RHU CASSIOPEIA

The CASSIOPEIA project has been selected by the French National Agency for Research (ANR) within the framework of the "Investments for the Future" programs (5th call of the Hospital-University Research – RHU program). The project CASSIOPEIA 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, head of the “Stress and Cancer” laboratory at Institut Curie. The CASSIOPEIA project started on September 1^st, 2022. The consortium of this collaborative project is composed of Institut Curie, Institut of Molecular chemistry of Bourgogne University (ICMUB), Roche and Institut Roche.

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 and three quarters of them do not respond to treatment. 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 i) a better prediction of efficacy and resistance to treatment, ii) an earlier detection and mapping of TNBC metastases and iii) 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. In particular, 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:

• 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 safety period of 2 cycles has been observed for both patient cohorts and showed no dose-limiting toxicity, allowing us to pursue patient recruitments. A total of 160 TNBC patients will be recruited in the SKYLINE clinical trial in the next 2 years. By combining multi-omics profiling of the clinically annotated tumor samples, radiomics analysis of the FDG and FAPI PET/CT images, and clinical data with machine learning approaches (Collab. Institut Roche, Dr. Magnus Fontes), we will define new features associated with early relapse, response and/or resistance to treatment that will in turn allow a better stratification of patients and at term impact both their treatment and clinical management.

• 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 2 clinical trial (SKYLINE, promotor Institut Curie, Pr. François-Clément Bidard) has been launched in Q1 2024 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). Indeed, the FAPI radiotracer, which is used for the first time in France, aims to complement the currently used FDG radiotracer, to precisely map primary tumors and metastatic lesions. The combined FAPI and FDG PET/CT should drastically improve the surveillance of high risk TNBC patients, by reducing the rate of relapse with altered general condition, thus allowing more efficient therapies.

• To identify new biomarkers and potential novel drug targets

By analyzing 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.

• 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.

Les Work Packages du projet CASSIOPEIA

Dissemination activities, training and teaching programs are established to promote project results and maximize expected socio-economic impacts. Different aspects of CASSIOPEIA have already been introduced during the several International Courses at Institut Curie, Paris (with the help of the training unit): 5^th edition (October 2024) and 6^th edition (October 2024) of Breast Cancers: from biology to clinics (Collab. Anne Vincent-Salomon) and the 3^rd edition of the Radiomics theory and practice course (Collab. Irène Buvat).  

The Project Management Board is composed of Fatima Mechta-Grigoriou, coordinator of the project, François-Clément Bidard, PU-PH medical oncologist responsible of the clinical trials, and Agathe Peltier, 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.

• 6^th edition of the International Course on Breast Cancers: from biology to clinics. October 14-18, 2024. Hold at Institut Curie, Paris. It is still time to register!

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.