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)
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.
#1William Rogers (Maastricht University Medical Centre)H-Index: 1
#2Sithin Thulasi Seetha (Maastricht University Medical Centre)H-Index: 1
Last. Philippe Lambin (Maastricht University Medical Centre)H-Index: 113
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Historically, medical imaging has been a qualitative or semi-quantitative modality. It is difficult to quantify what can be seen in an image, and to turn it into valuable predictive outcomes. As a ...
36 CitationsSource
#1Florian J. Bock (Glas.: University of Glasgow)H-Index: 16
#2Stephen W.G. Tait (Glas.: University of Glasgow)H-Index: 47
Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential...
286 CitationsSource
#1Guangyao Wu (UM: Maastricht University)H-Index: 8
#2Henry C. Woodruff (UM: Maastricht University)H-Index: 23
Last. Philippe Lambin (UM: Maastricht University)H-Index: 113
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Objectives Develop a CT-based radiomics model and combine it with frozen section (FS) and clinical data to distinguish invasive adenocarcinomas (IA) from preinvasive lesions/minimally invasive adenocarcinomas (PM).
8 CitationsSource
#1Sheau W. Lok (WEHI: Walter and Eliza Hall Institute of Medical Research)H-Index: 2
#2James R. WhittleH-Index: 9
Last. Geoffrey J. LindemanH-Index: 64
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Venetoclax, a potent and selective BCL-2 inhibitor, synergizes with endocrine therapy in pre-clinical models of ER-positive breast cancer. Using a phase 1b 3+3 dose escalation and expansion study design, 33 patients with ER and BCL-2-positive metastatic disease (mean prior regimens, 2; range 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated 9on-target9 lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the esc...
56 CitationsSource
#1Pascal O. ZinnH-Index: 24
#2Sanjay K. Singh (University of Texas MD Anderson Cancer Center)H-Index: 21
Last. Rivka R. Colen (University of Texas MD Anderson Cancer Center)H-Index: 32
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Purpose: Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma. Methods: Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glio...
41 CitationsSource
#1Sebastian Sanduleanu (Maastricht University Medical Centre)H-Index: 10
#2Henry C. Woodruff (Maastricht University Medical Centre)H-Index: 23
Last. Philippe Lambin (Maastricht University Medical Centre)H-Index: 113
view all 7 authors...
Abstract Introduction: In this review we describe recent developments in the field of radiomics along with current relevant literature linking it to tumor biology. We furthermore explore the methodologic quality of these studies with our in-house radiomics quality scoring (RQS) tool. Finally, we offer our vision on necessary future steps for the development of stable radiomic features and their links to tumor biology. Methods: Two authors (S.S. and H.W.) independently performed a thorough system...
91 CitationsSource
#1Federico Lucantoni (RCSI: Royal College of Surgeons in Ireland)H-Index: 6
#2Heiko Düssmann (RCSI: Royal College of Surgeons in Ireland)H-Index: 24
Last. Jochen H. M. Prehn (RCSI: Royal College of Surgeons in Ireland)H-Index: 80
view all 4 authors...
// 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: Keywords: breast cancer; BCL2 inhibitors; cell death; bioenergetics; OXPHOS Received: January 16, 2018 Accepted: April 28, 2018 Published: May 25, ...
24 CitationsSource
#1Ahmad Chaddad (McGill University)H-Index: 19
#2Paul Daniel (McGill University)H-Index: 7
Last. Tamim Niazi (McGill University)H-Index: 15
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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...
19 CitationsSource
#1Federico Lucantoni (RCSI: Royal College of Surgeons in Ireland)H-Index: 6
#2Andreas U. Lindner (RCSI: Royal College of Surgeons in Ireland)H-Index: 8
Last. Jochen H. M. Prehn (RCSI: Royal College of Surgeons in Ireland)H-Index: 80
view all 5 authors...
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...
20 CitationsSource
#1Andreas U. Lindner (RCSI: Royal College of Surgeons in Ireland)H-Index: 8
#2Manuela Salvucci (RCSI: Royal College of Surgeons in Ireland)H-Index: 7
Last. Jochen H. M. Prehn (RCSI: Royal College of Surgeons in Ireland)H-Index: 80
view all 22 authors...
Objective The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC). Design Absolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy...
28 CitationsSource
Cited By2
#1Andreas U. Lindner (University of Medicine and Health Sciences)H-Index: 8
#2Salvucci M (University of Medicine and Health Sciences)
Last. Jochen H M PrehnH-Index: 1
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Cancer cells ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells and quantification of 20 cell lineage and apoptosis proteins. Ordinary differential equation-based modelling of apoptosis sensitivity at single cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in a...
#1Wytske M. van Weerden (Erasmus University Medical Center)H-Index: 33
This series of 12 articles, consisting of 9 original articles and 3 reviews, is presented by international leaders in translational cancer research [...]