- Email: [email protected]
Editorial DDT: Cancer models in drug development
Drug Discovery Today: Disease Models
DRUG DISCOVERY
TODAY
DISEASE
MODELS
Vol. 21, No. 2016
Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA
Cancer models in drug development
EDITORIAL
Editorial DDT: Cancer models in drug development Robert M. Mader Department of Medicine I, Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Email: ([email protected])
Preclinical models are supposed to portray the reality of human diseases. As this is a very complex and ambitious task, we are continuously refining our approaches to mimic Robert M. Mader received his doctor’s degree in chemistry in 1986 from the Technical University of Vienna. Always being highly interested in medicine, he accepted a research opportunity at the University Hospital of Vienna, where he started an academic career in biomedical research. In several pharmacological investigations conducted in vitro and in vivo, he and his team investigated the pharmacology of anticancer agents including anthracyclines and the biochemical modulation of 5-fluorouracil focusing on the stereospecific pharmacokinetics of folates in patients with colorectal cancer. In close collaboration with the Department of Clinical Pharmacology, the intratumoural pharmacokinetics of drugs were described using the microdialysis technique, which allowed for the first time the continuous monitoring of the concentration-time profile of several cytotoxics in the malignant lesion in vivo. With emphasis on molecular pharmacology, drug resistance mechanisms became a central part of his research with a focus on a variety of cellular cancer models. For the time being, microRNA are investigated as regulatory molecules during the development of drug resistance and endothelial intravasation during metastasis formation, where exosomal microRNA function as ‘‘malignant’’ messengers between cells. Actually, he serves as Program Director for ‘‘Molecular Pharmacology’’ and he is the Director for Translational Research at the Department of Medicine I of the Medical University of Vienna, where he coordinates the research cluster ‘‘Experimental Therapy & Drug Resistance’’ at the Comprehensive Cancer Center of the Medical University of Vienna.
1740-6757/$ © 2017 Published by Elsevier Ltd.
https://doi.org/10.1016/j.ddmod.2017.10.001
the essential traits of disease conditions. Paradoxically, the big disadvantage of malignant diseases was the initial advantage to easily establish preclinical models in many cancer subtypes. With malignant cells proliferating usually well under laboratory conditions, most of the initial research efforts were centred on cellular models. Using these relatively simple models we have learned many valuable things about malignant mechanisms only to discover later that these insights need to be completed by mechanisms at the extracellular level and the tissue environment. The growing number of models we can use today provides several opportunities to address very complex phenomena, which highly corresponds to the complexity of the malignant foe with deregulations at the molecular level, the cellular level, and the organ level, which concomitantly interact in order to trigger pathophysiological processes in favour of the malignoma’s deleterious intentions. In this issue of DDT, we provide some fine examples of what has been achieved in the last years. Starting chronologically, childhood cancer is a medical challenge in a particularly sensitive population and age, where social, emotional and ethical aspects are central issues. Survivors of cytotoxic therapies may suffer from a variety of sequelae, which may even include a secondary malignant disease. The work presented by Rausham Kurmansheva and Peter Houghton tackles these issues with refined predictive models of childhood cancer. Most importantly, their article focuses on targeted therapies, where models now support the development treatment strategies with increased disease response by concomitantly sparing side-effects. As the authors point out, there is considerable progress in the generation of cellular 1
Drug Discovery Today: Disease Models | Cancer models in drug development
models to investigate therapeutic strategies in rare paediatric brain tumours, where clinical evidence is particularly scarce. The authors critically discuss patient derived xenografts, which are nevertheless valuable preclinical tools. Although these models are not suitable to assess immunotherapies, they qualify to investigate targeted strategies in a genetically defined background. Most importantly, these models are now available to investigators all over the world opening new opportunities in the demanding field of rare childhood cancer. In the following article, Elke Kaemmerer and co-authors from Vicky Avery’s group review recent advances in breast cancer models, where sophisticated cellular models simulate features of tumorigenesis. To this aim, 2D, 3D and microfluidics technology are applied to shape predictive breast cancer models. In this overview, we see significant improvements in 3D models, where breast cancer cells are cultured together with endothelial cells (HUVEC) and mesenchymal stem cells to address angiogenesis and simulate anti-angiogenetic strategies. These models are completed by cellular coculture microfluidic systems to mimic the tumour environment under dynamic conditions, e.g. the influence of growth factors, chemokines or anticancer drugs. As primary breast cancer cell culture is notoriously difficult to establish in vitro, novel and more complex breast cancer models are indicative for our efforts to mirror the complex nature of the most frequent type of cancer in females. Cancer models in general benefit from gene editing approaches, where specific alterations can be tested against different genetic and biologic backgrounds. With the discovery of CRISPR/Cas9, oncogenic pathways can be targeted at the molecular level thus advancing gene therapy to the next stage. The questions arising from this new technology for gene editing have not changed over the years, but the answers provided now differ. Safe and efficient delivery of genes has seen some progress with the CRISPR/Cas9 system already overcoming some of the unresolved issues of the past as pointed out by Nicole
2
www.drugdiscoverytoday.com
Vol. 21, No. 2016
Lindsay-Mosher and Cathy Su. Although a variety of issues still needs to be addressed and some shortcomings still persist, progress has materialised in the specific gene delivery using viral as well as non-viral systems. Considering the enormous potential of targeted gene editing for therapeutic purposes, the delivery via nanoparticles – to pick one example – deserves intense investigations as this methodology may alleviate some of the problems associated with viral vectors, e.g. immunogenicity. All models mentioned so far offer the opportunity to study biomarkers associated with the aberrant genotype and phenotype of cancer. The rigorous exploitation of biomarkers as drivers in the development of anticancer drugs is one of the prerequisites to advance precision medicine (companion diagnostics). This path is summarised by Olivia Rossanese from Vladimir Kirkin’s group in the ‘‘Pharmacological Audit Trail’’. In this conceptual framework, biomarkers are integrated in the use of in vitro and in vivo models to select patient populations for targeted drugs, to perform proof-ofconcept studies and to predict resistance mechanisms. Independent of the mechanism of action, every type of anticancer therapy fails after being efficient for a period of time. This makes drug resistance a mighty enemy for initially successful strategies and values the systematic approach, which individualises appropriate preclinical models to guide drug discovery based on selected parameters and models by defining a rational roadmap from preclinical investigation to clinical validation. As a last thought: knowledge is a child of curiosity, a curiosity that researchers live and share every day. Some of your personal curiosity as readers of these articles – I am sure about this! – will be satisfied with the lecture of these sublime overviews, which provide an optimistic perspective for the future. With so many activities around, expect more to come in the near future, because the ongoing refinement of tools and models is a central necessity to bridge the gaps between ground-breaking cancer biology, translational cancer pharmacology and successful clinical application.
DRUG DISCOVERY
TODAY
DISEASE
MODELS
Vol. 21, No. 2016
Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA
Cancer models in drug development
EDITORIAL
Editorial DDT: Cancer models in drug development Robert M. Mader Department of Medicine I, Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Email: ([email protected])
Preclinical models are supposed to portray the reality of human diseases. As this is a very complex and ambitious task, we are continuously refining our approaches to mimic Robert M. Mader received his doctor’s degree in chemistry in 1986 from the Technical University of Vienna. Always being highly interested in medicine, he accepted a research opportunity at the University Hospital of Vienna, where he started an academic career in biomedical research. In several pharmacological investigations conducted in vitro and in vivo, he and his team investigated the pharmacology of anticancer agents including anthracyclines and the biochemical modulation of 5-fluorouracil focusing on the stereospecific pharmacokinetics of folates in patients with colorectal cancer. In close collaboration with the Department of Clinical Pharmacology, the intratumoural pharmacokinetics of drugs were described using the microdialysis technique, which allowed for the first time the continuous monitoring of the concentration-time profile of several cytotoxics in the malignant lesion in vivo. With emphasis on molecular pharmacology, drug resistance mechanisms became a central part of his research with a focus on a variety of cellular cancer models. For the time being, microRNA are investigated as regulatory molecules during the development of drug resistance and endothelial intravasation during metastasis formation, where exosomal microRNA function as ‘‘malignant’’ messengers between cells. Actually, he serves as Program Director for ‘‘Molecular Pharmacology’’ and he is the Director for Translational Research at the Department of Medicine I of the Medical University of Vienna, where he coordinates the research cluster ‘‘Experimental Therapy & Drug Resistance’’ at the Comprehensive Cancer Center of the Medical University of Vienna.
1740-6757/$ © 2017 Published by Elsevier Ltd.
https://doi.org/10.1016/j.ddmod.2017.10.001
the essential traits of disease conditions. Paradoxically, the big disadvantage of malignant diseases was the initial advantage to easily establish preclinical models in many cancer subtypes. With malignant cells proliferating usually well under laboratory conditions, most of the initial research efforts were centred on cellular models. Using these relatively simple models we have learned many valuable things about malignant mechanisms only to discover later that these insights need to be completed by mechanisms at the extracellular level and the tissue environment. The growing number of models we can use today provides several opportunities to address very complex phenomena, which highly corresponds to the complexity of the malignant foe with deregulations at the molecular level, the cellular level, and the organ level, which concomitantly interact in order to trigger pathophysiological processes in favour of the malignoma’s deleterious intentions. In this issue of DDT, we provide some fine examples of what has been achieved in the last years. Starting chronologically, childhood cancer is a medical challenge in a particularly sensitive population and age, where social, emotional and ethical aspects are central issues. Survivors of cytotoxic therapies may suffer from a variety of sequelae, which may even include a secondary malignant disease. The work presented by Rausham Kurmansheva and Peter Houghton tackles these issues with refined predictive models of childhood cancer. Most importantly, their article focuses on targeted therapies, where models now support the development treatment strategies with increased disease response by concomitantly sparing side-effects. As the authors point out, there is considerable progress in the generation of cellular 1
Drug Discovery Today: Disease Models | Cancer models in drug development
models to investigate therapeutic strategies in rare paediatric brain tumours, where clinical evidence is particularly scarce. The authors critically discuss patient derived xenografts, which are nevertheless valuable preclinical tools. Although these models are not suitable to assess immunotherapies, they qualify to investigate targeted strategies in a genetically defined background. Most importantly, these models are now available to investigators all over the world opening new opportunities in the demanding field of rare childhood cancer. In the following article, Elke Kaemmerer and co-authors from Vicky Avery’s group review recent advances in breast cancer models, where sophisticated cellular models simulate features of tumorigenesis. To this aim, 2D, 3D and microfluidics technology are applied to shape predictive breast cancer models. In this overview, we see significant improvements in 3D models, where breast cancer cells are cultured together with endothelial cells (HUVEC) and mesenchymal stem cells to address angiogenesis and simulate anti-angiogenetic strategies. These models are completed by cellular coculture microfluidic systems to mimic the tumour environment under dynamic conditions, e.g. the influence of growth factors, chemokines or anticancer drugs. As primary breast cancer cell culture is notoriously difficult to establish in vitro, novel and more complex breast cancer models are indicative for our efforts to mirror the complex nature of the most frequent type of cancer in females. Cancer models in general benefit from gene editing approaches, where specific alterations can be tested against different genetic and biologic backgrounds. With the discovery of CRISPR/Cas9, oncogenic pathways can be targeted at the molecular level thus advancing gene therapy to the next stage. The questions arising from this new technology for gene editing have not changed over the years, but the answers provided now differ. Safe and efficient delivery of genes has seen some progress with the CRISPR/Cas9 system already overcoming some of the unresolved issues of the past as pointed out by Nicole
2
www.drugdiscoverytoday.com
Vol. 21, No. 2016
Lindsay-Mosher and Cathy Su. Although a variety of issues still needs to be addressed and some shortcomings still persist, progress has materialised in the specific gene delivery using viral as well as non-viral systems. Considering the enormous potential of targeted gene editing for therapeutic purposes, the delivery via nanoparticles – to pick one example – deserves intense investigations as this methodology may alleviate some of the problems associated with viral vectors, e.g. immunogenicity. All models mentioned so far offer the opportunity to study biomarkers associated with the aberrant genotype and phenotype of cancer. The rigorous exploitation of biomarkers as drivers in the development of anticancer drugs is one of the prerequisites to advance precision medicine (companion diagnostics). This path is summarised by Olivia Rossanese from Vladimir Kirkin’s group in the ‘‘Pharmacological Audit Trail’’. In this conceptual framework, biomarkers are integrated in the use of in vitro and in vivo models to select patient populations for targeted drugs, to perform proof-ofconcept studies and to predict resistance mechanisms. Independent of the mechanism of action, every type of anticancer therapy fails after being efficient for a period of time. This makes drug resistance a mighty enemy for initially successful strategies and values the systematic approach, which individualises appropriate preclinical models to guide drug discovery based on selected parameters and models by defining a rational roadmap from preclinical investigation to clinical validation. As a last thought: knowledge is a child of curiosity, a curiosity that researchers live and share every day. Some of your personal curiosity as readers of these articles – I am sure about this! – will be satisfied with the lecture of these sublime overviews, which provide an optimistic perspective for the future. With so many activities around, expect more to come in the near future, because the ongoing refinement of tools and models is a central necessity to bridge the gaps between ground-breaking cancer biology, translational cancer pharmacology and successful clinical application.