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Taking the path of least resistance
CAMBRIDGE, EnglandóHorizon Discovery and Philadelphia-based Fox Chase Cancer Center recently entered into a three-year collaboration focused on the application of rAAV gene targeting in mouse embryonic stem cells. The two companies will also work toward the discovery of genes involved in resistance to EGFR-targeted therapies in human cancer, such as PI3K, or phosphoinositide 3-kinases.
The collaboration will focus on generating new human isogenic disease models and knockout models, which Fox Chase will exclusively license to Horizon in return for future product royalties. Horizon will have an exclusive option to license new intellectual property that results during the collaboration as well.
"Fox Chase is a world-renowned center for cancer research and treatment," says Dr. Rob Howes, principal scientist and Center of Excellence program manager at Horizon. "Their interest in personalized medicine complements the aims of Horizon Discovery to provide tools to accelerate the discovery of novel cancer therapies."
Horizon's part in the collaboration will be to implement rAAV gene editing at Fox Chase, "including provision of any existing reagents, project management and ongoing technical support," Howes explains. Fox Chase, he notes, will take charge of developing and characterizing the new resulting cell lines.
"It's definitely a two-way partnership," says Dr. Jonathan Chernoff, chief scientific officer at Fox Chase. "What we get out of this is access to their technology and to their very deep knowledge of this gene-editing system that they're developing. On their part, I think they get access to certain aspects of the application of their technology to areas that they had not previously explored."
Howes says that the goals of the partnership are twofold. Horizon and Fox Chase will firstly seek to identify novel genes involved in resistance to EGFR-targeted therapies such as Erbitux and Vectibix. The second goal, he adds, is "to extend the applicability of rAAV to mouse gene targeting beyond its well-established ability to target human cells."
"Some of the projects we've proposed go beyond things that [Horizon has] done before," says Chernoff. "One of them is drug sensitization, with the EGF receptor inhibitors. These are drugs that are used in clinical trials now and are often effective, but often need additional drugs to show efficacy. We're attempting to use their technology to systematically look at genes that might confer sensitivity to these drugs."
Another part of the collaboration will be the establishment of a Center of Excellence in gene editing that will focus on advancing the application of rAAV gene editing in functional genomics and translational medicine within in-vivo mouse models, adding to the applications and models within the GENESIS Gene Editing Consortium.
One of the key aspects of the GENESIS platform is the utilization of rAAV vectors, which can perform accurate and efficient gene-editing functions in human cells by way of turning on a natural and high- fidelity DNA-repair mechanism called homologous recombination. When this mechanism is harnessed using these vectors, homologous recombination allows for the precise alteration of any DNA sequence, which makes it possible to correct genetic defects in gene therapy applications or accurately model genetic diseases in human cells in vitro.
"These efforts will allow us to more realistically model how combining new signaling inhibitors affects certain drug-resistant cancers," Chernoff says. "In addition, if we are able to use rAAV technology to modify mouse ES cells, this could open the door to rapid, high-throughput gene editing in the mouse."
EGFR-targeted therapies are already widely used to treat a variety of cancer types, "especially lung and colorectal," Howes notes, adding that the current market for Erbitux, according to 2008 worldwide sales, is $1.6 billion. However, some patients manifest resistance to these therapies "due to the presence of secondary mutations limiting their applicability." With the use of Horizon's technology, Chernoff says the two groups hope to identify genes that can "confer sensitivity to these drugs."
Howes adds that identifying such genes "involved in this resistance mechanism will hopefully allow the development of therapies to increase the efficacy of EGFR-targeted therapies. "
"Our collaboration with Fox Chase will identify genes which are involved in this resistance mechanism and provide novel targets for cancer treatment," says Howes. "The ability of rAAV to edit the genome of human cells is now routine. Establishing the rAAV Center of Excellence at Fox Chase will enable us to extend the applicability of rAAV to mouse gene targeting."