Recherche

BiiOSTeam est en étroite collaboration avec l’équipe du Dr Olivia FROMIGUE (chercheuse biologiste, U981, Gustave Roussy). Ensemble, nous avons mis en place un programme de recherche avec des techniques innovantes (WES, ADN tumoral circulant, RNA-seq en Bulk, single cell et spatial transcriptomic) à partir d’échantillons de patients et de modèles animaux dérivés des patients (PDX).

Nous avons trois objectifs :

1. Mieux caractériser les mécanismes cellulaires et micro-environnementaux impliqués dans l’évolution défavorable des ostéosarcomes (résistance au traitement, récidive, dissémination métastatique);

2. Identifier les meilleurs candidats pour la clinique;

3. L’établissement de stratégies de personnalisation des
traitements.

Translational research

Osteosarcoma is a rare bone cancer in adolescents and young adults with dismal prognosis because of metastatic disease and chemoresistance. Despite multiple clinical trials, no improvement of outcome has occurred in decades. There is an urgent need to better understand the resistant and metastatic disease.

1. Therapeutic stratification and biomarkers

No therapeutic stratification has emerged in Osteosarcoma over the last years despite the introduction of tumor Omics analyses in Trials. Therefore, patients are still treated with the same chemotherapeutic regimen despite we know ~35% of the tumors will develop resistances. Personalized medicine of Osteoarcoma requires as a foundation to first be able to characterize molecularly the hard-to-treat tumors to further treat them with relevant combination of treatments. Our group supervises two campaigns (BoOSTDataS and FOSTER) of Omics data collection from diagnosis to relapse in order to increase the size of the cohort and improve the statistical power of MultiOmics analyses. Researchers of the team, in collaboration with pediatric oncologists, generate data driven hypothesis to define therapeutic stratification and elite targets.

We built a PDX model programs to generate tumor avatars in Mice to characterize biologically the proposed stratification and to test the efficacy of new drug combinations inferred from the bioinformatic analyses.

2. Crossplay between Tumor and Microenvironment cells in Osteosarcoma

The crosstalk between Tumor cells and the growing bone microenvironment in Osteosarcoma is tightly associated to patient fate. Over the last years, several studies confirmed, at bulk and single cell level, the importance of the ME/tumor cell crosstalk in Osteosarcoma, especially the immune infiltrate. Taken together, all those recent works support the hypothesis that the early tight interaction between the microenvironment and tumor cells has locked or constrained some territories of the tumor in very aggressive and/or resistant states which persist or influence in metastatic relapse. To investigate this complex thesis, involving genetic and transcriptomic program alteration at the spatial level, our team implemented scRNA-seq and spatial RNA-seq to study Osteosarcoma in matched samples from diagnosis to relapse.

3. Improvment of patient care

Following patient progression to intercept relapse as quickly as possible is a challenge in solid tumors. Our team developed a program to evaluate the benefit of liquid biopsy as a prognosis and predictive tool. To do so, we quantify tumor circulating DNA using ultra-low coverage whole genome sequencing by the detection of abnormal copy number alterations in plasma along patient treatment.

Les essais

1. OS2006

2. Sarcome13

Sarcome 13 est le seul protocole en France permettant l’accès à une immunothérapie pour les patients atteint d’ostéosarcome en cours de traitement initial de la maladie. 

L’objectif de cette étude de phase II est d’évaluer l’efficacité du mifamurtide (une immunothérapie) lorsqu’il est associé à une chimiothérapie postopératoire chez des patients ayant un ostéosarcome à haut risque de récidive. Si l’étude aboutit à une conclusion positive de meilleur contrôle de la maladie, ce médicament pourrait alors être accessible à tous les patients hors essai clinique.

L’ostéosarcome représente l’un des cancers des os les plus fréquents de l’adolescent et du jeune adulte. Les traitements de référence sont l’utilisation d’une polychimiothérapie encadrant la chirurgie de la tumeur primitive (site ou la maladie a commencé) et des métastases (autre site de maladie à distance du site primitif) quand elles sont présentes. 

Le mifamurtide est un nouveau traitement d’immunothérapie à l’étude qui pourrait améliorer l’efficacité des chimiothérapies en activant le système immunitaire. Depuis plus de trois décennies, il s’agit du seul médicament, utilisé dans le cadre d’essais cliniques, qui semble apporter un gain de survie chez les patients de moins de 30 ans avec une forme localisée d’ostéosarcome. Les données obtenues jusqu’à présent restent insuffisantes pour les patients avec un ostéosarcome métastatique.

Le mifamurtide est disponible dans plusieurs pays européens mais n’est accessible en France que dans le cadre de l’étude Sarcome 13 pour les patients ayant un osteosarcome de haut risque.

Consortium and data sharing

1. BoOSTDataS

Objective : Constitution of a French osteosarcoma database to determine sub-classes of OTS underlined by different genetic clones and ME interactions, by an integrated innovative technique.

Final aim: To propose adapted follow-up and specific treatments for each osteosarcoma sub-classes.

2. FOSTER (Fight Osteosarcoma Through European Research)

The FOSTER consortium (Fight Osteosarcoma Through European Research) proposes to connect multidisciplinary and patient/parent advocate expertise, at a Pan-European level to improve biological, translational and clinical research on osteosarcoma, to ultimately improve survival.

With 240 members from across 19 countries, and 8 work packages from biology to late-effects, FOSTER consortium work is overseen by an Executive Committee, with the help of a project manager: to implement a strategic research plan agenda with regular meetings where knowledge sharing can be freely developed; to pursue the aim of gaining a comprehensive overview of current osteosarcoma biology knowledge and trial situation, and thus tackle the current gaps and remaining challenges in osteosarcoma.

Overreaching objective: To improve outcome of patients with osteosarcoma, in terms of duration and quality of life of survivors.

Specific objectives

– To encourage multidisciplinary interactions between researchers, clinicians and patient/parent advocates to accelerate early new drug development

– To promote collaborative translational research and biobanking in osteosarcoma

– To promote clinical research in systemic and local therapies for all patients with osteosarcoma independently of resectability, tumor location and staging across all Europe, with integration of new therapies in randomized clinical trials and then into standard of care

– To promote exchange of young investigators and clinicians in referral centers of the consortium

– To promote educational meetings for young investigators and clinicians

– To facilitate participation in age inclusive clinical trials with novel therapeutic agents for osteosarcoma

– To increase our knowledge of local and systemic treatment late effects

– To promote collaborative data sharing in osteosarcoma