SAN FRANCISCO — Findings from preclinical studies in a skin cancer model showed that next-generation BRAF inhibitors used alone, or first-generation BRAF inhibitors used in combination with an epidermal growth factor receptor inhibitor, may have the potential to prevent drug-induced skin lesions in BRAF mutation-positive patients treated for melanoma.
The studies, presented at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held Nov. 12-16, 2011, further elucidated the potential mechanism of action underlying this skin lesion side effect, which could further the development of next-generation drugs with improved safety and efficacy profiles for the treatment of BRAF mutation-positive melanoma, according to the researchers.
"Our data suggest that adding an epidermal growth factor receptor (EGFR) inhibitor may prevent skin lesions that sometimes appear during treatment with a first-generation BRAF inhibitor," said Gideon Bollag, Ph.D., senior vice president of research at Plexxikon in Berkley, Calif. "Perhaps more importantly, our data also suggest that our next-generation BRAF inhibitors (which we call 'paradox breakers') represent a novel, single-agent treatment that may avoid this side effect and may also extend treatment durability."
In a laboratory study, Bollag and colleagues used skin cells activated by oncogenes such as HRAS or by signaling through the EGFR receptor with a first-generation BRAF inhibitor. They observed that treatment led to upregulation of ligands for the family of HER receptors, consequent skin cell transformation and enhanced growth. In contrast, Plexxikon's novel "paradox breakers" did not induce this upregulation and, therefore, may prevent the skin lesion side effect observed for all first-generation BRAF inhibitors to date.
Bollag said he and his research team were initially surprised by the upregulation of growth factor expression but were able to identify its cause with a model system. They then used this model system to differentiate the new "paradox breaker" compounds.
The "paradox breakers," which are in preclinical development, are being studied in BRAF-mutant cancer, and Plexxikon is aiming to file an investigational new drug application in 2012.
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The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 laboratory, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards to young investigators, and it also funds cutting-edge research projects conducted by senior researchers. The AACR has numerous fruitful collaborations with organizations and foundations in the U.S. and abroad, and functions as the Scientific Partner of Stand Up To Cancer, a charitable initiative that supports groundbreaking research aimed at getting new cancer treatments to patients in an accelerated time frame. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care, and Educational Workshops are held for the training of young cancer investigators. The AACR publishes seven major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Prevention Research. In 2010, AACR journals received 20 percent of the total number of citations given to oncology journals. The AACR also publishes Cancer Today, a magazine for cancer patients, survivors and their caregivers, which provides practical knowledge and new hope for cancer survivors. A major goal of the AACR is to educate the general public and policymakers about the value of cancer research in improving public health, the vital importance of increases in sustained funding for cancer research and biomedical science, and the need for national policies that foster innovation and the acceleration of progress against the 200 diseases we call cancer.