ReDrugBC
Novel therapeutic approaches, based on drug repurposing, for high risk non muscle invasive bladder cancer driven by patients’ proteomic signatures
ReDrugBC is a EU-funded project (H2020-MSCA-IF-2019, ReDrugBC, Grant agreement ID: 898260) aiming to tackle high-risk non-muscle invasive bladder cancer (NMIBC) via drug repurposing. Considering the high heterogeneity observed in bladder cancer and the suboptimal therapeutic strategies, ReDrugBC paves the way for better treatment of NMIBC via drug selection based on the patient molecular signatures. As such, in the context of ReDrugBC project, high-resolution proteomics data of NMIBC tissue specimens will be analyzed in an integrative manner with existing knowledge at the transcriptome level with drug repurposing tools, followed by in vitro screening of selected candidates. This is expected to provide the required groundwork for further in vivo pre-clinical testing in future studies. The suggested pipeline in ReDrugBC could open new avenues towards effective BC treatment, especially at the earlier stages of the disease, using existing compounds- thus accelerating the pipeline to implementation.
Introduction
Bladder cancer (BC) ranks 10th in incidence worldwide, with ~549,000 new cases and 200,000 deaths reported in 2018 (1). BC management includes surgery, radiotherapy and systemic therapies, thus being the costliest cancer type to manage, accounting for 5% of the total cancer health expenditure (2).
Therefore, delivering better care for BC patients has both strong societal and economic impact. The majority of BC cases (~70%) are classified as Non Muscle Invasive (NMIBC, stages Ta,T1, Tis) and are treated by transurethral resection and Bacillus Calmette-Guerin (BCG) intravesical immunotherapy (3); whereas ~30% are Muscle Invasive (MIBC, stages T2-4) and are treated by radical cystectomy, (neo)adjuvant chemotherapy or (chemo)radiotherapy (4).
Additionally, patients suffering from NMIBC have a high probability of disease recurrence (31 to 78%) and progression (0.8% to 45%) within five years’ time (5), while ~40% of the NMIBC patients do not fully respond to BCG treatment and progress to MIBC, thus increasing the pool of patients who require more intensive therapy (6).
Muscle invasion and metastasis result in poor prognosis, with reported 5-year survival rates to be between 46-63% for MIBC and decreasing to 15% for metastasized cancer cases. Besides cisplatin-based chemotherapy and cystectomy, recently introduced immune checkpoint inhibitors, targeting the Programmed cell Death (PD)- 1 receptor and its ligand PD-L1, have become an additional standard treatment of patients with locally advanced or metastatic BC (7). Even though these agents are still being evaluated in clinical trials, a clear consensus exists. The vast disease heterogeneity necessitates better patient stratification to provide optimal, personalized treatment (8).
Drug repurposing is increasingly becoming an attractive proposition in pharmacology (9), since it involves the use of known de-risked drugs, thus significantly reduces the development costs and shortens timelines of new treatment invention (10).
Through the application of modern data-driven computational techniques, systemic analysis of gene expression data, chemical structure, genotype or proteomic data or patients’ individual electronic health records, can lead to the formulation of repurposing hypotheses (10). Such a pipeline could be particularly beneficial for patients with cancer, frequently requiring prompt and personalized treatments (11).
State-of-the-Art
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. With proteins being directly linked to cell function, proteomic signatures are sources of druggable targets and predictive markers, not adequately explored yet. Identification of new therapeutic approaches, based on patient proteomic profiles, for the management of high-risk NMIBC, is clearly missing in the field.
In the context of the ReDrugBC project, recently collected high-resolution proteomics data of 120 NMIBC tissue specimens will be analyzed in an integrative manner with existing knowledge from other molecular levels with drug repurposing tools, followed by in vitro screening of selected candidates with the scope to highlight novel biology-driven therapeutic schemes and provide the required groundwork for further in vivo pre-clinical testing in future studies.
To the best of our knowledge, such a combinatorial approach has not been applied so far for drug repurposing in NMIBC. Following the proposed approach in ReDrugBC, using proteomics and bioinformatics approaches as well as functional experimental analysis of such data, with a clear focus on drug response based on molecular signatures, an attempt to tackle therapeutic challenges at early stages of BC will be made.
Background
Building on existing knowledge
ReDrugBC builds and expands on our previous results within which tissue proteomics data were acquired from patients with bladder cancer, and revealed a continuum of conserved expression changes from less to more aggressive NMIBC and eventually MIBC (12). These changes at the protein level enabled the stratification of the NMIBC patients into three groups with NPS1 representing high-stage/-grade/-risk cancers and NPS3 mostly low-stage/-grade/-risk cancers (12). Many of the observed changes at the proteome level also overlapped with respective changes at the transcriptome level in part from the same but also published NMIBC datasets from progressors in comparison to non progressors NMIBC (12).
To identify new therapeutic schemes for the treatment of high-risk disease, in the context of ReDrugBC, this molecular signature will be used to identify therapeutic agents that are able to reverse aggressive bladder cancer in silico, hence hopefully exhibiting therapeutic potential.
Specific Objectives
The main goal of the ReDrugBC proposal is the identification of novel drug candidates for high-risk NMIBC using the molecular signatures of the patients. This objective is expected to be achieved through the following three specific aims:
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 compound.
2022©
ReDrugBC is a Marie Sklodowska Curie Actions (MSCA) Individual Fellowship programme funded by the European Commission (H2020-MSCA-IF-2019, Grant agreement ID: 898260).