Periodic Reporting for period 3 - ONCOBIOME (Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response.)
Période du rapport: 2022-01-01 au 2022-12-31
Beyond its role in regulating multiple physiological functions that impact health, the intestinal metagenome is implicated in cancer initiation, progression and responses to therapies, even for extraintestinal neoplasia. Hence, there is an urgent need to fully identify and functionally characterize minimalist commensal ecosystems relevant to cancer, with reliable and robust methods, to validate cancer-associated gut microbiome fingerprints of high clinical relevance, and to develop diagnosis tools that will become part of the oncological arsenal for the optimization and personalization of therapy. Based on retro-and pro-spective studies, with large discovery and validation cohorts enrolling >5,000 cancer patients across 10 countries, ancillary to ongoing innovative clinical trials or FDA/EMA approvals across 4 frequent cancer types, ONCOBIOME will pursue the following aims: 1/ identify and validate core or cancer-specific Gut OncoMicrobiome Signatures (GOMS) associated with cancer occurrence, prognosis, response to, or progression on, therapy (polychemotherapy, immune checkpoint inhibitors, dendritic cell vaccines) or adverse effects, 2/ decipher the functional relevance of these cancer-associated gut commensal ecosystems in the regulation of host metabolism, immunity and oncogenesis, 3/ integrate these GOMS with other oncology hallmarks (clinics, genomics, immunomics, metabolomics), 4/ design optimal companion tests, based on those integrated signatures to predict cancer occurrence and progression. With high carat interdisciplinary experts, ONCOBIOME expects to validate cancer or therapy-specific Gut OncoMicrobiome Signatures (GOMS) across breast, colorectal, melanoma and lung cancers adjusting for covariates, to unravel the mode of action of these GOMS in innovative platforms, thus lending support to the design of cancer preventive campaigns using well characterized pre-and pro-biotics.
The consortium has made significant progress during this third period, beyond expectations. In total so far, the consortium enrolled more than 3,500 cancer patients and sequenced (by shotgun metagenomic sequencing) about 2,600 fecal specimen to comprehensively define the taxonomic composition of the intestinal ecosystem of cancer patients, across 4 histological types and 8 european and canadian countries. Moreover, the Karolinska Institute and Radboudumc epidemiologists extracted about 5,398 specimen from national registries for cases for whom prior stool storage for prophylactic and preventive detection of colon cancers were available to address the question of dysbiosis preceding cancer incidence. Overall, UNITN and KI already performed the metagenomic sequencing and analysis of 10,569 fecal samples (about 4,500 sequenced under P3, compared to 6,000 under P1-P2). The partners prepared a Data Sharing Agreement (currently being signed by all parties) as the fundamental base to practically centralise the whole consortium clinical and metagenomics data within the web iCloud (CO-DB System). A one-day event, dedicated to the patients and general public, has been organized with patient representatives during P3. Gathering 350 participants it aimed to diffuse the results of the ONCOBIOME project and raise awareness among the general public. The Consortium has already published >200 peer-reviewed papers, including in top level journals (Science, Nature Medicine, Cell, etc.). Eleven publications directly acknowledging ONCOBIOME were issued during P3.
Original scientific progress and research advances have been unarguably obtained through this consortium. The first Gut Oncomicrobiome Signature (GOMS) for lung cancer has been validated and reported in about 400 stage IV NSCLC 1L+2L by Dr Segata/Italy, Dr Routy/CHUM, Dr Zitvogel/France (Derosa et al. Nat Med, 2022) and filed as a new patent (with these 3 partners institutions as co-owners). The GOMS for early breast cancer pre-and post-chemotherapy have been discovered and a dedicated paper has been accepted with all BC ONCOBIOMERs (Terrisse et al. Cell Death & Differ 2021). The GOMS associated with colon cancer progression have been better characterized across two geographically distant institutions (Dr Segata/Italy, and Dr Budinska/Czech Republic). GOMS associated with responses and toxicity to PD1 blockade in metastatic melanoma has also been characterized (Lee et al. Nat Med 2022). Pan-cancer GOMS have been described and reported (Dr Zitvogel/France, Dr Segata/Italy, Yonekura et al. Cancer Discov 2022). This consortium has also analysed the consequences of prebiotics and specific diets on the taxonomic changes assessed by miRNA profiling and shotgun metagenomics analysis (Messaoudene et al. Cancer Discov 2022). The metabolomics platform has accomplished some significant advances by identifying distinct metabolites associated with long term responders of preclinical significance. Both biotech companies have developed or extended the indications of their prototypes such as the immunoscore for HalioDX and Akkermansia for everImmune. Exploitation of metagenomics species led everImmune Biotech Cie to complete a serie A fund raising, and succeed in the manufacturing of a master batch of Oncobax® AK that allowed to launch a Phase I/II trial in August 2022.