المؤلفون: Megan C. Cox, Rita Mendes, Fernanda Silva, Teresa F. Mendes, Adelyn Zelaya-Lazo, Kathleen Halwachs, Julie J. Purkal, Inês A. Isidro, Ana Félix, Erwin R. Boghaert, Catarina Brito

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract The current standard preclinical oncology models are not able to fully recapitulate therapeutic targets and clinically relevant disease biology, evidenced by the 90% attrition rate of new therapies in clinical trials. Three-dimensional (3D) culture systems have the potential to enhance the relevance of preclinical models. However, the limitations of currently available cellular assays to accurately evaluate therapeutic efficacy in these models are hindering their widespread adoption. We assessed the compatibility of the lactate dehydrogenase (LDH) assay in 3D spheroid cultures against other commercially available readout methods. We developed a standardized protocol to apply the LDH assay to ex vivo cultures, considering the impact of culture growth dynamics. We show that accounting for growth rates and background release levels of LDH are sufficient to make the LDH assay a suitable methodology for longitudinal monitoring and endpoint assessment of therapeutic efficacy in both cell line-derived xenografts (xenospheres) and patient-derived explant cultures. This method has the added value of being non-destructive and not dependent on reagent penetration or manipulation of the parent material. The establishment of reliable readout methods for complex 3D culture systems will further the utility of these tumor models in preclinical and co-clinical drug development studies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/6ba6021cf4734f4ebc89722a5ae55c02Test

المؤلفون: Erwin R. Boghaert, Megan C. Cox, Kedar S. Vaidya

المصدر: Cancer Research. 82:1858-1869

مصطلحات موضوعية: body regions, Cancer Research, Immunoconjugates, Oncology, Neoplasms, Humans, Antineoplastic Agents, Antibodies

الوصف: Antibody–drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::266b12108b15eac2d4db9fe316bd20c5Test
https://doi.org/10.1158/0008-5472.can-21-3236Test

المؤلفون: Rita Mendes, Catarina Brito, Megan C. Cox, Inês A. Isidro, Kathleen Halwachs, Fernanda Silva, Julie J Purkal, Adelyn L Zelaya-Lazo, Ana Félix, Erwin R. Boghaert, Teresa F. Mendes

المساهمون: Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
Scientific Reports
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP

مصطلحات موضوعية: Cancer microenvironment, Science, Drug development, Antineoplastic Agents, Article, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Lactate dehydrogenase, Cell Line, Tumor, Neoplasms, Spheroids, Cellular, Drug Discovery, Tumor Cells, Cultured, Medicine, Animals, Humans, General, Cancer models, 030304 developmental biology, 0303 health sciences, Multidisciplinary, L-Lactate Dehydrogenase, business.industry, Culture growth, 3. Good health, Clinical trial, chemistry, 030220 oncology & carcinogenesis, Cancer research, Drug Screening Assays, Antitumor, business, Ex vivo

الوصف: Funding Information: This work was supported by AbbVie and by iNOVA4Health – UIDB/04462/2020, a program financially supported by Fundação para a Ciência e Tecnologia (FCT) / Ministério da Educação e Ciência, through national funds. RM and TFM were recipients of PhD fellowships funded by FCT (SFRH/BD/132163/2017 and PD/BD/128377/2017, respectively) and CB was funded by “The Discoveries Centre for Regenerative and Precision Medicine” (European Commission Horizon 2020 Research and Innovation programme, under the Grant Agreement 739572). Publisher Copyright: © 2021, The Author(s). The current standard preclinical oncology models are not able to fully recapitulate therapeutic targets and clinically relevant disease biology, evidenced by the 90% attrition rate of new therapies in clinical trials. Three-dimensional (3D) culture systems have the potential to enhance the relevance of preclinical models. However, the limitations of currently available cellular assays to accurately evaluate therapeutic efficacy in these models are hindering their widespread adoption. We assessed the compatibility of the lactate dehydrogenase (LDH) assay in 3D spheroid cultures against other commercially available readout methods. We developed a standardized protocol to apply the LDH assay to ex vivo cultures, considering the impact of culture growth dynamics. We show that accounting for growth rates and background release levels of LDH are sufficient to make the LDH assay a suitable methodology for longitudinal monitoring and endpoint assessment of therapeutic efficacy in both cell line-derived xenografts (xenospheres) and patient-derived explant cultures. This method has the added value of being non-destructive and not dependent on reagent penetration or manipulation of the parent material. The establishment of reliable readout methods for complex 3D culture systems will further the utility of these tumor models in preclinical and co-clinical drug development studies. publishersversion published

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d8ac81b3c771941eb41563f083c9b56Test
https://doaj.org/article/6ba6021cf4734f4ebc89722a5ae55c02Test

المؤلفون: Scott S. Verbridge, Laura M. Reese, Lissett R. Bickford, Megan C. Cox

المصدر: ACS biomaterials scienceengineering. 1(10)

مصطلحات موضوعية: Drug, Drug discovery, business.industry, media_common.quotation_subject, Industry standard, Cancer drugs, Tumor spheroid, Biomedical Engineering, Pipeline (software), Biotechnology, Biomaterials, Clinical trial, Risk analysis (engineering), Health care, Medicine, business, media_common

الوصف: Despite a cost of approximately $1 billion to develop a new cancer drug, about 90% of drugs that enter clinical trials fail. A tremendous opportunity exists to streamline the drug selection and testing process, and innovative approaches promise to reduce the burdensome cost of health care for those suffering from cancer. There is great potential for 3D models of human tumors to complement more traditional testing methods; however, the shift from 2D to 3D assays at early stages of the drug discovery and development process is far from widely accepted. 3D platforms range from simple tumor spheroids to more complex microfluidic hydrogels that better mimic the tumor microenvironment. While several companies have developed and patented advanced high-throughput 3D platforms for drug screening, their cost and complexity have limited their adoption as an industry standard. In this review, we will highlight the various tumor platforms that have been developed, emphasizing the approaches that have successfully led to commercial products. We will then consider potential directions toward more relevant tumor models, advantages of the adoption of such platforms within the drug development and screening process, and new opportunities in personalized medicine that such platforms will uniquely enable.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::81f5b3f5e14fa23581b90a5a0c6eb4f5Test
https://pubmed.ncbi.nlm.nih.gov/33429520Test

المؤلفون: Andrea S. Kuliasha, Liwu Li, Scott S. Verbridge, Megan C. Cox

المصدر: ACS biomaterials scienceengineering. 4(2)

مصطلحات موضوعية: 0301 basic medicine, Pathology, medicine.medical_specialty, Tumor microenvironment, Innate immune system, Lipopolysaccharide, Angiogenesis, Biomedical Engineering, Context (language use), Inflammation, Biology, Biomaterials, Vascular endothelial growth factor, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, chemistry, Tumor progression, Cancer research, medicine, medicine.symptom

الوصف: Lipopolysaccharide (LPS) plays a major role in innate immune responses and has been shown to impact vascular dynamics when present at high concentrations. However, the impact of ultralow levels of LPS (100 pg/mL), present in the body during states of chronic inflammation, on vascular dynamics is unclear. In this study, we have integrated a 3D collagen hydrogel tissue mimic with advanced imaging and cell characterization assays to assess the potential impact of chronic inflammation on vascular dynamics, and uncover any alterations in the vascular response to low vs high dose LPS in the context of tumor progression. Accounting for both frequency of sprouting and invasiveness of the sprouts, the treatments of ultralow dose LPS with vascular endothelial growth factor (VEGF), a potent angiogenic promoter and present in excess in the tumor microenvironment, produced enhanced vascular development of human brain microvascular endothelial cells (HBMECs) in our in vitro model. There was no evidence of altered proliferation or apoptosis among the various VEGF treatment groups, indicating an enhanced migratory endothelial cell phenotype results from exposure to ultralow dose LPS with VEGF. The lack of enhanced vascular development upon treatments of high doses of LPS in the presence of VEGF could be partially attributed to an LPS dose-dependent increase in the activation of NF-κB. This study provides insight into the dynamic regulation of vascular development by varying levels of LPS and the potential role of chronic inflammation to prime a pro-angiogenic microenvironment and contribute to tumor progression.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66afb569b95b21eeb848c33f0fe95514Test
https://pubmed.ncbi.nlm.nih.gov/33418730Test

المؤلفون: Scott S. Verbridge, Lynette B. Naler, Megan C. Cox, Chang Lu, Chengyu Deng

مصطلحات موضوعية: 0206 medical engineering, Biomedical Engineering, Brain tumor, Cancer, 02 engineering and technology, Computational biology, Biology, 021001 nanoscience & nanotechnology, medicine.disease, 020601 biomedical engineering, Phenotype, Article, Biomaterials, Cancer Medicine, medicine, Epigenetics, Adaptation, 0210 nano-technology, Chromatin immunoprecipitation, Epigenomics

الوصف: Personalized cancer medicine offers the promise of more effective treatments that are tailored to an individual's own dynamic cancer phenotype. Meanwhile, tissue-engineering approaches to modeling tumors may complement these advances by providing a powerful new approach to understanding the adaptation dynamics occurring during treatment. However, in both of these areas new tools will be required to gain a full picture of the genetic and epigenetic regulators of phenotype dynamics occurring in the small populations of cells that drive resistance. In this study, we perform epigenomic analysis of brain tumor cells that are collected from micro-engineered three-dimensional tumor models, overcoming the challenges associated with the small numbers of cells contained within these micro-tissue niches, in this case collecting ~1,000 cells per sample. Specifically, we use a high-resolution epigenomic analysis method known as microfluidic-oscillatory-washing-based chromatin immunoprecipitation with sequencing (MOWChIP-seq) to analyze histone methylation patterns (H3K4me3). We identified gene loci that are associated with the H3K4me3 modification, which is generally a mark of active transcription. We compared methylation patterns in standard 2D cultures and 3D cultures based on type I collagen hydrogels, under both normoxic and hypoxic conditions. We found that culture dimensionality drastically impacted the H3k4me3 profile and resulted in differential modifications in response to hypoxic stress. Differentially H3K4me3-marked regions under the culture conditions used in this study have important implications for gene expression differences that have been previously observed. In total, our work illustrates a direct connection between cell culture or tissue niche condition and genome-wide alterations in histone modifications, providing the first steps towards analyzing the spatiotemporal variations in epigenetic regulation of cancer cell phenotypes. This study, to our knowledge, also represents the first time broad-spectrum epigenomic analysis has been applied to small cell samples collected from engineered micro-tissues.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6413922433950fea5dc7203ae2645d36Test
https://europepmc.org/articles/PMC6886720Test/