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Horizon's Cell Lines to Aid Sanger, Mass General in Guiding Oncologics Administration with PGx

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Originally published Aug. 24.

By Turna Ray

As part of an effort to expedite personalization of cancer drugs, the Wellcome Trust Sanger Institute will use Horizon Discovery's X-MAN isogenic cell lines in addition to its own patient-derived cell lines in order to analyze genes thought to be linked to response to certain cancer treatments.

Horizon said this week that it would be contributing its cell lines to the Genomics of Drug Sensitivity in Cancer project, an effort being conducted by the Sanger Institute and the Massachusetts General Hospital Cancer Center. The aim of the five-year drug-sensitivity study is to individualize treatments for various cancers by exposing 400 single agents or combination therapies to more than 1,000 genetically characterized human cancer cell lines.

UK-based Horizon said that it will provide Sanger with more than 200 genetically defined X-MAN in vitro human cancer models with cancer-causing mutations, which will help researchers profile clinical and pre-clinical oncologics. The partnership between Horizon and Sanger was inked in July and will continue for three years.

According to Horizon CEO Chris Torrance, the company's X-MAN label refers to its strategy of investigating "Gene X" in a "pair of lines Mutant And Normal."

According to Horizon, its X-MAN cell lines provide researchers a platform for generating hypotheses on drug response gene markers by comparing models of mutated and normal cells against the same genetic background. Without the aid of such isogenic cell lines, researchers would have to use two non-isogenic lines from two different cancer patients, which would pose challenges for differentiating between actual response markers and noise.

"It may be difficult to reveal the full range of genetic factors that impart sensitivity or resistance in such complex and 'non-isogenic' models; however when used in combination with other 'isogenic' models, specific or isolated genetic interactions can be quickly and definitively deciphered regarding their effects on drugs; which can then be tested in more complex model systems (non-isogenic lines) for the modulating effects of other genetic factors, [such as] resistance mechanisms," Torrance told PGx Reporter via e-mail.

"If you take two non-isogenic cancer cell lines generated from two different cancer patients; where one line has the mutation of interest and the other doesn't, interpreting drug effects can be difficult given that there are … hundreds of other genetic variations between the two lines, which could also be altering the drug response," Torrance said. The isogenicity of our X-MAN lines … brings genetic background normalization and definitive information of the target genetic difference being studied."

In July, Sanger and Mass General researchers released the first data sets from the Genomics of Drug Sensitivity in Cancer project. The initial data confirmed "several genes that predict therapeutic response in different cancer types," Sanger said in a statement at the time. "These include sensitivity of melanoma, a deadly form of skin cancer, with activating mutations in the gene BRAF to molecular therapeutics targeting this protein, a therapeutic strategy that is currently being exploited in the clinical setting."

Some of the drugs for which the project reported gene-response leads include Pfizer's Sutent, which targets PDGF-Rs, FLT3, and KIT; AstraZeneca's AS628 targeting BRAF mutations; Wyeth's HKI-272 targeting abnormalities in EGFR and ERBB2; and Genentech/OSI/Roche's EGFR inhibitor Tarceva.

According to Cyril Benes, director of the Center for Molecular Therapeutics at Mass General, several biotech and pharmaceutical companies approached researchers involved in this project to screen their compounds. "Although they do have a PGx strategy, the information we can provide is unique due to the size of our cell line collection and associated genomic information," Benes told PGx Reporter in July.

The initial data release provides a number of new gene-drug response associations, Benes noted, adding that further validation of this data is needed to assess their relevance in human disease.

In participating in the Genomics of Drug Sensitivity in Cancer project, industry collaborators will be permitted to exercise their rights to intellectual property before study data is released to the public, Benes added.

In addition to the Genomics of Drug Sensitivity in Cancer project, Darrell Broger, co-director of Mass General's Translational Research Lab, told PGx Reporter last year that the Cancer Center aimed to molecularly profile all cancer patients presenting to the facility, starting with lung cancer patients. Furthermore, Broger said at the time that through this project, researchers hoped to inform the administration of "smart drugs" that block certain gene mutations and pathways linked to tumor cell growth (PGx Reporter 03/11/09).

Beyond its collaboration with Sanger and Mass General, Horizon believes that its cell lines also have value for drug companies looking to quickly and more accurately validate gene markers for drug personalization by testing the activity of a drug on cells carrying genetic abnormalities and normal cells.

"Pharma companies are adopting whole panels of these [isogenic] lines (each covering a specific genetic event) to define which cancer patients would benefit most from their drug candidates, and to speed up the isolation of 'on-target' compounds in drug development," Torrance said. "Horizon is also extending these single-gene models with double or triple … models to essentially build cancers from the ground up to study ever more complex genetic interaction in an isogenic setting."

Since they can provide insight into the function of gene variants in cancer progression, the X-MAN lines can also be useful in validating diagnostic tests, Torrance said. "These models can equally be used to develop and validate genetic-based diagnostic biomarkers and kits; in particular their sensitivity limits using fixed ratios of matched control mutant and normal cell lines; so that both sides of the personalized medicine coin can be addressed," he said.

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