Humanized Large Animal Cancer Models Accelerating Time And Effectiveness Of Clinical Trials

This eBook provides futuristic perspectives with respect to the emerging requirements of large animal cancer models to address unmet clinical needs. As the vast majority of drugs tested in small animal cancer models fail in human clinical trials, there is a need for large animal models to translate results obtained in small animal models to human clinical practice.

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Based on results from the past ten years, this ready reference systematically describes how to prepare, carry out, and evaluate animal studies for cancer therapies, addressing the widely recognized lack of reliable and reproducible results. Following a short historical introduction and a discussion of the ethics surrounding animal experiments, the book describes correct study design as well as the handling and housing of animals. It then goes on to describe the animal models available for different cancer types, from natural cancer models in mice and dogs to humanized animals. An evaluation of previously unpublished long-term data from the Swiss canine and feline cancer registry is also included. The final part of the book reviews the lessons learned over the last decade on how to interpret data from animal studies for improving human therapy and gives recommendations for future drug development.

Traditional preclinical mouse models of cancer have been very useful for studying the biology of cancer, however they often lack key characteristics of human cancers. As a result, many novel drug candidates fail in human clinical trials despite evidence of drug efficacy in those preclinical models. Thus, researchers are seeking new approaches to augment preclinical knowledge before undertaking clinical trials for human patients. Recently, there has been renewed interest in comparative oncology - the study of naturally developing cancers in animals as models for human disease - as one way to improve cancer drug development and reduce attrition of investigational agents. Tumors that spontaneously develop in pet dogs and other companion animals as a result of normal aging share many characteristics with human cancers, such as histological appearance, tumor genetics, biological behavior, molecular targets, and therapeutic response. In June 2015 the Institute of Medicine hosted a workshop to examine the rationale and potential for integrating clinical trials for pet patients with naturally occurring cancers into translational cancer research and development. Participants discussed the research needs, strategies, and resources to support greater integration of clinical trials for pets with cancer into translational research pathways, and challenges and potential solutions for facilitating that integration. This report summarizes the presentations and discussions from the workshop.

For many years, experiments using chimpanzees have been instrumental in advancing scientific knowledge and have led to new medicines to prevent life-threatening and debilitating diseases. However, recent advances in alternate research tools have rendered chimpanzees largely unnecessary as research subjects. The Institute of Medicine, in collaboration with the National Research Council, conducted an in-depth analysis of the scientific necessity for chimpanzees in NIH-funded biomedical and behavioral research. The committee concludes that while the chimpanzee has been a valuable animal model in the past, most current biomedical research use of chimpanzees is not necessary, though noted that it is impossible to predict whether research on emerging or new diseases may necessitate chimpanzees in the future.

Patient Derived Tumor Xenograft Models: Promise, Potential and Practice offers guidance on how to conduct PDX modeling and trials, including how to know when these models are appropriate for use, and how the data should be interpreted through the selection of immunodeficient strains. In addition, proper methodologies suitable for growing different type of tumors, acquisition of pathology, genomic and other data about the tumor, potential pitfalls, and confounding background pathologies that occur in these models are also included, as is a discussion of the facilities and infrastructure required to operate a PDX laboratory. Offers guidance on data interpretation and regulatory aspects Provides useful techniques and strategies for working with PDX models Includes practical tools and potential pitfalls for best practices Compiles all knowledge of PDX models research in one resource Presents the results of first ever global survey on standards of PDX development and usage in academia and industry

The classic immunodeficient mutants nude, scid and rnu have an important function in experimental cancer research: they allow unique methods of investigation and provide data of clinical relevance. This volume presents the state of the art of research work based on the use of these immunodeficient animal models. One section is dedicated to the biological aspects and immunological properties of immunodeficient mutants. Another part includes articles on xenogenous transplantation of human tumors, focusing on the establishment of transplantable lines, growth characteristics and tumor markers. Special attention is given to new approaches in the fields of chemotherapy, radiation therapy and immunotherapy. Various contributors consider in vitro methods as alternative models. In addition to current data, this publication contains useful technical and methodological information and is therefore valuable not only for specialists but also for scientists entering the field of experimental cancer research.

"99% of mouse protein-coding genes have an equivalent homolog in the human genome, despite the striking differences in appearance between mouse and man. This remarkable genetic similarity, together with our ability to finely engineer the murine genome, has made the mouse the ideal animal in which to model and analyze human biology and disease. This

Cancer cell biology research in general, and anti-cancer drug development specifically, still relies on standard cell culture techniques that place the cells in an unnatural environment. As a consequence, growing tumor cells in plastic dishes places a selective pressure that substantially alters their original molecular and phenotypic properties.The emerging field of regenerative medicine has developed bioengineered tissue platforms that can better mimic the structure and cellular heterogeneity of in vivo tissue, and are suitable for tumor bioengineering research. Microengineering technologies have resulted in advanced methods for creating and culturing 3-D human tissue. By encapsulating the respective cell type or combining several cell types to form tissues, these model organs can be viable for longer periods of time and are cultured to develop functional properties similar to native tissues. This approach recapitulates the dynamic role of cell–cell, cell–ECM, and mechanical interactions inside the tumor. Further incorporation of cells representative of the tumor stroma, such as endothelial cells (EC) and tumor fibroblasts, can mimic the in vivo tumor microenvironment. Collectively, bioengineered tumors create an important resource for the in vitro study of tumor growth in 3D including tumor biomechanics and the effects of anti-cancer drugs on 3D tumor tissue. These technologies have the potential to overcome current limitations to genetic and histological tumor classification and development of personalized therapies.

The world has recorded losses in terms of human life as well as extensive time spent in experimentation with development of new drugs, elucidation of disease mechanism(s), and therapeutic agent discovery. Ethical and legal issues cojoin in slowing down scientific discoveries in medicine and biology. The past two (2) decades, therefore, have seen tremendous attempts that largely are successful in developing animal models with the characteristics of mimicking, approximating, or expressing transplanted human organs/tissues. These models or rather approaches seem to be fast, cost-effective, and easy to maintain compared to primates. This book is a collection of expert essays on animal models of human diseases of global interest. A visible objective of the book is to provide real-time experimental approach to scientists, clinicians, ethicists, medicolegal/medical jurisprudence workers, immunologists, postgraduate students, and vaccinologists and informative and multidisciplinary approach for the identification of new therapeutic targets and biomarkers using animal models as well as investigating the pathogenesis and therapeutic strategies of human diseases. An increased understanding of the genetic, molecular, and cellular mechanisms responsible for the development of human diseases has laid out the foundation for the development of rational therapies mainly with animal models.