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Unbiased discovery of cancer pathways and therapeutics using Pathway Ensemble Tool and Benchmark
Luopin Wang1,2, Aryamav Pattnaik2,3, Subhransu Sekhar Sahoo2,3
1Department of Computer Science, Purdue University, West Lafayette, IN, USA.
Abstract:
Correctly identifying perturbed biological pathways is a critical step in uncovering basic disease mechanisms and developing much-needed therapeutic strategies. However, whether current tools are optimal for unbiased discovery of relevant pathways remains unclear. Here, we create "Benchmark" to critically evaluate existing tools and find that most function sub-optimally. We thus develop the "Pathway Ensemble Tool" (PET), which outperforms existing methods. Deploying PET, we identify prognostic pathways across 12 cancer types. PET-identified prognostic pathways offer additional insights, with genes within these pathways serving as reliable biomarkers for clinical outcomes. Additionally, normalizing these pathways using drug repurposing strategies represents therapeutic opportunities. For example, the top predicted repurposed drug for bladder cancer, a CDK2/9 inhibitor, represses cell growth in vitro and in vivo. We anticipate that using Benchmark and PET for unbiased pathway discovery will offer additional insights into disease mechanisms across a spectrum of diseases, enabling biomarker discovery and therapeutic strategies.
Insights
This study introduces Benchmark and the Pathway Ensemble Tool (PET) to identify disease-related biological pathways. PET outperforms existing methods, aiding in biomarker discovery and therapeutic strategy development for various cancers.
Area of Science:
- Bioinformatics
- Computational Biology
- Systems Biology
Background:
- Identifying perturbed biological pathways is crucial for understanding disease mechanisms and developing therapies.
- Current tools for unbiased pathway discovery may not be optimal, necessitating critical evaluation.
Purpose of the Study:
- To critically evaluate existing pathway identification tools using a new benchmark.
- To develop an improved tool, the Pathway Ensemble Tool (PET), for unbiased pathway discovery.
- To identify prognostic pathways in cancer for biomarker and therapeutic development.
Main Methods:
- Development of 'Benchmark' for evaluating pathway identification tools.
- Creation of the 'Pathway Ensemble Tool' (PET) based on Benchmark findings.
- Application of PET to identify prognostic pathways across 12 cancer types.
Main Results:
- Existing pathway identification tools were found to be sub-optimal.
- PET demonstrated superior performance compared to existing methods.
- PET identified prognostic pathways in 12 cancer types, with associated genes serving as reliable biomarkers.
- Drug repurposing strategies targeting identified pathways showed therapeutic potential, exemplified by a CDK2/9 inhibitor for bladder cancer.
Conclusions:
- The Benchmark and PET provide a robust framework for unbiased biological pathway discovery.
- PET facilitates the identification of prognostic pathways, enabling biomarker discovery and the development of novel therapeutic strategies.
- This approach holds promise for advancing disease mechanism research and clinical applications across a range of diseases.
