New research indicates that the epidermal growth factor receptor mutations that occur in a deadly form of brain cancer called glioblastoma differ from those that occur in lung cancers.
This finding may explain the lack of response to epidermal growth factor receptor inhibitors seen in glioblastoma.
These results, published in Cancer Discovery
, a journal of the American Association for Cancer Research, and presented at an AACR Annual Meeting 2012 press conference here, provide further rationale for focused drug development approaches tailored to cancer type, according to Ingo K. Mellinghoff, M.D., of the Human Oncology and Pathogenesis Program and department of neurology at Memorial Sloan-Kettering Cancer Center in New York, N.Y.
Glioblastoma is the most common malignant brain tumor in adults. These tumors often harbor genetic alterations in the epidermal growth factor receptor (EGFR) gene, which encodes a protein that transmits growth and survival signals from the outside of the cell to the cell nucleus.
"In contrast to the experience in lung cancer with EGFR mutations, the EGFR kinase inhibitor erlotinib has only shown limited effectiveness for the treatment of glioblastoma," Mellinghoff said.
He and his colleagues had previously examined human glioblastoma samples and observed that EGFR mutations in this disease mostly affected the extracellular portion of the protein, whereas EGFR mutations in lung cancer affected the kinase domain inside the cell.
"Mutations in glioblastoma were almost exclusively found in the extracellular part of the receptor, which binds to growth factors," Mellinghoff said. "Mutations in lung cancer, on the other hand, typically map to the intracellular part of the receptor that executes its signaling program - the so-called kinase domain."
Mellinghoff and colleagues now report that the extracellular EGFR mutants in glioblastoma are more sensitive to type 2 EGFR kinase inhibitors, whereas most EGFR kinase domain mutants in lung cancer respond better to type 1 EGFR kinase inhibitors such as erlotinib.
Researchers then examined whether lapatinib, a type 2 EGFR kinase inhibitor, might show clinical activity against EGFR-mutated glioblastoma. Mellinghoff''s group evaluated lapatinib concentrations and EGFR activity in patients with glioblastoma who had received lapatinib prior to surgery for tumor recurrence.
"We found that standard lapatinib dosing does not result in sufficiently high drug concentrations in the tumor tissue to effectively shut off EGFR," Mellinghoff said. "We are now planning on a clinical trial with higher lapatinib doses given on an intermittent dosing schedule."
To advance this research, Mellinghoff said he and his colleagues need to conduct further preclinical testing of type 2 EGFR kinase inhibitors alone and in combination with other pathway inhibitors in EGFR-mutant experimental glioma models.
"We would also like to understand how extracellular and intracellular regions of EGFR communicate with each other," Mellinghoff said.
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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''s membership includes 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 seven 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 individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.
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