SIRIC2018 midterm review: encouraging first results with new patient perspectives
Research results with potential clinical applications
Breast cancers
New prognostic biomarkers associated with TRegs (Núñez et al. Nat Commun 2020) and with fibroblasts involved in metastatic propagation and immunotherapy resistance (Bonneau et al. Breast Cancer Res 2020; Kieffer et al. Cancer Discov 2020) were brought to light by the teams of Eliane Piaggio and Fatima Mechta-Grigoriou respectively. This research, analyzing fresh tissue at the single cell level, was carried out in close collaboration with the pathology and surgery teams from the Hospital Group.
The MONDRIAN clinical trial protocol has been finalized and should start shortly. In the frame of this study, François-Clément Bidard’s team are evaluating the efficiency of circulating tumor DNA as an early relapse detection tool and as a way to steer treatment in metastatic triple negative breast cancers.
Research by Elisabetta Marangoni’s group on PDXs established from resistant tumors has identified new therapeutic options:
→ For triple negative cancers
- PI3K and MEK inhibitors for metaplastic cancers presenting a PIK3CA, AKT1, BRAF and FGFR4 mutations
(Coussy et al. J Hem Oncol 2020) - TOP1 inhibitors and Irinotecan in BRCAness tumors with an elevated expression of SLFN11 and RB1 loss
(Coussy et al. Sci Trans Med 2020) - mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancers with PIK3CA and AKT1 mutations
(Coussy et al. Theranostics 2020),
→ For metastatic resistant HR+ cancers :
- PLK1 inhibitors
(Montaudon et al. Nat Commun 2020)
Pediatric cancers
The work of Gudrun Schleiermacher’s team on ALK alterations in neuroblastoma led to the integration of Lorlatinib (ALK inhibitor) as a first-line treatment in the international HR NBL2 study on high-risk neuroblastoma.
In Ewing sarcoma,drug repositioning studies carried out by Olivier Delattre’s team permitted the identification of new therapeutic pathways for this disease.
Likewise, promising clinical approaches were highlighted with the discovery of ERBB4/SRC activation in a medulloblastoma sub-group (Forget et al. Cancer Cell 2018). Celio Pouponnot’s team showed the importance of two transcription factors specific to NRL and CRX photoreceptors in an aggressive medulloblastoma sub-group which led them to identify the anti-apoptic protein BCLXL as a therapeutic target for these cancers (Garancher et al. Cancer Cell 2018).
In rhabdoid tumors, the results of Franck Bourdeaut’s group in collaboration with Eliane Piaggio and Joshua Waterfall’s SIRIC teams generated international interest for the establishment of protocols based on immunotherapy, epidrug and kinase inhibitor combinations. (Leruste et al. Cancer Cell 2019).
Uveal melanoma
Marc-Henri Stern’s team identified MDB4 as a predisposing gene for uveal melanoma (Derrien et al. J Natl Cancer Inst. 2021) and showed that the hypermutated phenotype linked to MBD4 could explain unexpected responses to immune checkpoints in uveal melanoma but also in other tumors.
A study by Samar Alsafadi’s group demonstrated the interest of a Bcl-2/XL/W and MDM2 co-inhibition in uveal melanoma (Decaudin et al. Eur J Cancer 2020).
Identification of specific mutated SF3B1 tumor neo-epitopes paves the way for new immunotherapy approaches.
New radiotherapy approaches with Yolanda Prezado's team
SIRIC has been recruiting and supporting translational research teams since 2012.
The New Approaches in RAdiotherapy (NARA) team led by Yolanda Prezado joined Institut Curie as a SIRIC endorsed team in 2019.
Since their arrival, the team has made an improvement of the mini-beam generation technique (Schneider et al. Sci Rep. 2020) and carried out the first dose calculations for patient treatment (Lansonneur et al. Sci Rep. 2020). In collaboration with Gilles Créhange, the team is currently putting in place a phase I trial on the evaluation of mini-beams as a treatment of cerebral metastases.
Human and social sciences
2 studies are underway in the human and social sciences domain: the 1st, led by Anne Brédart and Sylvie Dolbeault, aims to improve communication between doctors and patients in the frame of the metastatic disease (HECTOR, Help to Communication when Treatment resistance OccuRs). This study encompasses the 3 SIRIC pathologies. The 2nd study, coordinated by Sophie Piperno-Neumann, studies early integration of palliative care alongside medical treatment of metastasis in uveal melanoma (Early Together). Recruitment has started in both studies.
Health democracy group actions
The development of health democracy has been of the SIRICs’ missions since 2017. If the concept is now widely spread in the context of healthcare, its application in a research context such as within the SIRIC project is still limited. In the first phase of the SIRIC, the health democracy workgroup, which unites researchers, clinicians and people who are or have been confronted with the disease, committed themselves to developing concrete actions: co-construction of research projects, proofreading of protocols, patient days…
Results of the OSIRIS group for clinical and biological data interoperability
SIRIC Curie has been strongly involved in the national OSIRIS consortium since 2013. After multiple years of collaborative work, the group is proposing a new standard for the interoperability of clinical and biological data in oncology (Guérin et al. JCO Clinical Cancer Informatics 2021). This work is cause for hope for improving data sharing and accelerating research that benefits patients.
Perspectives
After 2.5 years our SIRIC was evaluated at the end of 2020 by INCA’s international committee of experts including patient representatives and INCa’s partners (DGOS and Inserm). The feedback from the evaluation committee is very encouraging and commits us to continuing the program.
SIRIC Curie will stay the course in the coming years by focusing, in particular, on the transfer to the clinic of scientific results from the 1st phase.
We will maintain our support of programs and technological platforms (CRISPR’it, Single Cell, LIP, BioPhenICs, PATHEX). We will also renew our internal call for projects to support the emergence of new translational research projects.
