Carving out new cancer territory

Blueprint Medicines announces discovery of novel oncology drug targets

Jeffrey Bouley
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CAMBRIDGE, Mass.—Blueprint Medicines, which describes itself as a leader in discovering and developing highly selective kinase inhibitors for genomically defined cancers, announced Sept. 10 the identification of several new cancer drug targets known as fusion genes, findings that were made through a proprietary computational approach and which have already given rise to two new drug discovery programs at Blueprint Medicines.
Specifically, Blueprint Medicines uncovered 14 known fusions in new cancer types and identified 18 novel fusions that likely play a key role in cancer. Fusion genes—formed from the association of two normally separated genes as a result of a translocation or other chromosomal rearrangements—are known to contribute to the development of cancers, the company says. They are proven cancer drug targets, and a number of approved or exploratory drugs currently exist for many of the newly discovered fusions. Blueprint Medicines’ research and scientific approach were published in the Sept. 10, 2014, edition of Nature Communications
“The genomic discoveries highlighted in this publication are significant. They not only offer the potential to lead to truly novel therapeutics, but also have immediate implications for the diagnosis and treatment of cancer patients,” said Dr. Brian Druker, scientific founder of Blueprint Medicines and director of the Knight Cancer Institute and JELD-WEN Chair of Leukemia Research at Oregon Health & Science University. “These findings provide important insights in the fight against cancer. I am pleased they were published quickly in the interest of patients.”
Some might suggest “too quickly.” Questioned by some in the media about whether publishing the data so soon after unearthing it might cut into the company’s competitive position, Blueprint’s Chief Scientific Officer, Dr. Christoph Lengauer, who was a co-author on the Nature Communications paper, said the company is confident that its drug discovery process is so accelerated that Blueprint has an advantage of two to three years over anyone else eager to exploit the genetic alterations described in the research.
“This research represents an important observation in cancer genomics, with potential clinical trial implications in oncology,” said Dr. Levi Garraway, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School in the Department of Medical Oncology, the co-director of the Cancer Genetics Program at Dana-Farber/Harvard Cancer Center and a senior associate member at the Broad Institute of MIT and Harvard. “It also shows how thoughtful computational algorithms can engender novel discoveries through focused applications to the treasure trove of existing cancer genome data.”
Blueprint Medicines is currently advancing two drug discovery programs against kinase fusion targets. In addition, Blueprint Medicines expects to initiate clinical trials in 2015 with its more advanced programs: BLU-285, a selective inhibitor of KIT Exon 17 mutants for the underserved systemic mastocytosis patient population, as well as a genomically defined subset of patients with gastrointestinal stromal tumors, and BLU-554, a paralog-selective FGFR4 inhibitor for patients suffering from hepatocellular carcinoma with FGFR4 pathway activation. 
“We are proud of our target identification capabilities, which, coupled with our proprietary chemical library of carefully crafted compounds tailored to the kinome, enable us to uniquely fulfill our mission of consistently discovering and developing highly selective medicines for patients with genomically defined cancers,” said Lengauer. “The work published in Nature Communications underlines the productivity of the scientists in our target discovery team, who yielded several important results just three years since the company’s inception.”
Just days after that big news, Blueprint Medicines disclosed the first-ever comprehensive genomic study of malignant mixed Mullerian tumors (MMMT), an aggressive and deadly cancer of the female reproductive system, also known as carcinosarcoma. The new study, published in the current online edition of Nature Communications, uncovers genetic alterations previously not associated with MMMT. These genetic alterations likely play a role in development of the tumors and can serve as targets for anticancer drugs.
Researchers from Personal Genome Diagnostics (PGDx) and Blueprint Medicines, with colleagues from Johns Hopkins University and Oregon Health and Science University, discovered that MMMT/carcinosarcomas have many mutations located in clinically relevant genes, such as PIK3CA, KRAS and DNA repair pathway genes. Some of these previously unidentified genetic mutations may be addressed by existing therapies or by investigational drugs currently in clinical trials.
“By defining the mutational landscape of this understudied cancer with a poor prognosis, PGDx and Blueprint Medicines were able to identify alterations in specific genes and pathways that may be promising targets for existing and new drug therapies, as well as enabling earlier and more effective diagnoses,” said Dr. Sian Jones, a co-first author of the study and director of genomic analysis at PGDx. “It is noteworthy that many of the genetic alterations we identified were not previously associated with MMMT/carcinosarcomas. These findings show how comprehensive genomic analysis of a complex type of cancer can increase understanding of the condition, identify potential new treatment options and enable personalized patient management.”
The analysis also revealed that a high fraction of mutations were in “chromatin remodeling” genes, which regulate the structure of chromosomes and, when mutated, are thought to have dramatic effects on the biology of the cell. Chromatin remodeling genes are currently being evaluated as potential targets for epigenetic and other novel therapies.
“The collaborative work between Blueprint Medicines and PGDx demonstrates our resolute commitment to uncovering the genomic drivers of underserved cancers and sharing this information broadly to improve cancer research, diagnosis and treatment for the benefit of patients,” Lengauer said. “Our research further shows the potential of the Blueprint and PGDx platforms to develop innovative genomics-based techniques and tools to elucidate novel genomic drivers of cancer for drug discovery purposes.”

Jeffrey Bouley

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