“ We are examining the genomic and cellular signaling perturbations in select human cancers —and our goal is to identify suitable targets for intervention in cancer.” – JONATHAN CHERNOFF, MD, PhD
HOW DOES TWEAKED PHOSPHORYLATION LEAD TO NEOPLASTIC TRANSFORMATION? Oncogenic Signals: A Trail of Clues in the Cell To solve crimes, detectives follow the money. To cure cancer, researchers follow the protein kinases. These enzymes transmit signals inside cells—their currency is phosphorylation—and they often become hyperactive in cancer. Acting on orders from GTPases like Cdc42 and Rac, they regulate downstream molecules to alter cell motility, proliferation, or survival. In the labs of Jonathan Chernoff, MD, PhD, the large family of p21-activated kinases (PAKs) is under surveillance. The goal is to identify the substrates that take the PAK phosphorylation payoff to pull the trigger and disrupt cell function. The Fox Chase group is studying PAK activity in disease models of neurofibromatosis, mesothelioma, breast cancer, and noncancer conditions. They are also exploring the role of protein tyrosine phosphatase 1B in cancer. Jeffery R. Peterson, PhD, takes a wide-lens view of the more than 500 human protein kinases identified thus far. His team has created high-throughput screening techniques and other biochemical, microscopic, and cell and animal models to characterize and catalog the “kinome.” This systems-level analysis has led to identification and testing of drug-like molecules capable of inactivating kinase function that could lead to new cancer therapies. The group led by Joseph R. Testa, PhD, was the first to link AKT kinase to human cancer. Since that seminal finding, Dr. Testa’s laboratory went on to identify genes that overlap and interact with this major AKT oncogenic pathway. They also discovered that specific tumor suppressors elevate the risk of highly invasive malignant mesothelioma. Their recent BAP1 findings prompted development of a test for early detection of mesothelioma and led to recognition of a cancer susceptibility known as BAP1 Syndrome.
CANCER
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