Clinical Sequencing Technology Identifies New Targets in Diverse Cancers
PHILADELPHIA — Novel abnormalities in the FGFR gene, called FGFR fusions, were identified in a spectrum of cancers, and preliminary results with cancer cells harboring FGFR fusions suggested that some patients with these cancers may benefit from treatment with FGFR inhibitor drugs, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.
FGFR genes are receptors that bind to members of the fibroblast growth factor family of proteins and play a role in key biological processes of a human cell. Because of a chromosomal abnormality, this gene sometimes fuses with another gene and forms a hybrid, or a gene fusion, resulting in a gene product with an entirely different function, causing cancers.
“We found targetable FGFR gene fusions across a diverse array of cancer types. Although rare for any individual cancer type, if found in an individual patient, these fusions are likely a major driver of that patient’s cancer,” said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor. “We were surprised to find so many different FGFR fusions in so many different cancers.
“This study demonstrates the benefit of broad-based sequencing efforts in personalized oncology. It has the potential to identify novel, rare mutations that are ‘actionable’ therapeutic targets,” Chinnaiyan added. “Such advances in sequencing technology facilitate rational precision therapies for individuals with late-stage cancer.”
The Michigan Oncology Sequencing Program (MI-ONCOSEQ) facilitates integrative sequencing analysis of tumors from patients with advanced cancers. More than 100 patients have been enrolled since 2011. Through the project, researchers analyze the mutational landscape of each patient’s tumor and suggest clinical trials or approved drugs that might be appropriate for that patient, according to Chinnaiyan.
He and his colleagues identified novel fusions of the gene FGFR2 in the tumors of four patients recruited to MI-ONCOSEQ. Of these four patients, two had metastatic tumors of the bile duct; the third had metastatic breast cancer and the fourth had metastatic prostate cancer.
To further analyze whether FGFR fusions are present across different types of cancers, the researchers extended their assessment and analyzed data generated from an internal cohort of 322 patients, as well as from a large cohort of 2,053 patients recruited to The Cancer Genome Atlas. They identified several distinct FGFR fusions in nine different types of cancers, including bladder cancer, brain cancer and lung cancer.
Chinnaiyan and colleagues then conducted studies using cancer cells and found that the different FGFR fusion proteins all seemed to drive cancer cell proliferation by activating FGFR signaling. The researchers were able to inhibit proliferation of the cells in vitro using the FGFR inhibitors PD173074 and pazopanib. In addition, they injected mice with human cancer cells and found that the tumors grown in mice could be inhibited with PD173074.
One of the four patients whose metastatic bile duct tumor failed to respond to conventional chemotherapy was recruited to an FGFR inhibitor trial, and he is currently undergoing treatment, according to Chinnaiyan.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit www.AACR.org.