The research projects that I develop with my team have focused on deciphering the biological response to radiotherapy. Our collective goal is to find innovative tools - pharmacological or technological - able to protect normal tissue and enhance tumor control.
FLASH radiotherapy, a novel radiotherapy modality at ultra high dose rate
My group has been the first to develop FLASH-Radiotherapy, a novel modality of radiation therapy at ultra high dose rate that minimizes normal tissue toxicity but eradicates tumors. We named this impressive differential effect: the FLASH effect.Nowadays, the FLASH effect has the potential to revolutionize the field of radiation oncology and is investigated worldwide by various companies and academic institutions.
My group has been awarded two international research grants (Synergia/SNF and PO1/NIH) to investigate the mechanisms underlying the FLASH effect. These investigations are performed with a unique FLASH irradiator (5.5 MeV LINAC, eRT6) and require multidisciplinary team and approaches (to investigate physics, chemical, biological and clinical aspects) as well as various models of increasing complexity (water, liposome, plasmid, normal and tumor cells, zebrafish embryos, normal tissues and tumors in WT and Tg mouse, domestic cats, mini-pig). Our ultimate aim is to secure the translation of FLASH-RT into the clinic. At CHUV, a first human patient has been treated and two clinical trials will start in 2021.Collaborations with accelerator physicists at CERN and PSI are also ongoing to develop the FLASH machines to be used for patients' benefit in the near future.
Combination of radiotherapy and immunotherapy to improve treatment of lung and H&N cancer
This past decade immunotherapy has demonstrated impressive responses in some cancer patients. In addition, the ability of radiotherapy to stimulate both innate and adaptive immune cells' function has been shown to enhance the therapeutic benefit of immunotherapy in some cases. In the hope of generalizing the efficacy of radio-immunotherapy to all cancer paptients, we are developing preclinical strategies to better understand the modulation induced by irradiation on the microenvironment.
We mainly focused our investigation on radiation impact on innate immunity and found a role of interstitial macrophages in radiation-induced lung fibrogenesis. Next, using a lung adenocarcinoma model (KP), we demonstrated that modulation of neutrophil phenotype was able to enhance the tumor response to radiation therapy without any stimulation of fibrosis. Stimulation of dendritic cell activation was also able to promote a potent antitumor effect with 70% complete response and increased overall survival of mice implanted with an orthotopic head & neck tumor. Our next challenge will be to decipher the immunogenic impact of FLASH-RT.
Sex-specific differences in normal tissue toxicity induced by anti-cancer treatments
Neurocognitive and cardiac toxicity are severely impacting cancer survivors’ quality of life. Our past work suggested that a member of the small GTPase pathway, i.e. RhoB had a causative role in the development of these radiation-induced complications in various organs (including the heart, lung and gut). In parallel, growing evidence suggests that the long-term neurocognitive changes as well as cardiac toxicity induced by anti-cancer treatments might differ between the sexes in both human cancer patients and in rodent models. Interestingly our recent investigations identified a sex-based mechanisms dependant of RhoB and estrogen signaling in the systemic neurotoxicity induced by paclitaxel and in the cardiotoxicity induced by RT.
Central nervous system dysfunction after exposure to deep-space relevant doses of pions
The possibility of space travel to Mars is today being explored by Space agencies including NASA. Previous results showed some unexpected and potentially concerning effects of cosmic radiation exposure on the brain and investigating the impact of cosmic rays on cognitive function of animals is required to determine whether travel to Mars will be possible for Astronauts. In this project, we specifically investigate the impact of brain exposure to Pion irradiation taking advantage of the ONLY pion beam available worldwide at the Paul Scherrer Institute (PSI) in Villigen (CH).
The lab is developing a wide array of biological models.
- Cell culture: normal and tumors cells (murine and human)
- Alternative models:
- WT and Transgenic zebrafish embryos
- Brain organoids in col with UCI, Pr C Limoli
- Organ-on-chip in col with Arizona U, Pr F Zernhausern
- WT and transgenic mouse models to investigate in parallel normal tissue toxicity and tumor response: brain, skin, gut, hematopoietic system
Clinical trials with domestic animals (cats with spontaneous cancer), in col with Zurich Vet School, Pr C Rohrer.
- Labiano S, Roh V, Godfroid C, Hiou-Feige A, Romero J, Sum E, Rapp M, Boivin G, Wyss T, Simon C, Bourhis J, Umaña P, Trumpfheller C, Tolstonog GV, Vozenin MC, Romero P. CD40 Agonist Targeted to Fibroblast Activation Protein α Synergizes with Radiotherapy in Murine HPV-Positive Head and Neck Tumors. Clin Cancer Res. 2021 Apr 26. doi: 10.1158/1078-0432.CCR-20-4717. Online ahead of print.PMID: 33903200.
- Montay-Gruel P, Acharya MM, Gonçalves Jorge P, Petit B, Petridis IG, Fuchs P, Leavitt R, Petersson K, Gondré M, Ollivier J, Moeckli R, Bochud F, Bailat C, Bourhis J, Germond JF, Limoli CL, Vozenin MC. Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice. Clin Cancer Res. 2021 Feb 1;27(3):775-784. doi: 10.1158/1078-0432.CCR-20-0894. Epub 2020 Oct 15.PMID: 33060122
- G Boivin, P-B Ancey, R Vuillefroy de Silly, P Kalambaden, C Contat, B Petit, J Ollivier, J Bourhis, E Meylan and M-C Vozenin. Anti-Ly6G binding and trafficking mediates positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy.Oncoimmunology 2021
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