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      Biosimulation-based target deconvolution of cancer metabolism



            Cancer cells exhibit mutations in metabolic hub genes and dysregulated metabolic phenotypes towards biomass production, consistent with enhanced cell replication and avoidance of growth suppression. Here we explored the hypothesis that the reprogramming of cellular metabolism initiates and/or sustains the proliferation and replicative immortality of cancer cells through the accumulation of oncometabolites (i.e., metabolites with pro-oncogenic functions). We specifically leveraged biological knowledge, multi-omics data, and artificial intelligence (AI) for the construction and parametrization of a compartmentalized genome-scale (~104 species and reactions) mechanistic model of cellular metabolism. The model consisted of coupled ordinary differential equations (ODEs) whose solution provided the temporal dynamics of the included molecular species. To navigate the huge combinatorial space underlying the modulation of the chemical reactions within the model, we developed a deep reinforcement learning-based algorithm capable of identifying biological targets by simulating how the combined modulation of these targets could reproduce a given phenotype (in other words, solving the inverse problem of target deconvolution). We considered common patterns of altered oncometabolites level in personalized phenotypes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) database for about 1,000 patients across 25 cancer types. We predicted enzyme combinations targeting mitochondrial bioenergetics that are largely consistent with the literature and could potentially be of therapeutic value. Notably, already marketed drugs exist for many of the involved targets. Overall, our AI-assisted modeling and simulation platform provides a simple and explainable framework to study combination therapy and drug repurposing in cancer.


            Author and article information

            RExPO24 Conference
            8 May 2024
            [1 ] Netabolics SRL, Rome, Italy;
            Author notes
            Author information

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            Munich, Germany
            3-5 July 2024
            : 3 May 2024

            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Quantitative & Systems biology,Cancer biology
            artificial intelligence,biological networks,cancer,combination therapy,disease understanding,drug repurposing,modeling and simulation,oncometabolites,systems biology,target deconvolution


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