Implementing Systems Modelling and Molecular Imaging to Predict the Efficacy of BCL-2 Inhibition in Colorectal Cancer Patient-Derived Xenograft Models

Published on Oct 14, 2020in Cancers6.126
· DOI :10.3390/CANCERS12102978
Alice C. O’Farrell4
Estimated H-index: 4
(RCSI: Royal College of Surgeons in Ireland),
Monika A. Jarzabek9
Estimated H-index: 9
(RCSI: Royal College of Surgeons in Ireland)
+ 20 AuthorsJochen H. M. Prehn80
Estimated H-index: 80
(RCSI: Royal College of Surgeons in Ireland)
Sources
Abstract
Resistance to chemotherapy often results from dysfunctional apoptosis, however multiple proteins with overlapping functions regulate this pathway. We sought to determine whether an extensively validated, deterministic apoptosis systems model, 'DR_MOMP', could be used as a stratification tool for the apoptosis sensitiser and BCL-2 antagonist, ABT-199 in patient-derived xenograft (PDX) models of colorectal cancer (CRC). Through quantitative profiling of BCL-2 family proteins, we identified two PDX models which were predicted by DR_MOMP to be sufficiently sensitive to 5-fluorouracil (5-FU)-based chemotherapy (CRC0344), or less responsive to chemotherapy but sensitised by ABT-199 (CRC0076). Treatment with ABT-199 significantly improved responses of CRC0076 PDXs to 5-FU-based chemotherapy, but showed no sensitisation in CRC0344 PDXs, as predicted from systems modelling. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were performed to investigate possible early biomarkers of response. In CRC0076, a significant post-treatment decrease in mean standard uptake value was indeed evident only in the combination treatment group. Radiomic CT feature analysis of pre-treatment images in CRC0076 and CRC0344 PDXs identified features which could phenotypically discriminate between models, but were not predictive of treatment responses. Collectively our data indicate that systems modelling may identify metastatic (m)CRC patients benefitting from ABT-199, and that 18F-FDG-PET could independently support such predictions.
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// Federico Lucantoni 1, 2 , Heiko Dussmann 1, 2 , Irene Llorente-Folch 1, 2 and Jochen H.M. Prehn 1, 2 1 Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland 2 Center for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland Correspondence to: Jochen H.M. Prehn, email: jprehn@rcsi.ie Keywords: breast cancer; BCL2 inhibitors; cell death; bioenergetics; OXPHOS Received: January 16, 2018 Accepted: April 28, 2018 Published: May 25, ...
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Purpose: Colorectal cancer (CRC) is markedly heterogeneous and develops progressively towards malignancy through several stages which include stroma (ST), benign hyperplasia (BH), intraepithelial neoplasia (IN) or precursor cancerous lesion and carcinoma (CA). Identification of the malignancy stage of CRC pathology tissues allows the most appropriate therapeutic intervention. Methods: This study investigates multiscale texture features extracted from CRC pathology sections using 3D wavelet trans...
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Triple negative breast cancer (TNBC) is an aggressive form of breast cancer which accounts for 15–20% of this disease and is currently treated with genotoxic chemotherapy. The BCL2 (B-cell lymphoma 2) family of proteins controls the process of mitochondrial outer membrane permeabilization (MOMP), which is required for the activation of the mitochondrial apoptosis pathway in response to genotoxic agents. We previously developed a deterministic systems model of BCL2 protein interactions, DR_MOMP t...
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This series of 12 articles, consisting of 9 original articles and 3 reviews, is presented by international leaders in translational cancer research [...]
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