PDK1 Gene Identified as New Target for Melanoma Treatment
According to new research at Sanford-Burnham Medical Research Institute a gene encoding the enzyme phosphoinositide-dependent kinase-1 (PDK1) plays an essential role in the development and progression of melanoma. The finding, published online in Oncogene, may offer insight toward a new approach to treating melanoma.
The team of researchers, led by Ze’ev Ronai, PhD, Professor and Scientific Director of Sanford-Burnham Medical Research Institute in La Jolla, California, used genetic mouse melanoma models to show the importance of the PDK1 gene in melanoma. Specifically, mice lacking the PDK1 gene in their melanocytes had smaller melanoma tumors, a significant loss of metastasis, and a prolonged survival time. In some cases, the median survival time was increased by more than 50%. Further, by treating mice that carried the PDK1 gene with an inhibitor of PDK1, the scientists were able to delay the development of melanoma and inhibit metastasis.
“We have shown that PDK1 is required for melanoma metastasis, and that by inactivating the PDK1 enzyme we can delay the onset of melanoma lesions and almost completely abolish metastasis,” Dr. Ronai said. Prior to this study, it was known that PDK1 activity played an important role in normal cell processes such as cell metabolism, protein translation, and cell survival. PDK1 activity was also known to be associated with specific tumor types. For example, inactivation of PDK1 activity has been shown to inhibit pancreatic cancer. This study provides genetic evidence for the importance of PDK1 in melanoma.
Novel Treatment Approach
David Fisher, MD, PhD, Professor and Chairman of the Edward Wigglesworth Department of Dermatology, Director of the Melanoma Program, and Director of Cutaneous Biology at Massachusetts General Hospital, Harvard Medical School, commented, “The study by Ronai and colleagues is novel and important for melanoma therapeutics because it identifies a new and tractable treatment approach. The investigators achieved impressive results which validate PDK1 as a new treatment target for melanoma.”
“This collaboration between Sanford-Burnham and Yale researchers shows unequivocally that melanoma cells require PDK1 for both development and metastasis. The team also demonstrates that a molecular inhibitor is capable of duplicating the effects of the genetic approaches suggesting that the cancer field should invest more efforts into PDK1 targets,” said Meenhard Herlynn, DVM, DSc, Director of Melanoma Research and Leader, Molecular and Cellular Oncogenesis program at the Wistar Institute in Philadelphia.
“It is important now to demonstrate the impact of PDK1 inhibition in combination with other therapies currently used in melanoma, including [BRAF inhibitors] or immunological targets (PD1/CTL4A), on melanoma development and metastasis. A number of [PDK1 inhibitors] are available and others are in development, offering an important addition to the currently available combination therapies. Ultimately, our goal is to see if inhibition of PDK1 will contribute to better outcomes for patients with melanoma,” Dr. Ronai said.
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