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PGDx, Blueprint Team to Identify Genomic Alterations in Cancer for Targeted Drug Development


Originally published May 28.

With the help of Personal Genome Diagnostics, a Johns Hopkins University spinout with expertise in characterizing a tumor's unique genomic features, Blueprint Medicines is hoping to develop kinase inhibiting cancer treatments that target the molecular underpinnings of the disease.

Under a collaboration announced earlier this month, PGDx will use various technologies to assess genomic changes that are the hallmarks of certain cancer subtypes and based on these findings, Blueprint will develop selective kinase inhibitors that target those markers to advance personalized cancer treatments. Blueprint would not disclose the specific kinase inhibitors it is developing in its portfolio, but told PGx Reporter that all of the company's drug development programs are in the preclinical stage.

The collaboration between the two nascent companies offers Blueprint a way of "accelerating their research program while minimizing [its] investment in non-core infrastructure and expertise," Antony Newton, chief commercial officer of PGDx, told PGx Reporter.

PGDx, located in the Science and Technology Park at Johns Hopkins in Baltimore, was founded in 2010 by Victor Velculescu, director of cancer genetics at JHU's Ludwig Center for Cancer Genetics, and Luis Diaz, director of translational medicine at the Ludwig Center. Velculescu is the chief scientific officer of PGDx and Diaz serves as the company's chief medical officer. PGDx offers a comprehensive cancer genome analysis service that combines exome sequencing with digital karyotyping (CSN 5/16/2012).

Cambridge, Mass.-based Blueprint was founded in 2011. In April of that year, the company closed a $40 million Series A financing round led by venture capital firm Third Rock Ventures. Alexis Borisy is co-founder and interim CEO of Blueprint, as well as a partner at Third Rock.

As part of its collaboration with Blueprint, PGDx will conduct exome analysis and mutational analysis and it will utilize a bioinformatics method, called CHASM, as well as digital karyotyping technologies to identify genomic changes in cancer patients' tumors that Blueprint's drugs can target.

The firm's mutational analysis technologies will enable it to identify "point alterations using vast amounts of sequence data" to identify tumor-specific mutations, a PGDx spokesperson said. Meanwhile, CHASM, developed by Johns Hopkins researchers and licensed to PGDx, applies a machine learning method to differentiate driver and passenger somatic mutations. Finally, PGDx will use digital karyotyping, another technology developed at the university and licensed to the company, to gauge structural alterations within a tumor.

The compounds advanced as part of this collaboration will be plucked from Blueprint's proprietary small molecule kinase library. Although the collaboration is still very much in its infancy, Blueprint envisions that some of its kinase inhibitors may be commercialized with a companion diagnostic to pick out best responders.

"Many of the drugs discovered and developed by Blueprint will likely require some form of patient selection and stratification," a company spokesperson said. "Blueprint will develop and utilize companion diagnostics applying a variety of technologies tailored towards each program."

A spokesperson from PGDx added that if certain drugs developed through this collaboration do require a companion test, that diagnostic will "likely be based on a non-next-generation sequencing platform in order to allow the test to be run more simply and economically by many types of health systems worldwide."

The collaboration between Blueprint and PGDx is currently open-ended, and the partners did not disclose a target timeframe for when the first commercial drug might emerge from their work. The deal follows an agreement Blueprint announced in March, under which it aims to identify novel cancer targets by screening its kinase inhibitor compounds in cancer cell lines built by Wellcome Trust Sanger Institute and the Massachusetts General Hospital Cancer Center.

Molecularly targeted kinase inhibitors are a key area of focus for drug developers interested in personalizing cancer care. Protein kinases, such as serine/threonine and tyrosine, are enzymes that catalyze phosphorylation and regulate cellular pathways. Mutations in genes that encode these kinases have often been implicated in different types of cancer.

For example, the majority of chronic myeloid leukemia patients have a chromosomal translocation that results in the fusion of part of the Abl gene with a section of the BCR gene. This mutation, in turn, causes the encoded tyrosine kinase to continuously activate proteins leading to unregulated growth of cells that drive CML. Novartis' Gleevec, a highly profitable tyrosine kinase inhibitor, is a treatment for CML that works by blocking the Bcr-Abl tyrosine kinase enzyme from phosphorylating the protein necessary for cancer development.

Blueprint's efforts to develop selective targeted kinase inhibitors will particularly benefit from its collaboration with PGDx, since the company has expertise in unraveling the workings of the "kinome," kinase genes that are altered in tumors. Johns Hopkins researchers and founders of PGDx have published several papers identifying genomic alterations in various kinases that play a role in the development of cancer.

For example, in 2004, researchers led by Yardena Samuels of Johns Hopkins, published data in Science from a study in which they sequenced genes encoding the Phosphatidylinositol 3-kinase, or PI3K, and identified mutations in PIK3CA genes in colorectal cancers, glioblastomas, and several other cancer types. Subsequent research has shown that PIK3CA is among the most frequently mutated genes in cancer.