Biomarker May Identify Neuroblastomas With Sensitivity to BET Bromodomain Inhibitors
February 21, 2013
- MYCN gene is commonly amplified in neuroblastoma and associated with poor prognosis.
- A BET bromodomain inhibitor downregulated MYCN expression.
- The drug prolonged survival in three animal models of MYCN-amplified neuroblastoma.
PHILADELPHIA — Neuroblastoma, the most common malignant tumor of early childhood, is frequently associated with the presence of MYCN amplification, a genetic biomarker associated with poor prognosis. Researchers have determined that tumors containing MYCN amplification are sensitive to a new class of drugs, BET bromodomain inhibitors.
The researchers made this discovery in a preclinical study, which was funded in part by a Stand Up To Cancer Innovative Research Grant and was published in Cancer Discovery
, a journal of the American Association for Cancer Research.
“BET bromodomain inhibitors are a class of drugs that many researchers are hopeful may offer a new therapeutic option for treating patients with certain cancers,” said Kimberly Stegmaier, M.D., assistant professor of pediatrics in the Department of Hematology/Oncology at Dana-Farber/Children’s Hospital Cancer Center in Boston, Mass. “The challenge has been identifying biomarkers that can help direct clinical translation of these drugs by pinpointing those patients with the highest likelihood of response.”
To identify genetic biomarkers of responsiveness to BET bromodomain inhibitors, Stegmaier and colleagues screened more than 600 cancer cell lines with known genetic characteristics for sensitivity to a prototypical BET bromodomain inhibitor.
Using this high-throughput, cell-based screening process, the researchers found that neuroblastoma cells in which the MYCN gene was amplified were sensitive to BET bromodomain inhibitors.
“Neuroblastoma is a devastating childhood cancer, and only a minority of children with high-risk disease will be cured with currently available treatments,” Stegmaier said. “Prior research has shown that MYCN amplification is common in neuroblastoma, but it has been an elusive drug target.”
To further validate their findings, the researchers tested a BET bromodomain inhibitor, from the laboratory of James E. Bradner, M.D., at the Dana-Farber Cancer Institute, using cultured MYCN-amplified neuroblastoma cell lines and three animal models of MYCN-amplified neuroblastoma. Together, they found that the drug decreased levels of MYCN protein in cultured cells, and that this led to impaired cell growth and cell death. In each animal model, including a mouse model of neuroblastoma that is known to be resistant to many standard therapies, the drug was shown to have anti-tumor effects and to prolong survival.
“My Stand Up To Cancer grant, which focused on modulating difficult drug targets in childhood cancers, was instrumental to us being able to do this exciting work,” Stegmaier said. “These types of studies are generally considered high-risk, particularly because they start with unbiased screening, and they are generally less likely to be supported by traditional sources of funding.”
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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 17,000 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
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