Targeting Cancer-Associated Fibroblasts to tackle metastases and resistance to treatment in Triple Negative Breast Cancer.
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 Fatima Mechta-Grigoriou, head of the “Stress and Cancer” team within the U830 unit "Cancer, heterogeneity, instability and plasticity" at the Institut Curie Research Center. The CASSIOPEIA project started on September 1st, 2022. The consortium of this collaborative project is composed of Institut Curie, Roche and Institut Roche.
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.
To improve diagnosis, prognosis and treatment 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 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:
- an earlier detection and mapping of TNBC metastases
- a better prediction of efficacy and resistance to immunotherapy
- 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 Fatima 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
► 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 (CUPCAKE, promotor Institut Curie, Pr. François-Clément Bidard) will be launched in Q2 2023 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) and the analysis of circulating tumor DNA (ctDNA, Collab. Roche).
Indeed, the novel FAPI radiotracer, which aims to complement the currently used FDG tracer, will be used to map metastatic lesions revealed by circulating tumor DNA, which will be monitored to detect molecular relapse at early stages of the disease. The combined FAPI PET/CT and ctDNA monitoring 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 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) will be launched in Q2 2023 to propose a novel immunotherapy treatment to early and metastatic TNBC patients, consisting in chemotherapy associated to atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) (Collab. Roche).
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, 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 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 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 ANTRX1. CASSIOPEIA will deliver first-in-man trial results for the therapeutic agent targeting ANTRX1, as well as its companion agent (labelled-anti-ANTXR1 antibody) for PET/CT imaging (Collab Franck Perez). This will offer a new therapeutic option to those patients identified as resistant to immunotherapy.
The Work Packages of CASSIOPEIA
Dissemination activities, training and teaching programs will be established to promote project results and maximize expected socio-economic impacts. Different aspects of CASSIOPEIA have already been introduced during the 5th edition of the International Course on Breast Cancers: from biology to clinics, organized in October 2022 at Institut Curie Paris (Collab. Anne Vincent-Salomon, with the help of the Training Unit of Institut Curie).
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 Anastasia Lanzi, project manager.
- CASSIOPEIA Kick-off meeting. June 28, 2022. Hold at Institut Curie, Paris in presence of Roche, Institut Roche and ANR.
- 5th edition of the International Course on Breast Cancers: from biology to clinics. October 3-7, 2022. Hold at Institut Curie, Paris.
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.