Team 09 - Sarcotarget

Équipe 09 – Sarcotarget

The Pr Antoine ITALIANO laboratory is devoted to translational research and pursue laboratory-based research to better understand the therapeutic vulnerabilities of sarcomas. Current lab research efforts focus on:

  • Learning more about the biology and potential therapies for soft-tissue sarcomas
  • Investigating role of DNA Damage Repair targeting in soft-tissue sarcomas
  • Studying the role of  epigenetic targets such as PRMT5 and bromodomain inhibitor in soft-tissue sarcomas
  • Learning more about the microenvironment of soft-tissue sarcomas

New combination therapies are explored by analyzing a large panel of cell lines and mice models established from tumor samples of patients treated at Institut Bergonié.


Keywords

sarcomas, tumor genetics, microenvironment, radiomics

News


Projects

1 - Integration of massive sequencing data to identify molecular networks of sensitivity and resistance to systemic therapies in sarcomas.

This task aim to define molecular features associated with primary and secondary resistance to therapies in advanced soft-tissue sarcomas.

The MULTISARC study will provide omic, biological and clinic data for a 900 sarcoma patients to be included between 2019 and 2022. We expect that subgroups of tumors characterized by known cancer phenotype, clinical and biological criteria can be established with minimum sample size of 20-30 samples per group. For all these patients, liquid biopsies will be performed from the diagnosis of metastatic disease to death to assess the genetic evolution of disease through therapies.

Our goal is to identify genomic and transcriptomic networks of features that are associated with primary and secondary resistance.

Methodology

To identify omic networks superseding “resistance” we are going to use Supervised Learning and Deep Learning strategies.


Project members

2 - Predictive and prognostic value of immunological profiling of soft-tissue sarcoma

The task aim to define the immune landscape of immune cells in soft-tissue sarcoma and to evaluate the association between immune gene profiling and clinical outcome of soft-tissue sarcoma patients treated with immune checkpoint inhibitors

Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumours, including more than 70 different histological subtypes and representing 1% of cancer in adults and 15% in children. We have recently reported a novel classification of STS, based on the composition of the tumour microenvironment in large cohorts of STS. We have more particularly identified a subgroup of sarcomas encompassing several histological subtypes and characterized by the highest expression of genes specific of immune populations such as T cells, CD8+ T cells, NK cells, cytotoxic lymphocytes. Strikingly, the strongest determinant of this class of sarcomas was the high expression of the B lineage signature. We validated in two independent cohorts by using immunohistochemistry that this class of sarcomas was characterized by a high density of B cells and the presence of tertiary lymphoid structures (TLS). Moreover, we have shown by analysing retrospective data that TLS-positive sarcomas have better outcome and are more likely to respond to PD1 inhibition. Based on these data, we have set up two studies, the PEMBROSARC and the CONGRATS studies (sponsor: Institut Bergonié, Bordeaux, France) investigating the efficacy of immune-checkpoint inhibitors in patients with advanced sarcoma characterized by the presence of TLS. These studies are the first biomarker-driven study investigating immunotherapy in sarcoma patients. All patients included in these studies had sequential blood and tumor sampling (at baseline, at cycle 2 and at secondary progression). We will perform an integrative analysis (multiplex IF, exome/seq RNA, metabolomics, PBMC profiling) of this large collection of biological samples in order to investigate predictive biomarkers of long-term efficacy of PD1 inhibition in TLS+ sarcomas and to understand more in depth mechanisms of secondary resistance. Moreover, in order to better assess the prognosis (risk of relapse) of patients with localized sarcoma who underwent surgery, we have planned to investigate the prognostic value of the presence of TLS in a large cohort of sarcoma patients. Altogether, this project will provide significant insights for deciphering the role of immunotherapy in sarcomas and therefore propose new strategies for patient stratification that might benefit from current immunotherapies.


Project members

3 - Targeting the DNA damage repair pathway in soft-tissue sarcomas.

Gene expression profiling of a large cohort of STS by allowed the identification and validation of a 67 gene signature of chromosome instability named CINSARC (for genome Complexity INdex in SARComas) and which is the most significant predictor of metastasis free survival in these tumors (Chibon et al Nat Medicine 2010) . Many of the genes identified encode for proteins involved in DNA repair.

 

Moreover, a recent international study has shown that germline variants in several genes encoding proteins involved in DNA repair such as BRCA2, ATM, ATR, and ERCC2, contributed significantly to sarcoma risk (Ballinger et al Lancet Oncol 2016).

 

Our group was the first to investigate the clinical impact of DNA Damage Repair targeting in patients with locally advanced sarcoma by combining the PARP inhibitor olaparib with radiation therapy (study RADIOSARP, NCT02787642). The clinical results are quite encouraging and will be presented as an oral presentation at the 62nd Annual Meeting of American Society for Radiation Oncology (ASTRO), 2020. All the patients in this study had initial biopsy and post-treatment resection allowing an analysis of the impact of PARP inh in combination with radiotherapy on DNA damage and tumor microenvironment.

 

We have also recently reported the first pre-clinical and clinical evidence that inhibition of the ATR/CHK1 pathway is synergistic with chemotherapy in patients with advanced sarcomas (Laroche-Clary et al Ann Oncol 2018; Laroche-Clary et al Scientific Reports 2020). Based on this date, we will start in 2021 the first randomized trial investigating an inhibitor of ATR in combination with chemotherapy versus chemotherapy alone in patients with advanced leiomyosarcomas. All the patients will have sequential biopsies (pre-treatment and on –treatment). An integrated analysis of the tumor samples obtained during this clinical trial will allow to investigate for the first time the impact of ATR inhibition on DNA damage (H2AX staining) and expression profile (RNA seq).

We will also investigate a new target, the activity of a new DNA-PK inhibitor (AZD7648) as a single agent and in combination with chemotherapy in a panel of 20 STS cell lines and in Patient-derived xenograft models. The results of this pre-clinical project will impact the possibility to set up a clinical trial investigating AZD7648 + doxorubicin in sarcoma patients with advanced disease.


Project members

Jobs offers


Team’s noteworthy publications

Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.
Italiano A, Soria JC, Toulmonde M, Michot JM, Lucchesi C, Varga A, Coindre JM, Blakemore SJ, Clawson A, Suttle B, McDonald AA, Woodruff M, Ribich S, Hedrick E, Keilhack H, Thomson B, Owa T, Copeland RA, Ho PTC, Ribrag V
The Lancet. Oncology ; 2018 May 01
CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications.
Laroche-Clary A, Lucchesi C, Rey C, Verbeke S, Bourdon A, Chaire V, Algéo MP, Cousin S, Toulmonde M, Vélasco V, Shutzman J, Savina A, Le Loarer F, Italiano A
Annals of oncology : official journal of the European Society for Medical Oncology ; 2018 Apr 01
High throughput profiling of undifferentiated pleomorphic sarcomas identifies two main subgroups with distinct immune profile, clinical outcome and sensitivity to targeted therapies.
Toulmonde M, Lucchesi C, Verbeke S, Crombe A, Adam J, Geneste D, Chaire V, Laroche-Clary A, Perret R, Bertucci F, Bertolo F, Bianchini L, Dadone-Montaudie B, Hembrough T, Sweet S, Kim YJ, Cecchi F, Le Loarer F, Italiano A
EBioMedicine ; 2020 Dec 01
MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies.
Roy S, Laroche-Clary A, Verbeke S, Derieppe MA, Italiano A
Cancers ; 2020 Aug 12
GSK3-beta as a candidate therapeutic target in soft tissue sarcomas.
Verbeke S, Perret R, Chaire V, Richard E, Velasco V, Giles F, Cavalcante L, Italiano A
Journal of hematology & oncology ; 2021 Dec 02


Partners

Team leaders

Antoine ITALIANO
Professor Clinician / PU-PH


Team members

Rihab AZMANI
Engineer / IE

Frédéric BERTOLO
Engineer / IE

Quentin CAVAILLE
Engineer / IE

Vanessa CHAIRE
Technician / Tech

Jean-Michel COINDRE
Professor Clinician / PU-PH

Paul DUBOS
Engineer / IE

Antoine ITALIANO
Professor Clinician / PU-PH

Hajer KHALFAOUI
Engineer / IE

Mathilde LAFON
Research student / Année recherche

Yec’han LAIZET
Research Engineer / IR

Audrey LAROCHE-CLARY
Research Engineer / IR

Van Linh LE
Post PhD Researcher / Post-doc

François LE LOARER
Professor Clinician / PU-PH

Audrey MICHOT
PhD Student / Doc

Florent PEYRAUD
PhD Student / Doc

Tony SOURISSEAU
Research Engineer / IR

Mariella SPALATO CERUSO
PhD Student / Doc

Veronica VALVERDE TIMANA
Technician / Tech

Stéphanie VERBEKE
Research Engineer / IR