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Translational Medicine A tumor originates when tissue cells ac- quire specific genetic changes. The progression of the tumor is dependent on its surrounding microenvironment. In the course of its growth the tumor's genome spontaneously acquires additional mutations. This makes tumors in each patient subtly genetically different. To reproduce this process, Aveo devel- oped a unique in vivo mouse system that recapitulates the hallmarks of cancer: genet- ics, context, and variation. The tumor donor mouse is engineered to express desired on- cogenes, such as Her2. Tumorigenesis is al- lowed to progress naturally, a process that includes the spontaneous acquisition of ad- ditional genetic alterations. After the tumor has developed, it is re- moved and transferred into the anatomi- cally appropriate locations (e.g., breast) of multiple mouse recipients. This strategy gives rise to a population consisting of hundreds of genetically different tumors originating from the same initial genetic model. Aveo performs a comprehensive molecular characterization of the parent and the progeny tumors. "A Her2-driven tumor population would have a certain proportion of other intrinsic mutations previously associated with cancer. We can identify them because we know the starting genetic background. This would not be possible in classical xenograft models be- cause of high background diversity," contin- ues Dr. Robinson. "Our population-based model closely re- flects what happen in humans. Now we have an opportunity to correlate activity of antican- cer treatments with specific tumor genetics." Aveo's leading clinical drug candidate, tivozanib, just completed Phase III trial as the first-line therapy for advanced renal car- cinoma. "We tested tivozanib in our population of Her2 tumors and identified two novel bio- markers of response," adds Dr. Robinson. "Next, we looked for these biomarkers in the context of the clinical trial and found excellent correlation of the biomarker signa- ture with the response to the drug." The company plans to employ the same approach to seek biomarkers of acquired resistance to oncology drugs and use this knowledge to develop rational combinations of therapies to overcome resistance. Neurotherapeutic Development Genetically engineered mice became a preferred animal model because, until very recently, they have been the only mammalian species where targeted genetic manipulations were possible, according to Kevin Gamber, Ph.D., product manager, Sigma Advanced Genetic Engineering (SAGE) Labs, Sigma- Aldrich (www.sigmaaldrich.com). But the rat remains the preferred species for neuroscience, cardiovascular, and toxi- cology research applications, among others, adds Dr. Gamber. "Moreover, the anatomy, physiology, and social behavior of rat is closer to human than the mouse is, and we are seeing phenotypes modeling human disease in rat models that are not present in the equivalent mouse mod- els," he explains. "The lack of rat knockouts has significant- ly hampered development of therapeutics." SAGE Labs reportedly opened new op- portunities for drug development by creating rat knockout (KO) models using zinc finger nucleases (ZFNs). ZFNs recognize and cut specific DNA sequences and can be used on fertilized oocytes, opening the door to genetic manipulations in species other than mouse. The introduced genetic change is heredi- tary and can be stably maintained by in- breeding. SAGE Labs produces a variety of rat KO lines covering a range from oncology to neurosciences to cardiovascular disease. In collaboration with the Michael J. Fox Foundation, SAGE Labs designed several rat models lacking genes associated with Par- kinson's disease. The pathological hallmark of the disease is loss of dopamine neurons, a phenotype that so far has been difficult to reproduce in mouse models. In the absence of neurodegeneration, mouse models cannot be used to test novel neuroprotective agents. "Two of our rat KO models show a pro- gressive neurodegenerative phenotype," con- tinues Dr. Gamber. "Hind limb deficits occur at about five months of age and progress rap- idly. More subtle motor deficits occur even ear- lier. The preliminary tissue analysis indicates significant loss of dopaminergic neurons." Highly developed social behavior in rats can be used to model diseases such as au- tism and Fragile X. SAGE Labs designed six KO rat models using genes linked to certain components of autism spectrum disorders. Disruption of the FMR1 gene, the primary cause of Fragile X syndrome, indeed results in curtailing of rats social play, a behavior that cannot be assessed in mouse. Sigma-Aldrich has created rat knockout models using ZFNs. According to the company, genetically engineered mice had become the preferred animal model as they were the only mammalian species where targeted genetic manipulations were possible. With the latest advances, rats have resumed their place as the preferred species for neuroscience, cardiovascular, and toxicology research. In collaboration with Autism Speaks, SAGE Labs continues to design rat models for measuring neuronal signaling and its ef- fect on social interactions. "Genetically engineered rats complement mouse in many research areas, especially where translation of mouse to human has shown to be inadequate," says Dr. Gamber. "We will continue expanding our plat- form by providing comprehensive phenotyp- ing capabilities to our genetically engineered rat models." 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