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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BioMedBC (Molecular profiling of Bladder Cancer to support personalized medicine)

Teaser

Summary

Clinical Problem/ Disease burden
Bladder Cancer (BC) is the 4th most common cancer type in men and the 11th in women. It is characterized by the highest recurrence rate and is the costliest cancer type to manage. The majority of BC (~70%) are classified as Non Muscle Invasive (stages Ta,T1, Tis) and are treated by transurethral resection and BCG intravesical immunotherapy; whereas ~30% are Muscle Invasive (stages T2-4) and treated by radical cystectomy, (neo)adjuvant chemotherapy or (chemo)radiotherapy. Apart from cisplatin-based chemotherapy and cystectomy, recently introduced immunotherapy that targets PD-L1 molecule is recommended. Still the majority of BC patients do not respond to the current treatment.

Clinical Challenges â€“ Societal Impact
Unraveling the molecular background of BC is important for the establishment of earlier therapeutic interventions. Moreover, accurate biomarkers (BM) for patient stratification are needed to guide intervention. BioMedBC Project focused on improving our understanding of BC at the molecular level and in deciphering molecular key elements implicated in disease outcome, in order to address the challenge of stratifying BC patients for their risk of progression and investigate novel drug targets based on the molecular pathology. This has a double impact, as patients can benefit from an earlier intervention, but also in drug development as patient stratification to those more likely to develop progressive disease or respond to therapy, is beneficial for selecting the most appropriate treatment.

BioMedBC overall objectives
BioMedBC focused on the identification of prognostic biomarkers based on molecular profiles for patient stratification and in order to assist appropriate treatment selection towards BC personalized medicine. This aim was formulated according to the following objectives:
1. The molecular characterization of BC, through cross-omics correlation of tissue and urinary proteomics datasets combined with publicly available transcriptomics data,
2. The delivery of predictive algorithms/ biomarkers, associated with disease outcome (prognostic value) and
3.The integration of data via bioinformatics tools to reveal molecular pathways and potential drug targets.

Conclusions of the action
BioMedBC project was completed according to the proposed plan in Annex I, without major deviations. The main achievements within the Project were:
1. The successful integration of the MSCA-IF Fellow
2. The close interaction between the MSCA-IF Fellow and the Supervisor, including a full training of the MSCA-IF Fellow
3. The development of prognostic biomarkers to stratify patients for the disease progression, focusing on urine as a desired context of use
4. The characterisation of the molecular pathology of BC and introduction of molecularly driven drug targets
Altogether, BioMedBC Project resulted in the development of two sets of predictive biomarkers for patientsâ€™ stratification and response to treatment. Moreover, potential therapeutic approaches were introduced through Connectivity Map Analysis (CMap). The results were disseminated through several publications in scientific journals and also presented by the MSCA-IF fellow in international conferences (among others the 68th Lindau Nobel Laurette Meeting and the Benelux Precision Medicine Forum). Furthermore, the MSCA-IF fellow was trained in supervising and project management through the interaction with fellows from other EU projects, while in the context of BioMedBC project, the MSCA fellow co-edited a Special Issue in Proteomics Clinical Application.

Work performed

BioMedBC pipeline included the integration of existing and newly acquired high resolution -omics datasets by machine learning algorithms and systems biology approaches.

Within WP1, the prognostic potential of urinary biomarkers based on Capillary Electrophoresis coupled to Mass Spectrometry (CE-MS) was investigated. 36 peptides were identified with a significant correlation with BC relapse (hazard ratio (HR) of 5.76 (CI 95%, 2.35-14.12), p-value = 0.0001). Among the significant urinary peptides were collagen alpha-1 fragments, fibrinogen, polymeric immunoglobulin receptor, nebulin, forkhead box protein D2 and CD99 antigen.

As part of WP2, tissue proteomics datasets were acquired from 45 BC patients (during MSCA-IF Fellow\'s secondment). Combination with existing high throughput proteomics and transcriptomics data was followed to perform pathway analysis and identify molecular pathways associated to disease outcome. 444 genes and 500 proteins were found consistently deregulated across BC stages in the omics datasets. 293 common features were identified and were considered for pathway analysis. 46 significant pathways were obtained using Reactome. 20 of the identified pathways, including Interferon, Interleukin-12, FGFR1 and P53 signalling, were previously investigated in BC and 17 others were related to cancer in general.

Within WP3, validation of the prognostic value of the previous results was performed. CE-MS analysis was performed in 710 newly acquired urine samples, confirming the positive corelation of the biomarkers with BC relapse (HR of 2.57; 1.10-6.02; 95% CI). Further validation was performed considering the tissue proteomics datasets (WP2) and publicly available gene expression data from TCGA. Additional analysis using CMap based on the high-resolution proteomics data revealed 14 drugs, predicted to reverse the BC phenotype, that are to be further explored for their clinical significance.

Exploitation and Dissemination
BioMedBC also focused on dissemination and training activities (WP4). Dissemination, among others, was achieved through publication of 6 articles in scientific journals, participation in international meetings, an oral presentation in a MSCA fellow meeting, launch of BioMedBC website and an interview for H2020 magazin. Moreover, the MSCA- IF fellow edited a Special Issue in Proteomics Clinical Applications Journal, highlighting the value of clinical implementation of proteomics in the era of personalised medicine. Training included mentoring and ethical courses, and active interaction with H2020 MSCA-ITN Fellows and INNOSUP research Associates.
The exploitation of BioMedBC results was achieved as part of the translation of existing scientific knowledge into potentially clinically meaningful biomarkers. In the context of the clinical trials in the field of BC, we have communicated the BioMedBC biomarkers, as stratification/companion tools to pharmaceutical industry. Relevant flyers were also produced to inform BC patients on the prognostic markers and their clinical potiential.

Final results

High-resolution proteomics data from tissue and urine enabled the identification of protein changes in pathological conditions and when combined with extensive literature data can target the disease associated molecular pathways. As such, BioMedBC Project, built a foundation for the identification of biology-driven therapeutic targets, with high economic and societal impact.

Towards the clinical implementation of the BioMedBC results, the impact is directed according to the three following proposed applications:
a) patientsâ€™ stratification for their risk to progress and thus guide intervention
b) patient stratification to assist drug development pipeline and
c) novel molecularly driven therapeutic targets, with higher efficacy rate and lower side effects.