs, and the establishment of a diverse collection of patient-derived OS xenografts provide a robust preclinical platform for OS. These models enable evidence to be accumulated across multiple stages of preclinical evaluation. Chemical and genetic screening has identified therapeutic targets, often demonstrating cross species activity. Clinical trials in both PDX models and in canine OS have effectively tested new therapies for prioritization.SummaryImproving clinical outcomes in OS has proven elusive. The integrated target discovery and testing possible through a cross species platform provides validation of a putative target and may enable the rigorous evaluation of new therapies in models where endpoints can be rapidly assessed.
Source: Current Osteoporosis Reports - Category: Orthopaedics Source Type: research

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In this study, we found that the proliferation of MG-63 cells was significantly decreased after treatment with 25, 50, 100, or 200 μM ZOL for 48 and 72 h compared to that of untreated control cells. The expression levels of p-AKT/AKT and p-GSK-3β/GSK-3β in MG-63 cells and U-2 OS cells were inhibited by ZOL in both a dose- and time-dependent manner. Significant decreases in the expression of Cyclin D1, β-Catenin, and c-Myc were observed in the groups that underwent ZOL treatment. Additionally, compared to ZOL (100 μM) treatment alone, cotreatment with ZOL (100 μM) and Li2CO3 (1mM) rescued cell prolif...
Source: Neoplasma - Category: Cancer & Oncology Authors: Tags: Neoplasma Source Type: research
Authors: Roslan Z, Muhamad M, Selvaratnam L, Ab-Rahim S Abstract Low-density lipoprotein receptor (LDLR) has been an object of research since the 1970s because of its role in various cell functions. The LDLR family members include LRP5, LRP6, and LRP8. Even though LRP5, 6, and 8 are in the same family, intriguingly, these three proteins have various roles in physiological events, as well as in regulating different mechanisms in various kinds of cancers. LRP5, LRP6, and LRP8 have been shown to play important roles in a broad panel of cancers. LRP5 is highly expressed in many tissues and is involved in the modulation...
Source: Journal of Oncology - Category: Cancer & Oncology Tags: J Oncol Source Type: research
AbstractPurpose of ReviewThis review provides an update on the recent literature describing the role of microRNAs (miRNAs) in cancer formation and bone metastasis. We confined our focus on osteosarcoma, breast cancer, prostate cancer, and epithelial-mesenchymal transition.Recent FindingsIn all areas covered, major discoveries on the role of miRNAs in tumorigenesis and metastasis have been made. Novel signaling networks were identified with miRNAs having a central function. Potential improvements in the diagnosis of malignant diseases and the long-term follow-up might become possible by the use of miRNAs. Furthermore, miRNA...
Source: Current Osteoporosis Reports - Category: Orthopaedics Source Type: research
Authors: Sarigol-Calamak E, Hascicek C Abstract Healing fractures resulting from bone disorders such as osteoporosis, osteoarthritis, osteomyelitis, and osteosarcoma remain a significant clinical challenge. In this chapter, we focus on scaffold based local drug delivery applications for promoting bone regeneration. For this purpose, we first review bone disorders, which require drug treatment and current fabrication techniques for bone tissue scaffold as a drug carrier. Next, we address the role of antimicrobial agents, anti-inflammatory drugs, anti-cancer drugs and bisphosphonates in promoting vascularized bone re...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
ConclusionsBased on the estimated 242,782 person-years of observation as of the eighth annual linkage and projecting current enrollment rate to study end in 2024, it is anticipated that the completed study will be able to detect a fourfold increase in the risk of osteosarcoma if one exists.
Source: Osteoporosis International - Category: Orthopaedics Source Type: research
AbstractAlthough osteoradionecrosis (ORN) is a serious complication of craniofacial radiotherapy, the current management methods remain suboptimal. Teriparatide (TPTD), a recombinant human parathyroid hormone (1 –34), has shown beneficial effects on osseous regeneration in medication-related osteonecrosis of the jaw or periodontitis. However, TPTD therapy in irradiated bones has not been indicated yet because of the theoretical risk of osteosarcoma seen in rat models. Hence, we first report here two patie nts with tongue cancer with late-emerging ORN who were successfully treated with TPTD for 4–6 months w...
Source: Osteoporosis International - Category: Orthopaedics Source Type: research
Osteosarcoma is the most common type of primary bone tumor, and novel therapeutic approaches for this disease are urgently required. To identify effective agents, we screened a panel of Food and Drug Administration (FDA)‐approved drugs in AXT cells, our newly established mouse osteosarcoma line, and identified calcitriol as a candidate compound with therapeutic efficacy for this disease. Calcitriol inhibited cell proliferation in AXT cells by blocking cell cycle progression. From a mechanistic standpoint, calcitriol induced endoplasmic reticulum (ER) stress, which was potentially responsible for downregulation of cyclin ...
Source: Cancer Science - Category: Cancer & Oncology Authors: Tags: Original Article Source Type: research
AbstractPurpose of ReviewWnt signaling plays a central role in development and homeostasis, and its dysregulation is a common event in many types of human cancer. Here we explore in detail the contributions of Wnt signaling to the initiation and maintenance of three types of saroma: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. This review provides an overview of the Wnt signaling pathway and explores in detail the current knowledge about its role in the initiation or maintenance of three tumor types: Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors.Recent FindingsRecen...
Source: Current Osteoporosis Reports - Category: Orthopaedics Source Type: research
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Source: Cancer Science - Category: Cancer & Oncology Authors: Tags: Original Article Source Type: research
CONCLUSION: Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma. PMID: 27993113 [PubMed - as supplied by publisher]
Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research
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