RHU CASSIOPEIA

The CASSIOPEIA project was selected by the French National Research Agency (ANR) within the framework of the “Investments for the Future” program (5th call of the Hospital-University Research – RHU program). The CASSIOPEIA project benefits from a grant of 9.96 million euros for 5 years. The project is coordinated by Dr. Fatima Mechta-Grigoriou, Research Director of Exceptional Class at Inserm, Director of the “Cancer Biology and Chemistry” Unit (Inserm U1339 – CNRS UMR3666), and Head of the “Stress and Cancer” team at Institut Curie. The consortium of this collaborative project is composed of the Institut Curie, the Institut of Molecular Chemistry of the University of Burgundy (ICMUB), Roche, and the Institut Roche. Launched on September 1st, 2022, for an initial duration of five years, the CASSIOPEIA project received a favourable mid-term evaluation. Following this positive assessment, the ANR approved a two-year extension, ensuring the successful completion of the project and the achievement of its scientific objectives.
 

Improving the diagnosis, treatment and prognosis of triple-negative breast cancer

CASSIOPEIA aims to address critical unmet needs in the diagnosis, prognosis and treatment of Triple Negative Breast Cancer (TNBC). Among the 60,000 new cases of breast cancer diagnosed each year in France, TNBC affects approximately 15% of patients. Defined as a research priority in France by the “Plan Cancer 2021-2030”, TNBC is often diagnosed in younger women, with a higher risk of early metastatic recurrence and a shorter overall survival compared to other breast cancer subtypes.

The most important challenges in TNBC include:

• a better prediction of efficacy and resistance to treatment, 
• an earlier detection and mapping of TNBC metastases,
• the development of new therapeutic options to significantly improve TNBC treatment currently relying on conventional chemotherapy.

To tackle these issues, CASSIOPEIA is based on the results of the "Stress and Cancer" laboratory led by Dr. Mechta-Grigoriou, who has identified the role of different populations of cancer-associated fibroblasts (CAF) in tumor growth and progression. In contrast to cancer cells and immune cells, these CAF populations are not yet targeted by any treatment, while they directly participate to metastatic spread and resistance to immunotherapies. Two specific markers identify two distinct CAF populations: FAP+ CAF involved in metastatic spread in breast cancer, and ANTXR1+ FAP+ CAF, which are predictive, at diagnosis, of resistance to immune checkpoint inhibitors.

CASSIOPEIA aims to translate these consolidated data and patented discoveries on CAF that are not yet exploited in clinical practice into real advances for TNBC patient management and treatment.
 

The objectives of CASSIOPEIA are:

1) To give TNBC patient access to innovative immunotherapies and establish new patient stratification based on an unprecedented multimodal characterization of tumors and their micro-environment

A phase 2 clinical trial (SKYLINE, promotor Institut Curie, Pr. François-Clément Bidard) is recruiting TNBC patients since March 2024 and proposes a novel immunotherapy treatment to early and metastatic TNBC patients, combining Atezolizumab (anti-PD-L1) and Tiragolumab (anti-TIGIT) to chemotherapy (Collab. Roche). 
The study also incorporates an innovative imaging strategy using a FAPI radiotracer for whole-body PET scanning, an approach that remains unprecedented in France, enabling more sensitive detection of metastases and disease recurrence. A six-week safety monitoring period was conducted in the first six patients enrolled in the study and revealed no dose-limiting toxicities, allowing patient recruitment to continue. To date, a total of 81 patients has been enrolled in the trial.
Beyond its therapeutic objective, the SKYLINE trial aims to perform high-resolution, multimodal analyses that integrate single-cell RNA sequencing and spatial transcriptomics with PET imaging data, combined with clinical data through machine learning approaches (Collab. Institut Roche, Magnus Fontes). This integrated approach is designed to identify novel features associated with early relapse, treatment response, and treatment resistance. Ultimately, these findings will contribute to more accurate patient stratification and support precision medicine strategies in triple-negative breast cancer.

2) To develop and validate novel detection methods of early metastases and relapse

The current follow-up of TNBC patients at high risk of metastatic relapse does not involve any imaging or blood monitoring. A phase 3 clinical trial (CUPCAKE, promotor Institut Curie, Pr. François-Clément Bidard) has been launched in 2026 to assess a surveillance strategy based on the use of a new radiotracer, FAPI, detecting the FAP+ CAF using whole-body PET/CT imaging (Collab. Dr. Irène Buvat) combined with the analysis of circulating tumor DNA (ctDNA) (Collab. Personalis).
Indeed, the novel FAPI radiotracer, which is intended to complement the FDG tracer currently used in routine clinical practice, will be employed to map metastatic lesions identified through circulating tumor DNA (ctDNA) analysis. ctDNA will be monitored to detect molecular relapse at the earliest stages of disease recurrence. The combined FAPI and FDG PET/CT with the ctDNA monitoring is expected to significantly enhance the surveillance of high-risk TNBC patients, by reducing the rate of relapse with altered general condition, thus allowing more efficient therapies.

3) To identify new biomarkers and potential novel drug targets

By analysing the tumor samples collected during the SKYLINE trial using cutting-edge multi-omics technologies, such as single cell and bulk RNA sequencing as well as spatial transcriptomics, we will characterize tumor heterogeneity (considering both cancer cells and their micro-environment) at diagnosis and describe tumor plasticity all along therapy. The new biological features identified will be validated by performing functional assays, including innovative microfluidic devices mimicking tumors in 3-dimensions. This will reveal new vulnerability points of the tumor microenvironment to be targeted in TNBC patients and thereby anticipate mechanisms of resistance, including to the new anti-TIGIT & anti-PD-L1 treatment.

4) To develop new therapeutic options tackling ANTXR1+ CAF involved in immunotherapy resistance

Among FAP+ CAF, those positive for ANTXR1 (FAP+ ANTXR1+ CAF) are associated with resistance to immune checkpoint inhibitors, while FAP+ ANTXR1- CAF are not. Our objective is therefore to develop agents targeting ANTXR1. CASSIOPEIA will deliver first-in-man trial results for the therapeutic agent targeting ANTXR1, as well as its companion agent (labelled-anti-ANTXR1 antibody) for PET/CT imaging (Collab Dr. Franck Perez). This will offer a new therapeutic option to those patients identified as resistant to immunotherapy.
 

CASSIOPEIA Work Packages

Dissemination activities, training, and teaching programs are established to promote project results and maximize its socio-economic impacts. Different aspects of CASSIOPEIA have been presented during several International Courses at Institut Curie, Paris (with the help of the training unit): 5th edition (October 2022) and 6th edition (October 2024) of the Breast Cancers: From Biology to Clinical Practice course (Collab. Anne Vincent-Salomon), as well as the 3rd edition (April 2024), 4th edition (April 2025), and 5th edition (May 2026) of the Radiomics: Theory and Practice course (Collab. Irène Buvat).
The Project Management Board is composed of Dr. Fatima Mechta-Grigoriou, Coordinator of the project; Prof. François-Clément Bidard, PU-PH medical oncologist responsible of the clinical trials; and Mr. Christian Daveaux, Project Manager.

CASSIOPEIA will bring a true paradigm change in the care management of patients at high risk of relapse and offer sound foundations for the development of future treatments benefiting to all TNBC patients, and potentially other cancer areas.

International Scientific and Advisory Board (ISAB)

The RHU CASSIOPEIA is supported by a public grant overseen by the French National Research Agency (ANR) as part of the Investments for the Future program (PIA) under grant agreement No. ANR-21-RHUS-0002.