Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma

Abstract This report summarizes the proceedings of the 4th European Bone Sarcoma Networking Meeting, held in London, England, on 21 June 2017. The meeting brought together scientific and clinical researchers and representatives from sarcoma charities from 19 countries representing five networks across Europe, to present and discuss new developments on bone sarcoma. In view of the challenges is poses, the meeting focussed primarily on osteosarcoma with presentations on developments in our understanding of osteosarcoma genetics and immunology as well as results from preclinical investigations and discussion of recent and ongoing clinical trials. These include studies examining the efficacy of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, as well as those with molecular profiling to stratify patients for specific therapies. Discussion was centred on generation of new hypotheses for collaborative biological and clinical investigations, the ultimate goal being to improve therapy and outcome in patients with bone sarcomas

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

Caracterisation biochimique des glycosaminoglycannes des cellules de rhabdomyosarcome de rat : etude de leur implication dans le processus metastatique

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

A One-Pot Synthesis of 1-Hydroxy-1,1-bis(phosphonic acid)s Starting from the Corresponding Carboxylic Acids

By starting with various carboxylic acids, a one-pot procedure for the synthesis of the corresponding 1-hydroxy-1,1-bis(phosphonic acid)s is reported. The efficiency of this simple methodology is illustrated by synthesizing well-known marketable amino hydroxy bis(phosphonate)s such as alendronate or N-methyl pamidronate without additional steps for the protection/deprotection of the amine function

Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

PURPOSE: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma. METHODS: The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by Western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated bone lesions, and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14(+) monocytes. RESULTS: In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50 nmol/L) and induced apoptosis with an increase of sub-G1 fraction and cleaved PARP. These biologic events were accompanied by decreased expression of Akt, p-ERK, c-Met, and c-RAF1. When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared with controls, and inhibited pulmonary metastases by blocking c-Met, FAK, and MMP9 signaling. In contrast to 17-allylamino-17-demethoxygeldanamycin (17-AAG), PF4942847 did not induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. CONCLUSIONS: All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma. Clin Cancer Res; 1-14. ©2015 AACR