A“Proteoglycan Targeting Strategy” for the Scintigraphic Imaging and Monitoring of the Swarm Rat Chondrosarcoma Orthotopic Model

Our lab developed 99mTc-NTP 15-5 radiotracer as targeting proteoglycans (PGs) for the scintigraphic imaging of joint. This paper reports preclinical results of 99mTc-NTP 15-5 imaging of an orthotopic model of Swarm rat chondrosarcoma (SRC). 99mTc-NTP 15-5 imaging of SRC-bearing and sham-operated animals was performed and quantified at regular intervals after surgery and compared to bone scintigraphy and tumoural volume. Tumours were characterized by histology and PG assay. SRC exhibited a significant 99mTc-NTP 15-5 uptake at very early stage after implant (with tumour/muscle ratio of 1.61 ± 0.14), whereas no measurable tumour was evidenced. As tumour grew, mean tumour/muscle ratio was increased by 2.4, between the early and late stage of pathology. Bone scintigraphy failed to image chondrosarcoma, even at the later stage of study. 99mTc-NTP 15-5 imaging provided a suitable set of quantitative criteria for the in vivo characterization of chondrosarcoma behaviour in bone environment, useful for achieving a greater understanding of the pathology

Drugs targeting the bone microenvironment: new therapeutic tools in Ewing's sarcoma?

Introduction: Ewing's sarcoma (ES) is the second most frequent malignant primary bone tumour in children, adolescents and young adults. The overall survival is 60 – 70% at 5 years but still very poor for patients with metastases, disease relapse or for those not responding to chemotherapy. For these high risk patients, new therapeutic approaches are needed beyond conventional therapies (chemotherapy, surgery and radiation) such as targeted therapies. Areas covered: Transcriptomic and genomic analyses in ES have revealed alterations in genes that control signalling pathways involved in many other cancer types. To set up more specific approaches, it is reasonable to think that the particular microenvironment of these bone tumours is essential for their initiation and progression, including in ES. To support this hypothesis, preclinical studies using drugs targeting bone cells (bisphosphonate zoledronate, anti-receptor activator of NF-κB ligand strategies) showed promising results in animal models. This review will discuss the new targeted therapeutic options in ES, focusing more particularly on the ones modulating the bone microenvironment. Expert opinion: Targeting the microenvironment represents a new option for patients with ES. The proof-of-concept has been demonstrated in preclinical studies using relevant animal models, especially for zoledronate, which induced a strong inhibition of tumour progression in an orthotopic bone model

Severe Compromise of Preosteoblasts in a Surgical Mouse Model of Bisphosphonate-Associated Osteonecrosis of the Jaw.

Objectives: The effect of amino-bisphosphonates on osteoblastic lineage and its potential contribution to the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BONJ) remain controversial. We assessed the effects of zoledronic acid (ZOL) on bone and vascular cells of the alveolar socket using a mouse model of BONJ. Material and Methods: Thirty-two mice were treated twice a week with either 100 μg/kg of ZOL or saline for 12 weeks. The first left maxillary molar was extracted at the third week. Alveolar sockets were assessed at both 3 weeks (intermediate) and 9 weeks (long-term) after molar extraction by semi-quantitative histomorphometry for empty lacunae, preosteoblasts (Osterix), osteoclasts (TRAP), and pericyte-like cells (CD146). Also, the bone microarchitecture was assessed by micro-CT. Results: Osteonecrotic-like lesions were observed in 21% of mice. Moreover, a decreased number of preosteoblasts contrasted with the increased number of osteoclasts at both time points. In addition, osteoclasts display multinucleation and detachment from the endosteal surface. Furthermore, the number of pericyte-like cells increased at the intermediate time point. The alveolar bone mass increased exclusively with long-term ZOL treatment. Conclusion: The severe imbalance between bone-forming cells and bone-resorbing cells showed in this study could contribute to the pathogenesis of BONJ

The First European Interdisciplinary Ewing Sarcoma Research Summit

The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials

TThe ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24–25, 2015. Workshop Report

This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas

Mifamurtide for the treatment of nonmetastatic osteosarcoma

International audienceINTRODUCTION: The standard treatment for osteosarcoma requires both macroscopic surgical wide resection and postoperative multi-drug chemotherapy in neoadjuvant and adjuvant settings. However, the 5-year event-free survival has remained at a plateau of 60-70% of patients with nonmetastatic osteosarcoma for more than 30 years. AREAS COVERED: Mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine; L-MTP-PE) is a new agent. L-MTP-PE is a nonspecific immunomodulator, which is a synthetic analog of a component of bacterial cell walls. L-MTP-PE activates macrophages and monocytes as a potent activator of immune response in addition to standard chemotherapy. It also improves the overall survival from 70 to 78% and results in a one-third reduction in the risk of death from osteosarcoma. This review summarizes the most recent findings about L-MTP-PE and its therapeutic application for nonmetastatic osteosarcoma. EXPERT OPINION: Recently, L-MTP-PE has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. L-MTP-PE in combination with traditional treatment is expected to go mainstream and to be beneficial for patients with osteosarcoma. Information about potential benefit regarding mifamurtide use in the neoadjuvant setting (i.e., before surgery) and/or usefulness of L-MTP-PE in metastatic in relapsed and metastatic osteosarcoma requires analysis of expanded access and/or future clinical trials of L-MTP-PE in high-burden and low-burden situations

Ciblage thérapeutique des tumeurs osseuses primitives par transfert de gène

L'ostéosarcome est la plus fréquente des tumeurs osseuses primitives affectant principalement une population jeune. Bien que les traitements actuels aient contribué à la progression de la survie des patients, ils montrent désormais leurs limites d'où la nécessité de développer de nouvelles thérapies. L'hypothèse biologique de l ostéosarcome repose sur l'existence d un cercle vicieux s'instaurant entre la prolifération tumorale et la résorption osseuse. Récemment découverte, la triade moléculaire Receptor Activator of NF B (RANK) / RANK ligand / Ostéoprotégérine (RANK/RANKL/OPG) est fortement impliquée dans la régulation de la résorption osseuse et du développement tumoral, ainsi l inhibition de l interaction RANK/RANKL représente une cible thérapeutique majeure. L'objectif de cette thèse a été de développer de nouvelles approches thérapeutiques dans des modèles expérimentaux d'ostéosarcomes afin de rompre ce cercle vicieux, notamment par l'utilisation de l'OPG ou de RANK-Fc, molécules anti-résorption osseuse, libérés par transfert de gène non viral, puis de tenter de comprendre le rôle de l OPG et de RANKL dans le microenvironnement tumoral osseux.Osteosarcoma is the most frequent primary bone tumor that affects mainly young patients. Despite current treatments have contributed to increase the survival rate, they show now their limitations with the need to develop new therapeutic approaches. The biological hypothesis of osteosarcoma is based on the existence of a vicious cycle between tumor proliferation and bone resorption. Recently discovered, the molecular triad Receptor Activator of NF B (RANK) / RANK ligand / Osteoprotegerin (RANK / RANKL / OPG) is strongly implicated in the regulation of bone resorption and tumor development, and the inhibition of the interaction RANK / RANKL represents a major therapeutic approach. The objectives of this thesis were to develop new therapeutic approaches in experimental models of osteosarcoma in order to break this vicious cycle, including the use of OPG and RANK-Fc, anti-bone resorption molecules, released by non-viral gene transfer, and then to try to understand the place of OPG and RANKL in the tumor bone microenvironment.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Nouvelles approches thérapeutiques des ostéosarcomes.

L'ostéosarcome est la plus fréquente des tumeurs osseuses primitives non hématologiques affectant une population relativement jeune, dont les thérapies conventionnelles montrent désormais leurs limites, et nécessite par conséquent de développer de nouveaux traitements. Récemment découverte, la triade moléculaire Receptor Activator of NFkB / RANK Ligand / Ostéoprotégérine (RANK / RANKL / OPG) représente un pivot dans la régulation de la balance apposition/ résorption osseuse. Cet équilibre est affecté lors développement de l'ostéosarcome. L'objectif de cette thèse a été de développer de nouvelles approches thérapeutiques dans des modèles expérimentaux d'ostéosarcomes basées sur une meilleure connaissance de la biologie osseuse, notamment le rôle physiologique et le potentiel thérapeutique de triade. Par ailleurs, en raison de l'interaction des systèmes osseux et immunitaire, l'élaboration de protocoles d'immunothérapie active par l'utilisation de cellules dendritiques a été entreprise.Osteosarcoma is the most frequent primary bone tumour that develops mainly in the young, the median age of diagnosis being 18 years. Despite recent improvements, current strategy for treatment of high-grade osteosarcoma lead to pulmonary metastasis apparition and new therapeutic approaches need to be developed. Recently discovered, the molecular triad Receptor Activator of NFkB / RANK Ligand / Ostéoprotégérine (RANK / RANKL / OPG) is a pivotal key in bone formation/degradation balance regulation. Osteosarcoma affects this regulation. The aim of this thesis was to develop new therapeutic design based upon better knowledge in bone biology, most notably physiologic role and therapeutic potential of OPG/RANK/RANKL using animal models. Moreover, due to bone and immune systems interaction, we started active immunotherapy's protocols using dendritic cells.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Differential effects of interleukin-1 and transforming growth factor beta on the synthesis of small proteoglycans by rabbit articular chondrocytes cultured in alginate beads as compared to monolayers

International audienc