TRANSLATIONAL SCIENCE EXPERIENCES
Abstract: Coming soon
Preclinical Strategies for Precision Oncology Colorectal Cancer
Speaker: Andrea Bertotti, Laboratory of Translational Cancer Medicine, University of Torino, Italy
Almost twenty years after completion of the Human Genome Project, genetic alterations with causative roles in cancer have been identified. Inhibitors that target “druggable” mutant gene products have been developed. Finally, a number of these drugs have entered the clinic and are now used in patients.
Some fundamental issues need to be addressed before the informative potential of genome‐wide molecular surveys is translated into clinical benefit. First, given the heavy mutational load accrued during neoplastic progression, driver alterations are difficult to distinguish from passenger events. Second, next‐generation approaches are likely to identify previously neglected small subsets of very rare variants, which requires population‐scale studies for statistically solid genotype/response correlations. Third, not always does the presence of an oncogenic driver predict response. Therefore, treatment paradigm may not be decided on the sole basis of the mutational status of a single gene with potential cancer‐causing function, but rather on the basis of the heterogeneous context in which that mutation is found (‘precision medicine’).
All these challenges also apply to metastatic colorectal cancer (mCRC). Less than 20% of mCRC patients respond to anti‐EGFR antibodies – the gold standard targeted therapy – which calls for the identification of novel predictive biomarkers and suggests that uncharacterised drivers other than EGFR can sustain the growth of different CRC subsets.
The categorisation of tumour subpopulations featuring specific driver lesions, the validation of such lesions as targets, and the need for discrimination between ‘actionable’ opportunities and those with weak clinical transferability require reliable preclinical models. The scope of our studies is to refine genetic, mechanistic and therapeutic annotation of mCRC subsets using predictive in vivo models – namely, large collections of molecularly annotated patient‐derived tumour xenografts (PDXs) – as a means to systematically increase the success rate of rationally based clinical trials that emanate from preclinical findings.
Highly Translational Phenotyping of Mice Bearing Disease-Relevant Mutations
Speaker: Maksym V. Kopanitsa, Charles River Discovery Research Services, Kuopio, Finland
Neurovascular animal models of diseases have been crucial to advance in the knowledge, development and testing of treatment alternatives for many CNS disturbances. In this presentation, the participants will learn the most common large animal models currently used for arteriovenous malformations (AVM), stroke and aneurysms (side wall, bifurcational and survival long-term model). Requirements for constructions, challenges, critical animal care aspects and impact on the results of the study will be discussed.
The use of immune-competent animals in research requires a consistent but flexible approach. The expanding field of preclinical oncology necessitates diligence in monitoring the welfare of these animals, and providing the enrichment they deserve. Charles River’s Morrisville location is one of the premier contract research organization (CRO) sites in the world. In its early days the site supported a colony size of approximately 6000 and primarily dealt with athymic nude mice and marginal usage of C57BL/6, Balb/c, and SCID mice along with Sprague Dawley/nude rats. As client demand for increasingly difficult models grew, our site adapted to accommodate this ever-changing landscape. Our exceptional facility and animal husbandry staff has been able to meet and exceed requirements for housing our ever-expanding colony count, which can be maxed out (with over 60K animals) in 2017. The use of positive pressure BioBUBBLEs, laminar flow hoods, and biological safety cabinets have been critical to enabling our site to humanely interact with our colonies and maintain necessary biosecurity levels. The flexibility, efficiency, and biosecurity of our facility design has allowed us to expand our capabilities to now include PDX and humanized models and imaging platforms. We have also stayed on top of additional biosecurity risks by incorporating a stand-alone BSL2 room attached to our current facility. When combined with our in-house reverse osmosis watering system, cage wash/autoclave, and bedding filling station, our site is equipped operationally to handle the growing challenges facing facilities that utilize immune-compromised animals in their research.
In vitro testing has been mainstream in toxicology since the 1970’s. A genetox programme starts with in vitro bacterial (Ames), in vitro mammalian prior to testing in the rodent. Skin penetration studies utilizing human skin have virtually replaced in vivo testing for topical products. Other examples are hERG testing for safety pharmacology and in silico QSAR tests in support of genetox and acute toxicology testing. This testing is already very much part of an integrated testing approach incorporating in silico, in chemico and in vitro technologies with in vivo animal models. There are few areas where in vitro assays fully replace in vivo; however, advances in iPSC, 3D tissues and tissue and human-on-a-chip continue apace in pursuit of this goal. Now, we recognize that the advantages of in vitro models are that they utilize human tissue, help us to identify mechanisms, drive translation, screen and help dose setting for animal models as part of a truly 3Rs vision in toxicology.
The objective of this presentation is to provide the audience with information on different in vitro, in chemico and in silico (computational) tests within general and investigational toxicology, and explain how the tests are used within the regulatory testing environment within an integrated testing strategy. Specific examples will be used from different areas of toxicology. A vision of the direction for in vitro toxicology will be shared with the audience.
In vivo safety assessment of drugs, chemicals and consumer products has generally been a critical regulatory requirement prior to release of new products onto the market. However, in recent years, many in vitro assays have been developed and validated with the aim of replacing or reducing the use of in vivo tests. In vitro models of human skin and ocular epithelium have been developed that closely reproduce the 3D organotypic structure and function of in vivo tissues. These models have been accepted by international regulatory authorities as replacements for in vivo skin corrosion, skin irritation and ocular irritation. Additional organotypic in vitro human epithelial models including airway, vaginal, gingival and intestinal are also in development or validation for regulatory use. The objective of this presentation is to learn how these tissue models are produced and validated as microphysiological platforms to model highly-relevant and predictive human biology. A detailed discussion of how in vitro models are used by the biopharma industry and government regulators to complement or replace animal models today, and what is on the horizon, will be also be covered.
Conventional cell-based in vitro models lack the complexity of native tissue and thus have a limited capacity for predicting tissue-level responses. These systems fail to accurately reproduce in vivo phenotypes because of limited longevity and the inability to reproduce complex intercellular events. Advanced in vitro models, such as 3D bioprinted human tissues, have the potential to enhance animal model studies and improve clinical translation. The multicellular architecture, reproducible functionality, and long-term viability of bioprinted tissues allow for the recapitulation of many of the complex phenotypes of chronic toxicity mechanisms or disease states at a histological and molecular level. Data will be presented from studies on 3D bioprinted human liver and kidney tissues demonstrating utility in modeling drug-induced toxicity and complex diseases such as fibrosis.