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Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response.

Periodic Reporting for period 1 - ONCOBIOME (Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response.)

Reporting period: 2019-01-01 to 2020-06-30

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.
Deep cohorts (essential resources for ONCOBIOME) have been or are being gathered. In non-small cell lung cancers, French and Canadian partners have now included 397 patients in first or second line therapy with immune checkpoint inhibitors, and collected 595 stools at diagnosis or during therapy. In colon cancers, Czech, Italian and French partners have now included 851 patients at diagnosis, and collected 1048 stools. In breast cancers, German, UK clinicians included 108 patients in neoadjuvant and triple negative breast cancers while the French team started to analyze the results of the first 129 metagenomic samples of early RH+ breast tumors. Radboudumc and Erlangen hospitals enrolled 164 stage III or stage IV melanoma in dendritic cell-based therapy for which they could collect serum/plasma and stool samples that we already processed and analyzed for metagenomics and humoral immune responses against commensals. Moreover, the Karolinska Institute lined up with the Radboudumc epidemiologists to gather and register all cancer 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 already performed the metagenomic sequencing of more than 900 fecal samples and the analysis of more than 1600 fecal samples (including retrospective analysis). The Swedish partners set up the data management files and web iCloud (CO-DB System) for the centralization of the whole consortium clinical and metagenomics data.
Dissemination through ethic and patient representatives (Pr François Eisinger, independant ONCOBIOME's ethical advisor, Olivier Lecomte, Professor at Centrale Supélec and Gilliosa Spurrier, President of MélanomaFrance) and publications facilitated the integration of 9 additional cohorts (abiding by our internal rules and guidelines) that were not initially anticipated; but will accelerate significantly deep biobanking. The Consortium has already published >120 peer-reviewed papers, among which >10 in top level journals (Science, Nature Medicine, Cell, etc.). A web site (https://www.oncobiome.eu/) and communication plan have been created and heralded while a scientific advisory board (SAB) has been set up, including experts from USA (Dr Zoltan Szallazi, President of the SAB), and high dimensional metagenomics (Dr Zeller, Dr Patrice Cani among others) and pharma representatives (Dr Ariel Savina). Two important events already occurred, the ONCOBIOME Kick-off meeting in February 2019 in Paris and the 1st General Assembly in January 2020 in Torino. All the due Deliverables expected during this 1st period have been submitted on time (such as the Epidemiological study, ONCOBIOME Protocols for DNA extraction and Metagenomics analysis, the Standardisation of Data, the Ethics requirements for each cohort, setting up Management tools and Governing bodies).
Original scientific progress and research advances will be soon heralded. The first Gut Oncomicrobiome Signature (GOMS) is being validated on about 400 stage IV non-small cell lung cancers (NSCLC) first and second lines (Dr Segata, Dr Routy, Dr Zitvogel) and will be delivered as a manuscript to be submitted to Cell or Cancer Cell and filed as a new patent under preparation (with 3 partners institutions as co-owners). The GOMS for early breast cancer (BC) have also been discovered and a dedicated paper is currently being written with all BC Oncobiomers and will be submitted as an original manuscript before the fall 2020. ONCOBIOME has also developed new diagnosis tools such as 1/ the monitoring of humoral immune responses against intestinal microbes (IgG titers specific of distinct bacteria in serum) and their correlations with metagenomics detection of the same species in the feces, 2/ Metabolomics profiling in elite patients versus hyperprogressors is being studied in melanoma (Erlangen cohorts using INSERM platform), 3/ Culturomics analyses is developed in elite patients versus hyperprogressors bearing a NSCLC with preliminary interesting results.
Both biotech companies have developed or extended the indications of their prototypes such as the immunoscore for HalioDX and A. muciniphila anticancer probiotics for everImmune.