Hallmarks of Cancer Development
“In the near future oncology therapy will be undergoing a paradigm shift,” comments Murray Robinson, Ph.D., senior vp of research, Aveo Oncology.
“Physicians will have an ability to tailor therapy according to the tumor genotype and the gene-expression profile of each individual patient. Aveo is working on new animal models to support this emerging paradigm. Our approach is conceptually similar to the JAX Diversity Outbred mouse population. Only we create population-diverse tumors.”
A tumor originates when tissue cells acquire 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 developed a unique in vivo mouse system that recapitulates the hallmarks of cancer: genetics, context, and variation. The tumor donor mouse is engineered to express desired oncogenes, such as Her2. Tumorigenesis is allowed to progress naturally, a process that includes the spontaneous acquisition of additional genetic alterations.
After the tumor has developed, it is removed and transferred into the anatomically 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 because of high background diversity,” continues Dr. Robinson.
“Our population-based model closely reflects what happen in humans. Now we have an opportunity to correlate activity of anticancer 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 carcinoma.
“We tested tivozanib in our population of Her2 tumors and identified two novel biomarkers 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 signature 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.
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.
But the rat remains the preferred species for neuroscience, cardiovascular, and toxicology 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 models,” he explains.
“The lack of rat knockouts has significantly hampered development of therapeutics.”
SAGE Labs reportedly opened new opportunities 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 hereditary and can be stably maintained by inbreeding. 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 Parkinson’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 progressive neurodegenerative phenotype,” continues Dr. Gamber. “Hind limb deficits occur at about five months of age and progress rapidly. More subtle motor deficits occur even earlier. The preliminary tissue analysis indicates significant loss of dopaminergic neurons.”
Highly developed social behavior in rats can be used to model diseases such as autism 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.
In collaboration with Autism Speaks, SAGE Labs continues to design rat models for measuring neuronal signaling and its effect 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 platform by providing comprehensive phenotyping capabilities to our genetically engineered rat models.”