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Horizon Screening Isogenic Cell Lines to Target Mutant Pathways in Cancer Stem Cells

UK-based Horizon Discovery this week announced that it has signed a commercial discovery services contract with Europe’s Migrating Cancer Stem Cell’s Framework-6 consortium to screen a compound library of approved drugs that selectively affect cells with mutant PI3K and β-catenin genotypes. These mutant genotypes play rate-limiting roles in cancer stemness, a consortium official told CBA News.
The company said that the contract is valued at “six figures.” Further financial details of the agreement were not released.
The idea behind the program, which kicked off June 9, is that β-catenin signaling is the functional determinant of cancer stemness both in colon cancer and a sub-group of breast cancers, Riccardo Fodde, head of the consortium and a professor of experimental pathology at the Josephine Nefkens Institute of the Erasmus University Medical Centre in Rotterdam, said this week. “We are using this functional determinant to isolate cancer stem cells from mouse- and patient-derived tumors.”
The participants are looking at these pathways or genotypes that are mutated in cancer stem cells, which are responsible for cancer’s principal characteristics, including uncontrolled proliferation and metastasis. However, these cells only make up a minority of cells in a tumor.
Rather than use the cell surface antigens that are currently used to isolate and enrich for cancer stem cells, the consortium and Horizon are using features of the cancer stem cell that they feel are directly related to their function.
“The idea is that tumors are very heterogeneous, and only a small percentage of the tumor cells are functionally relevant. They are responsible for tumor growth and malignancy,” said Fodde. If this is true, these important but rare cancer stem cells should be isolated in order to develop any future cancer therapies.
Fodde said that “we need to concentrate on this minority of cancer stem cells that to us represent a much better target for therapy in the future, rather than addressing the therapy to the entire tumor cell population.”
“We want to … try to identify the functional determinants that underlie cancer stemness and malignancy,” said Fodde. “By doing this, we hope to characterize molecular pathways that can also function as therapeutic targets.”
Horizon will run the screens using isogenic human cancer cell lines engineered with its internally developed gene-engineering technology, called GENESIS.

“We need to concentrate on this minority of cancer stem cells that to us, represent a much better target for therapy in the future, rather than addressing the therapy to the entire tumor cell population.”

“We take cancer cell lines and we target one single mutation of one single gene in one of these cell lines,” said Fodde. “We induce in the endogenous gene a single point mutation.”
This results in an isogenic couple, meaning a parental cell line and a cell line that is identical, except for the one single point mutation in that one gene that the consortium members believe to be important for the onset of cancer stemness.
“We compare the parental cell line and the mutated, knock-in cell line, in the hopes of finding drugs that are very specific for cells carrying that specific mutation, in that specific biochemical pathway, that we know is often mutated in cancer patients,” said Fodde.
Fodde said that Horizon should be ready to start the screen within one or two months.              
“We aim to get this done in a year,” Horizon CEO Christopher Torrance told CBA News this week. The project is scheduled to run for a maximum of 18 months. The actual duration of the project will be difficult to predict, however, because certain screens to be performed by Horizon Discovery will be on newly created, genetically defined human cell lines.
“Once we have potential drug candidates, then we will obviously do more and more in vitro and in vivo preclinical testing,” Fodde said. “The in vitro testing will use the same cell lines, and see if we can induce selective inhibition of the mutated cell line, compared to the parental cell line.”
More importantly, the consortium has developed some unique mouse models for breast and intestinal cancers that it can use to test these drugs against potential targets for clinical efficacy, said Fodde.
Size Matters
“Our consortium is aimed at the isolation and characterization of cancer stem cells, in particular breast cancer and colon cancer,” said Fodde. He explained that the original intent was to keep the consortium small and meaningful, “in that we wanted to have a very small group of scientists from the European Union, so that their interactions could be as informal and direct as possible.”
One of these scientists is Alberto Bardelli, from the University of Torino in Italy, who is a close colleague of Horizon CEO Torrance, dating from when they were postdocs in Bert Vogelstein’s lab at Johns Hopkins in the early part of the decade. “Through Bardelli, I was aware of the technology that Horizon was developing to screen for drugs that may target specific biochemical pathways,” Fodde said.
The consortium is funded by the European Union. It was started in 2006, and was funded for three years for €2.15 million ($3.4 million),” said Fodde.
Consortium members are expected to match the funds with funding from other sources.
“A German company called MicroMet that produces therapeutic antibodies will collaborate with us,” Fodde said. The idea is that if antibodies specifically directed towards these cancer stem cells can be produced, they can also be an important therapeutic tool in the fight against cancer.
This project will begin in the last year of the consortium.

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