Novel therapeutic approaches, based on drug repurposing, for high risk non muscle invasive bladder cancer driven by patients’ proteomic signatures

Project Information

ReDrugBC

Grant agreement ID: 898260

DOI

10.3030/898260

Project closed

EC signature date 26 March 2020

Start date 1 June 2020

End date 31 May 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 162 806,40

EU contribution

€ 162 806,40

Coordinated by

MOSAIQUES DIAGNOSTICS GMBH
Germany

Periodic Reporting for period 1 - ReDrugBC (Novel therapeutic approaches, based on drug repurposing, for high risk non muscle invasive bladder cancer driven by patients’ proteomic signatures)

Reporting period: 2020-06-01 to 2022-05-31

Summary of the context and overall objectives of the project

The main problem that ReDrugBC is attempting to tackle is the therapeutic challenges at earlier stages of bladder cancer (BC). Despite the recent progress in diagnosis and management, BC remains among the most prevalent cancers worldwide and one of the most costly malignancies to treat on a per-patient basis. For patients with Non-Muscle Invasive BC (NMIBC; accounting for 70% of new BC cases) the standard of care is transurethral resection of the bladder tumor followed by adjuvant intravesical treatment regimens. For Muscle Invasive BC (MIBC; represents the remaining 30% of the BC cases), cisplatin-based chemotherapy followed by radical cystectomy is the gold standard for treatment. Despite recent progress in the treatment of advanced BC through the application of immune checkpoint inhibitors, management especially of high risk NMIBC is clearly suboptimal and to a large extent empirical. Better management, especially at this relatively earlier disease phase, can be of significant added value via impeding disease progression to more advanced, lethal and costly phases.

ReDrugBC project has both strong societal and economic impact. ReDrugBC Project introduces the concept of drug repurposing in BC, a concept not previously explored for this disease. Drug repurposing is a cost-effective strategy that targets the re-use of existing de-risked drugs for new therapeutic purposes by combining machine-learning computational methods with large-scale patients’ multi-omics data. The suggested pipeline in ReDrugBC could open new avenues towards effective BC treatment, especially at earlier stages of the disease that may accelerate clinical trials and open new avenues towards personalized therapy for BC.

In order to best address the current needs for improved BC treatment options, ReDrugBC aims at the identification of novel drug candidates that have the potential of reversing BC aggressiveness using the molecular signatures of the patients. This objective is expected to be achieved through the following three specific tasks:
1) Drug identification (via drug repurposing) based on the tissue molecular profile (available proteomics integrated with information on the transcriptome level) of patients with BC.
2) Evaluation of the impact of candidate drugs in vitro in BC cell lines.
3) Characterization of the proteomic profile of cell lines for the presence of the drug response signature and the molecular impact of the administered compounds.

Conclusions: ReDrugBC unveiled promising drug candidates that have the potential to reverse BC aggressiveness. The research and training activities boosted the IF fellow career in the industrial sector.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To develop the drug repurposing pipeline for BC, we initially focused on the proteomic signature characterizing aggressive NMIBC based on our previously published high-resolution tissue proteomics analyses. This signature was utilized as input data in the CMap tool (https://clue.io/) for data-driven drug repurposing. From the CMap analysis six compounds were initially predicted as most prominent to reverse the high-risk non-muscle invasive molecular signature according to their high relative connectivity scores. These included the mTOR inhibitors WYE-354, PP-30 and AZD-8055, the tubulin inhibitor NPI-2358, the PKC activator phorbol-12-myristate-13-acetate (PMA), and the caspase activator PAC-1. WYE-354, PP-30, and AZD-8055 were also retrieved when considering in the CMap analysis features with concordant expression patterns at the proteome and transcriptome level of aggressive NMIBC but also proteomic changes of MIBC (based on our previously published data). Among them WYE-354 was prioritized due to its novelty in the context of BC, its availability as well as the high connectivity scores for reversing both MIBC and aggressive phenotype of NMIBC to early NMIBC.

To establish the drug repurposing pipeline, the impact of WYE-354 was further checked on the tumorigenic properties of BC cell lines representing different stages during disease progression. WYE-354 significantly reduced the proliferation rate of the BC cell lines and impaired their colony forming ability by decreasing the size but not the number of the colonies. No significant impact on apoptosis or necrosis was observed demonstrating the absence of non-specific toxic effects of the inhibitor in the cells. Overall, the in vitro results supported the successful establishment of the drug repurposing pipeline.

To better characterize BC aggressiveness we have also extended the molecular analysis to include also differences observed between NMIBC and MIBC. To this end, different -omic signatures were created and investigated through our established pipeline using tissue proteomics, transcriptomics and omics data retrieved from the literature, but also proteomics and transcriptomics data from BC cell lines. CMap analyses using as input these molecular BC signatures resulted in 23 compounds that may have the potential to reverse the disease signature. Thirteen out of the 23 compounds were not previously evaluated in the context of BC. Three of the 13 compounds demonstrated a prominent impact on cell growth at relatively low concentrations. Additional functional experiments as well as the characterization of the proteomic profile of BC cell lines treated with the three most prominent compounds to unravel the drug response signature are currently ongoing.

Overall, ReDrugBC project resulted in the establishment of a drug repurposing pipeline for the identification of drugs that have the potential of reversing BC; a pipeline that can be further expanded to other cancer types. As part of the pipeline establishment, in vitro assessment of 1 compound was successfully completed. In addition 13 compounds with potential to reverse BC aggressiveness were identified and tested in vitro. Three of them are currently already under evaluation in preclinical animal models. Through the successful implementation of the work planned within ReDrugBC, two research articles and one opinion letter have been already published and additional manuscripts are in preparation. Furthermore, the MSCA-IF Fellow received an invitation to contribute a book chapter describing the developed pipeline within ReDrugBC. The Project results were also presented in international conferences and web-seminars. A website for the project was also launched (https://www.ReDrugBC.eu). In parallel to the scientific activities, the MSCA-IF Fellow received an extensive inter-sectorial training that strengthened her skills and supported her career development and independence as a researcher in the industrial setting.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Moving beyond the state of the art, ReDrugBC introduced the concept of drug repurposing in BC, a concept not previously explored for this disease that may accelerate clinical trials and open new avenues towards personalized therapy of BC. Through an integrated multi-layer approach that included cross-omics analyses as well as drug screening in BC cell lines, ReDrugBC unveiled promising drug candidates that have potential as BC drugs with reduced side effects. Overall, the integrated multi-omics data from the BC tissues and the BC cell lines provided a good resource for better understanding of the pathophysiology of BC at the molecular level. The developed pipeline can be further implemented for the identification of drugs that have increased chances of achieving better response from the patients.

Overview of ReDrugBC Approach