Tumor deconstruction as a tool for advanced drug screening and repositioning

High-grade serous ovarian carcinoma (HGSC) is associated with late-stage disease presentation and poor prognosis, with limited understanding of early transformation events. Our study presents a comprehensive analysis of tumor progression and organ-specific metastatic dissemination to identify hypoxia-associated molecular, cellular, and histological alterations during HGSC tumor growth. H&E staining and subsequent histological assessment of tumor volume-based categories revealed recapitulation of numerous clinical features, including the prevalence of >0.0625≤0.5cm3 volume tumors and metastatic spread by orthotopic xenografts. The constant evolution of the tissue architecture concerning increased hyaluronic acid deposition, tumor vasculature, necrosis, altered proliferative potential, and gland forming ability of the tumor cells was identified. Flow cytometry and label chase-based molecular profiling across the tumor regenerative hierarchy identified the hypoxia-vasculogenic niche and the hybrid epithelial-mesenchymal tumor-cell state as determinants of self-renewal capabilities of progenitors and cancer stem cells (CSCs). A regulatory network and mathematical model based on tumor histology and molecular signatures predicted hypoxia-inducible factor 1-alpha (HIF1A) as a central node connecting epithelial-mesenchymal transition, metabolic and necrotic pathways in HGSC tumors. Thus, our findings provide a temporal resolution of hypoxia-associated events that sculpt HGSC tumor growth, and an in-depth understanding of it may aid in the early detection and treatment of HGSC.

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Web-based Tools for Drug Repurposing: Successful Examples of Collaborative Research

Vanhaelen

2020

CMC

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: Computational approaches have been proven to be complementary tools of interest for identifying potential candidates for drug repurposing. However, although the methods developed so far offer interesting opportunities and could contribute to solve issues faced by the pharmaceutical sector, they also come with their own constraints. Indeed, specific challenges ranging from data access, standardization and integration to the implementation of reliable and coherent validation methods must be addressed to allow a systematic use at a larger scale. In this mini-review, we cover computational tools recently developed for addressing some of these challenges. This includes specific databases providing accessibility to large set of curated data with standardized annotations, web-based tools integrating flexible user interfaces to perform fast computational repurposing experiments and standardized datasets specifically annotated and balanced for validating new computational drug repurposing methods. Interestingly, these new databases combined to the increasing number of information about the outcomes of drug repurposing studies can be used to perform meta-analysis to identify key properties associated with successful drug repurposing cases. This information could further be used to design estimation methods to compute an a priori assessment of the repurposing possibilities.

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Tumor deconstruction as a tool for advanced drug screening and repositioning

Cited by 3 publications

References 61 publications

Design of efficient computational workflows for in silico drug repurposing

Design of efficient computational workflows for in silico drug repurposing

A Multistep Tumor Growth Model of High-Grade Serous Ovarian Carcinoma Identifies Hypoxia-Associated Signatures

Web-based Tools for Drug Repurposing: Successful Examples of Collaborative Research

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