Abstract
Simple SummaryCurrent therapies for bladder cancer present limitations as, regularly, not all patients benefit from treatment. Drug repurposing refers to the use of available drugs in new disease contexts. In this study, we identified drugs of potential to be repurposed, e.g., used in the treatment of aggressive bladder cancer. This was achieved by using earlier described molecular profiles (mRNAs, proteins) of tissue of patients with bladder cancer, matched to molecular profiles induced by drugs via mathematical tools. Through this process, multiple drugs potentially treating aggressive bladder cancer were predicted. Of these, an inhibitor of the mTOR molecular pathway was further investigated and found to significantly delay the growth of many bladder cancer cell lines. Collectively, this study provides a robust pipeline for drug repurposing based on tissue molecular profiles and highlights drug candidates meriting further experimental investigation in the treatment of aggressive bladder cancer.Multi-omics signatures of patients with bladder cancer (BC) can guide the identification of known de-risked therapeutic compounds through drug repurposing, an approach not extensively explored yet. In this study, we target drug repurposing in the context of BC, driven by tissue omics signatures. To identify compounds that can reverse aggressive high-risk Non-Muscle Invasive BC (NMIBC) to less aggressive low-risk molecular subtypes, the next generation Connectivity Map (CMap) was employed using as input previously published proteomics and transcriptomics respective signatures. Among the identified compounds, the ATP-competitive inhibitor of mTOR, WYE-354, showed a consistently very high score for reversing the aggressive BC molecular signatures. WYE-354 impact was assessed in a panel of eight multi-origin BC cell lines and included impaired colony growth and proliferation rate without any impact on apoptosis. Overall, with this study we introduce a promising pipeline for the repurposing of drugs for BC treatment, based on patients’ omics signatures.
Highlights
Bladder cancer (BC) is the 10th most common cancer worldwide [1] with Non-Muscle Invasive bladder cancer (BC) (NMIBC) accounting for approximately 70% of new BC cases and Muscle Invasive (MIBC) representing the remaining 30% [2]
We propose a drug repurposing approach driven by molecular signatures of patients with BC, using the Connectivity Map (CMap) resource, based on previously generated/published omics signatures
We report on a novel pipeline that can be applied for drug repurposing in BC using molecular signature-based computational approaches and patients’ omics data followed by in vitro evaluation of the compounds therapeutic potential in a panel of BC cell lines
Summary
Bladder cancer (BC) is the 10th most common cancer worldwide [1] with Non-Muscle Invasive BC (NMIBC) accounting for approximately 70% of new BC cases and Muscle Invasive (MIBC) representing the remaining 30% [2]. Based on clinicopathological characteristics stratification of NMIBC to subgroups of low-, intermediate- and high- risk for progression is applied [3]. For the former, the standard of care is transurethral resection of the bladder tumor (TURBT), whereas for intermediate- and high-risk NMIBCs, TURBT is followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy or chemotherapy for one to three years due to the substantial risk of recurrence and progression to MIBC [3]. Almost 40% of the NMIBC patients fail to respond to first-line BCG therapy [4] In these cases, radical cystectomy is recommended [3]. Within the last five years several immune checkpoint inhibitors have been assessed in the treatment of advanced urothelial carcinoma with five agents eventually receiving approval by the U.S Food and Drug
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