Biology subjects

Berges, R.

Publications and source records attributed to Berges, R..

3 recordsLinked to original sources

bioRxiv2024

A new nanoDSF approach to anti-tubulin compounds screening revealed novel MTAs among approved drugs.

Microtubule Targeting Agents (MTAs) constitute a vital category of tubulin-binding compounds, deployed across anticancer therapies. Despite the array of MTA drugs developed by pharmaceutical entities, the quest for novel efficacious molecules continues unabated. We unveil an innovative in vitro MTA screening methodology employing nano differential scanning fluorimetry (nanoDSF), presenting distinct advantages over known assays. This novel approach not only assesses compound-tubulin binding but also quantitatively analyzes their impact on tubulin polymerization. Proposed nanoDSF assay was rigorously validated using the Prestwick Chemical Library, which encompasses 1,520 approved compounds, successfully identifying all previously known MTAs. Furthermore, this screening has unearthed potential anti-tubulin agents among drugs currently utilized for non-related medical conditions, offering insights into their mechanisms of action in inhibiting cancer cell proliferation and/or inducing cytotoxicity. These discoveries herald new opportunities for drug repositioning involving the newly identified MTAs and substantially streamline the process of screening extensive chemical libraries for MTAs featuring novel chemical structures.

cancer biology↗

bioRxiv2022

Combination drug screen targeting glioblastoma core vulnerabilities reveals pharmacological synergisms

Synergistic drug combinations are an attractive anticancer strategy but prove challenging to identify. Here we present a stepwise approach consisting in revealing core cancer vulnerabilities and exploiting them through drug combination screen to uncover synergistic treatments for glioblastoma patients. MethodsWe established an innovative method, based on high-throughput screening, target deconvolution and functional genomics, to reveal core vulnerabilities in glioblastoma. Combination drug screen targeting these vulnerabilities was then designed to unveil synergistic associations. The therapeutic potential of the top drug combination was validated in two different clinically-relevant models: an organotypic ex vivo model and a syngeneic orthotopic mouse model of glioblastoma. ResultsLarge-scale monotherapy drug screening identified 83 potent anti-glioblastoma compounds. Target deconvolution using public chemoinformatic databases uncovered 1,100 targets and interactors of the hit compounds. Screening of a focused siRNA library targeting the top 292 drug interactors revealed 22 targetable vulnerabilities, 9 of which were confirmed as core glioblastoma vulnerabilities by mining the CRISPR screen cohort data from the online Cancer Dependency Map portal. Six selective inhibitors of the core vulnerabilities were then screened in combination with a custom-made library of 88 compounds and synergies amongst the 528 tested pairwise combinations were predicted. The combinations of CHK1 / MEK and AURKA / BET inhibitors were highlighted and validated in 3D tumor spheroids. Using an organotypic ex vivo model and a syngeneic orthotopic mouse model, we definitively ascertained the efficacy of dual AURKA / BET inhibition in glioblastoma. ConclusionsCollectively, we uncovered that dual inhibition of BET proteins and aurora kinase A is highly synergistic against GBM. Moreover, our study indicates that our approach to exploit drug poly-pharmacology for the rational design of drug combination screens represent a valuable strategy to discover synergistic treatments against refractory cancers.

pharmacology and toxicology↗

bioRxiv2021

Integrated cycles for urban biomass as a strategy to promote a CO2-neutral society - A feasibility study

Progressive global warming is one of the biggest challenges civilization is facing today. The establishment of a carbon dioxide (CO2)-neutral society based on sustainable value creation cycles is required to stop this development. The Integrated Cycles for Urban Biomass (ICU) concept is a new concept towards a CO2-neutral society. The integration of closed biomass cycles into residential buildings enable efficient resource utilization and avoid transport of biowaste. In this scenario, biowaste is degraded on-site into biogas that is converted into heat and electricity. The liquid fermentation residues are upgraded by nitrification processes (e.g., by a soiling(R)-process, EP3684909A1) to refined fertilizer, which can be used subsequently in house-internal gardens to produce fresh food for residents. Whereas this scenario sounds promising, comprehensive evaluations of produced amounts of biogas and food, saved CO2 and costs as well as social-cultural aspects are lacking. To assess these points, a feasibility study was performed, which estimated the material and energy flows based on simulations of the biogas process and food production. The calculations show that a residential complex with 100 persons can generate 21 % of the annual power (electrical and heat) consumption from the accumulated biowaste. The nitrogen (N) in the liquid fermentation residues enables the production of up to 6.3 t of fresh mass of lettuce per year in a 70 m2 professional hydroponic production area. The amount of produced lettuce corresponds to the amount of calories required to feed four persons for one year. Additionally, due to the reduction of biowaste transport and the in-house food and fertilizer production, 6 468 kg CO2-equivalent (CO2-eq) per year are saved compared to a conventional building. While the ICU concept is technically feasible, its costs are still 1.5 times higher than the revenues. However, the model predictions show that the ICU concept becomes economically feasible in case food prices further increase and ICU is implemented at larger scale, e.g.; at the district level. Finally, this study demonstrates that the ICU implementation can be a worthwile contribution towards a sustainable CO2-neutral society and enable to decrease the demand for agricultural land.

bioengineering↗