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Background and purpose: Radiomics analysis extracts quantitative data (features) from medical images. These features could potentially reflect biological characteristics and act as imaging biomarkers within precision medicine. However, there is a lack of cross-comparison and validation of radiomics outputs which is paramount for clinical implementation. In this study, we compared radiomics outputs across two computed tomography (CT)-based preclinical scanners. Materials and methods: Cone beam CT (CBCT) and µCT scans were acquired using different preclinical CT imaging platforms. The reproducibility of radiomics features on each scanner was assessed using a phantom across imaging energies (40 & 60 kVp) and segmentation volumes (44-238 mm3). Retrospective mouse scans were used to compare feature reliability across varying tissue densities (lung, heart, bone), scanners and after voxel size harmonisation. Reliable features had an intraclass correlation coefficient (ICC) > 0.8. Results: First order and GLCM features were the most reliable on both scanners across different volumes. There was an inverse relationship between tissue density and feature reliability, with the highest number of features in lung (CBCT=580, µCT=734) and lowest in bone (CBCT=110, µCT=560). Comparable features for lung and heart tissues increased when voxel sizes were harmonised. We have identified tissue-specific preclinical radiomics signatures in mice for the lung (133), heart (35), and bone (15). Conclusions: Preclinical CBCT and µCT scans can be used for radiomics analysis to support the development of meaningful radiomics signatures. This study demonstrates the importance of standardisation and emphasises the need for multi-centre studies.
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Existing guidelines on the preparation (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE)) and reporting (Animal Research: Reporting of In Vivo Experiments (ARRIVE)) of animal experiments do not provide a clear and standardized approach for refinement during in vivo cancer studies, resulting in the publication of generic methodological sections that poorly reflect the attempts made at accurately monitoring different pathologies. Compliance with the 3Rs guidelines has mainly focused on reduction and replacement; however, refinement has been harder to implement. The Oncology Best-practices: Signs, Endpoints and Refinements for in Vivo Experiments (OBSERVE) guidelines are the result of a European initiative supported by EurOPDX and INFRAFRONTIER, and aim to facilitate the refinement of studies using in vivo cancer models by offering robust and practical recommendations on approaches to research scientists and animal care staff. We listed cancer-specific clinical signs as a reference point and from there developed sets of guidelines for a wide variety of rodent models, including genetically engineered models and patient derived xenografts. In this Consensus Statement, we systematically and comprehensively address refinement and monitoring approaches during the design and execution of murine cancer studies. We elaborate on the appropriate preparation of tumor-initiating biologicals and the refinement of tumor-implantation methods. We describe the clinical signs to monitor associated with tumor growth, the appropriate follow-up of animals tailored to varying clinical signs and humane endpoints, and an overview of severity assessment in relation to clinical signs, implantation method and tumor characteristics. The guidelines provide oncology researchers clear and robust guidance for the refinement of in vivo cancer models.
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To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
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Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. 'glszm Zone Entropy'), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical 'discovery' radiomics in the neuro-oncology space.
Subject(s)
Brain Neoplasms , Radiomics , Humans , Animals , Mice , Mice, Inbred NOD , Mice, SCID , Brain Neoplasms/diagnostic imaging , Tomography, X-Ray Computed/methodsABSTRACT
Purpose To identify precise three-dimensional radiomics features in CT images that enable computation of stable and biologically meaningful habitats with machine learning for cancer heterogeneity assessment. Materials and Methods This retrospective study included 2436 liver or lung lesions from 605 CT scans (November 2010-December 2021) in 331 patients with cancer (mean age, 64.5 years ± 10.1 [SD]; 185 male patients). Three-dimensional radiomics were computed from original and perturbed (simulated retest) images with different combinations of feature computation kernel radius and bin size. The lower 95% confidence limit (LCL) of the intraclass correlation coefficient (ICC) was used to measure repeatability and reproducibility. Precise features were identified by combining repeatability and reproducibility results (LCL of ICC ≥ 0.50). Habitats were obtained with Gaussian mixture models in original and perturbed data using precise radiomics features and compared with habitats obtained using all features. The Dice similarity coefficient (DSC) was used to assess habitat stability. Biologic correlates of CT habitats were explored in a case study, with a cohort of 13 patients with CT, multiparametric MRI, and tumor biopsies. Results Three-dimensional radiomics showed poor repeatability (LCL of ICC: median [IQR], 0.442 [0.312-0.516]) and poor reproducibility against kernel radius (LCL of ICC: median [IQR], 0.440 [0.33-0.526]) but excellent reproducibility against bin size (LCL of ICC: median [IQR], 0.929 [0.853-0.988]). Twenty-six radiomics features were precise, differing in lung and liver lesions. Habitats obtained with precise features (DSC: median [IQR], 0.601 [0.494-0.712] and 0.651 [0.52-0.784] for lung and liver lesions, respectively) were more stable than those obtained with all features (DSC: median [IQR], 0.532 [0.424-0.637] and 0.587 [0.465-0.703] for lung and liver lesions, respectively; P < .001). In the case study, CT habitats correlated quantitatively and qualitatively with heterogeneity observed in multiparametric MRI habitats and histology. Conclusion Precise three-dimensional radiomics features were identified on CT images that enabled tumor heterogeneity assessment through stable tumor habitat computation. Keywords: CT, Diffusion-weighted Imaging, Dynamic Contrast-enhanced MRI, MRI, Radiomics, Unsupervised Learning, Oncology, Liver, Lung Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Sagreiya in this issue.
Subject(s)
Liver Neoplasms , Lung Neoplasms , Humans , Male , Middle Aged , Retrospective Studies , Reproducibility of Results , Radiomics , Lung Neoplasms/diagnostic imaging , Tomography, X-Ray Computed/methods , Machine Learning , Liver Neoplasms/diagnostic imagingABSTRACT
Chemotherapy using temozolomide is the standard treatment for patients with glioblastoma. Despite treatment, prognosis is still poor largely due to the emergence of temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. To induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells' molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell RNA sequencing on four of the cell cultures to track the evolution of temozolomide resistance. The induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as "adaptive" (ADA) or "non-adaptive" (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable. The adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor's ability to survive. Depending on the tumor's adaptability potential, subpopulations with acquired resistance mechanisms may arise.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Temozolomide/pharmacology , Temozolomide/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/metabolism , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , Cell Line, Tumor , Phenotype , Genomics , Drug Resistance, Neoplasm/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Gene Expression Regulation, NeoplasticABSTRACT
BACKGROUND: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). METHODS: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. RESULTS: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. CONCLUSION: GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.
Subject(s)
Brain Neoplasms , Glioblastoma , Glioma , Humans , Temozolomide/pharmacology , Temozolomide/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/metabolism , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Drug Evaluation, Preclinical , Biomarkers , DNA/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Drug Resistance, Neoplasm/genetics , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
BACKGROUND: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). METHODS: Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed. RESULTS: Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. CONCLUSION: Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Aged , Glioblastoma/pathology , Prognosis , Brain Neoplasms/pathology , Brain/pathology , SurvivorsABSTRACT
A series of mono- and bis-polyethylene glycol (PEG)-substituted BF2-azadipyrromethene fluorophores have been synthesized with emissions in the near-infrared region (700-800 nm) for the purpose of fluorescence guided intraoperative imaging; chiefly ureter imaging. The Bis-PEGylation of fluorophores resulted in higher aqueous fluorescence quantum yields, with PEG chain lengths of 2.9 to 4.6 kDa being optimal. Fluorescence ureter identification was possible in a rodent model with the preference for renal excretion notable through comparative fluorescence intensities from the ureters, kidneys and liver. Ureteral identification was also successfully performed in a larger animal porcine model under abdominal surgical conditions. Three tested doses of 0.5, 0.25 and 0.1 mg/kg all successfully identified fluorescent ureters within 20 min of administration which was sustained up to 120 min. 3-D emission heat map imaging allowed the spatial and temporal changes in intensity due to the distinctive peristaltic waves of urine being transferred from the kidneys to the bladder to be identified. As the emission of these fluorophores could be spectrally distinguished from the clinically-used perfusion dye indocyanine green, it is envisaged that their combined use could be a step towards intraoperative colour coding of different tissues.
Subject(s)
Spectroscopy, Near-Infrared , Ureter , Swine , Animals , Spectroscopy, Near-Infrared/methods , Fluorescent Dyes/chemistry , Kidney , Urinary Bladder , Polyethylene Glycols/chemistry , Optical Imaging/methodsABSTRACT
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
Subject(s)
Brain Neoplasms , Glioma , Tumor Microenvironment , Adult , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Evolution, Molecular , Genes, p16 , Glioma/genetics , Glioma/pathology , Humans , Isocitrate Dehydrogenase/genetics , Mutation , Neoplasm Recurrence, LocalABSTRACT
Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26-33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of delineating normal tissue from brain tumour to achieve the optimal extent of resection (EOR), with 5-Aminolevulinic Acid (5-ALA) the only clinically approved intra-operative fluorophore for GBM. This review aims to highlight the requirement for improved intra-operative imaging techniques, focusing on fluorescence-guided imaging (FGS) and the use of novel dyes with the potential to overcome the limitations of current FGS. The review was performed based on articles found in PubMed an.d Google Scholar, as well as articles identified in searched bibliographies between 2001 and 2022. Key words for searches included 'Glioblastoma' + 'Fluorophore'+ 'Novel' + 'Fluorescence Guided Surgery'. Current literature has favoured the approach of using targeted fluorophores to achieve specific accumulation in the tumour microenvironment, with biological conjugates leading the way. These conjugates target specific parts overexpressed in the tumour. The positive results in breast, ovarian and colorectal tissue are promising and may, therefore, be applied to intracranial neoplasms. Therefore, this design has the potential to produce favourable results in GBM by reducing the residual tumour, which translates to decreased tumour recurrence, morbidity and ultimately, mortality in GBM patients. Several preclinical studies have shown positive results with targeted dyes in distinguishing GBM cells from normal brain parenchyma, and targeted dyes in the Near-Infrared (NIR) emission range offer promising results, which may be valuable future alternatives.
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BACKGORUND: Prior data suggest pre-diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple-negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. METHOD: NOD/SCID mice were implanted with HER2+ MDA-MB-231/LN/2-4/H2N, trastuzumab-resistant HER2+ HCC1954 or a TNBC patient-derived xenograft (PDX). A daily low-dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA-MB-231/LN/2-4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre-treatment aspirin, 3 weeks post-resection, HCC1954/TNBC animals received standard-of-care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. RESULTS: Aspirin delayed time to metastasis in MDA-MB-231/LN/2-4/H2N xenografts and decreased growth of HER2+ /TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre-treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co-culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF-C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. CONCLUSION: Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo-preventative agent in the HER2+ or TNBC setting.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Humans , Animals , Mice , Female , Receptor, ErbB-2 , Triple Negative Breast Neoplasms/pathology , Vascular Endothelial Growth Factor C , Aspirin/pharmacology , Aspirin/therapeutic use , Cell Line, Tumor , Mice, SCID , Mice, Inbred NOD , Trastuzumab/therapeutic use , Breast Neoplasms/pathologyABSTRACT
PURPOSE: Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers. EXPERIMENTAL DESIGN: Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment. RESULTS: Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance. CONCLUSIONS: Subtype classification systems represent canonical "termini a quo" (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.
Subject(s)
Colorectal Neoplasms/drug therapy , Phenylurea Compounds/therapeutic use , Pyridines/therapeutic use , Xenograft Model Antitumor Assays , Animals , Biomarkers, Tumor , Colorectal Neoplasms/classification , Colorectal Neoplasms/genetics , Disease Models, Animal , Mice , Treatment OutcomeABSTRACT
Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF ßPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of ßPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of ßPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover ßPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with ßPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF ßPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.
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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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Chemotherapy combined with the angiogenesis inhibitor bevacizumab (BVZ) is approved as a first-line treatment in metastatic colorectal cancer (mCRC). Limited clinical benefit underpins the need for improved understanding of resistance mechanisms and the elucidation of novel predictive biomarkers. We assessed germline single-nucleotide polymorphisms (SNPs) in 180 mCRC patients (Angiopredict [APD] cohort) treated with combined BVZ + chemotherapy and investigated previously reported predictive SNPs. We further employed a machine learning approach to identify novel associations. In the APD cohort IL8 rs4073 any A carriers, compared to TT carriers, were associated with worse progression-free survival (PFS) (HR = 1.51, 95% CI:1.03-2.22, p-value = 0.037) and TBK1 rs7486100 TT carriers, compared to any A carriers, were associated with worse PFS in KRAS wild-type (wt) patients (HR = 1.94, 95% CI:1.04-3.61, p-value = 0.037), replicating previous findings. Machine learning identified novel associations in genes encoding the inflammasome protein NLRP1 and the ER protein Sarcalumenin (SRL). A negative association between PFS and carriers of any A at NLRP1 rs12150220 and AA for SRL rs13334970 in APD KRAS wild-type patients (HR = 4.44, 95% CI:1.23-16.13, p-value = 0.005), which validated in two independent clinical cohorts involving BVZ, MAVERICC and TRIBE. Our findings highlight a key role for inflammation and ER signalling underpinning BVZ + chemotherapy responsiveness.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Biomarkers, Tumor/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Endoplasmic Reticulum/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Adaptor Proteins, Signal Transducing/genetics , Aged , Apoptosis Regulatory Proteins/genetics , Cohort Studies , Colorectal Neoplasms/therapy , Combined Modality Therapy , Endoplasmic Reticulum/metabolism , Female , Genetic Association Studies , Humans , Inflammation/genetics , Machine Learning , Male , Membrane Proteins/genetics , Middle Aged , NLR Proteins , Outcome and Process Assessment, Health Care/methods , Polymorphism, Single Nucleotide , Progression-Free Survival , Signal TransductionSubject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Precision Medicine/methods , Protein Kinase Inhibitors/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials as Topic , Colorectal Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , GTP Phosphohydrolases/antagonists & inhibitors , GTP Phosphohydrolases/genetics , Gain of Function Mutation , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Microsatellite Instability , Mutation, Missense , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/genetics , Treatment OutcomeABSTRACT
Colorectal tumors have been classified based on histologic factors, genetic factors, and consensus molecular subtypes, all of which affect the tumor microenvironment. Elements of the tumor microenvironment serve as therapeutic targets and might be used as prognostic factors. For example, immune checkpoint inhibitors are used to treat tumors with microsatellite instability, and anti-angiogenic agents may be used in combination with other drugs to slow or inhibit tumor growth. We review the features of the colorectal tumor stroma that are associated with patient outcomes and discuss potential therapeutic agents that target these features.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Tumor Microenvironment/drug effects , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinogenesis/drug effects , Carcinogenesis/genetics , Carcinogenesis/immunology , Clinical Trials as Topic , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Humans , Microsatellite Instability , Prognosis , Progression-Free Survival , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologyABSTRACT
Glioblastoma (GBM) is the most common primary brain tumor with no available cure. As previously described, seliciclib, a first-generation cyclin-dependent kinase (CDK) inhibitor, down-regulates the anti-apoptotic protein, Mcl-1, in GBM, thereby sensitizing GBM cells to the apoptosis-inducing effects of the death receptor ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we have assessed the efficacy of seliciclib when delivered in combination with the antibody against human death receptor 5, drozitumab, in clinically relevant patient-derived xenograft (PDX) models of GBM. A reduction in viability and significant levels of apoptosis were observed in vitro in human GBM neurospheres following treatment with seliciclib plus drozitumab. While the co-treatment strategy induced a similar effect in PDX models, the dosing regimen required to observe seliciclib-targeted responses in the brain, resulted in lethal toxicity in 45% of animals. Additional studies showed that the second-generation CDK inhibitor, CYC065, with improved potency in comparison to seliciclib, induced a significant decrease in the size of human GBM neurospheres in vitro and was well tolerated in vivo, upon administration at clinically relevant doses. This study highlights the continued need for robust pre-clinical assessment of promising treatment approaches using clinically relevant models.