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Testing microRNAs on Horizon
CAMBRIDGE, EnglandóHorizon Discovery and Mirna Therapeutics have reached an agreement to test the impact of Mirna's proprietary miRNA mimics on a panel of Horizon's patient-relevant human isogenic cancer cell models.
The companies will combine Mirna's cancer therapeutic approach, which uses non-coding regulatory DNA called microRNA, and Horizon's ability to define the most relevant target patients to study in clinical trials using its X-MAN "patients-in-a-test-tube."
MicroRNA represent an important new approach that deserves to be studied rationally and comprehensively, states Horizon's CEO and chief scientific officer, Dr. Chris Torrance.
Citing a specific example, Torrance notes that work done by Horizon co-founder Alberto Bardelli has led to changes in the way EGFR-targeted therapies (Erbitux and Vectibix) are prescribed to colon cancer patients in the United States and Europe. In previous studies, patients with K-Ras mutations were assessed to be non-responsive to these EGFR therapies; and thus, testing of K-Ras mutational status is now mandatory prior to drug prescription, with all K-Ras mutant patients currently being excluded from therapy.
In an attempt to provide greater resolution to this situation; and in response to a small number of clinical anomalies to this resistance profile, Bardelli tested two X-MAN cell lines harboring the most predominant K-Ras mutations (G13D or G12V) for their response to Erbitux. While G12V cells were completely unresponsive to Erbitux, G13D along with parental "WT" cells, in contrast, were highly responsive.
These experimental data stimulated Bardelli and his colleagues to next perform a new and larger retrospective analysis of colon cancer patient samples, which ultimately validated the drug-response profiles generated in X-MAN cell lines. These data led to the definition that G13D mutant colon cancer patients should probably not be omitted from Erbitux therapy, although additional prospective clinical trials are required to confirm this important observation, Torrance adds.
Dr. Paul Lammers, president and CEO of Mirna, says: "Working with Horizon's patient-relevant cancer cell models will increase the understanding of how our highly potent tumor suppressor miRNA mimics act upon human cancer cells characterized by different disease-causing mutations. Such knowledge will help us better define the optimal patient population for our future clinical trials."
Lammers notes that Mirna has eight tumor suppressing mimics in its pipeline, with MiR-34 being the most advanced. It functions just downstream from p53 (also known as protein 53 or tumor protein 53), a tumor suppressor protein that in humans is encoded by the TP53 gene, which is mutated in about 50 percent of cancers, Lammers states.
Horizon's X-MAN cell lines are created using a gene-editing technology called GENESIS that provides researchers with the ability to alter any DNA sequence in a human cell, Torrance says.
"This technology enables the user to take a normal human cell and develop whole panels of disease models that harbor specific disease-causing mutations, just as they occur in real patients," he explains. "The panel of 250 lines at Horizon represents different patient populations, carrying a different disease-associated mutation. New drug candidates can be tested on these panels to see which respond best, so that much time and costs can now be saved in clinical trials."
Torrance notes that Horizon continues to add to its bank at a fast rate, with cancer an ongoing focus for the company.
"Human genetic variations play a part in our susceptibility to many diseases and we are developing models now to address other disease and therapeutic areas, such as infection," he says, and adds that Horizon is in discussions with experts in other disease areas regarding disease models that would be relevant to develop.
This project is funded in part by a Cancer Prevention and Research Institute of Texas (CPRIT) Commercialization grant.