Researchers from the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have identified specific enzymes called protein kinases that participate in critical steps of bone and prostate cancer metastatic process, suggesting these kinases as potential therapeutic targets. The findings, which were published in the Proceedings of the National Academy of Sciences under the title “Functional screen identifies kinases driving prostate cancer visceral and bone metastasis,” are relevant for the management and treatment of prostate cancer since failure of early detection commonly results in bone metastases that become more difficult to treat and can eventually lead to death.
In the United States, metastatic prostate cancer (PC) kills around 30,000 men each year, making it the second main cause of cancer death in men. Among PC patients, 90% will develop bone metastases, with additional sites of metastases including lymph nodes, liver, adrenal glands, and lungs. The gold-standard of therapies for metastatic disease are androgen blocking therapies that inhibit androgen synthesis or signaling through the androgen receptor. However, metastatic prostate cancer becomes resistant to androgen blocking. Unfortunately, second-line therapies like chemotherapy (docetaxel, cabazitaxel) and radiotherapy only prolong survival for 2 to 4 months. Therefore, there is an urgent need to identify new therapeutic targets for metastatic prostate cancer although it has been a very difficult task. “Once the cancer spreads outside the prostate and becomes less dependent on male hormones like testosterone, few treatment options remain,” Dr. Owen Witte, senior author of the study, stated in a press release.
The human DNA contains more than 500 protein kinases. These proteins are important for the activation of critical cell functions, like growth and survival, and are known to have a role in several tumors. Protein kinases have been effectively targeted with drugs called kinase inhibitors in tumors such as chronic myelogenous leukemia that develop in the bone marrow. The main challenge in developing drugs to target kinases is to identify the particular kinase that is causing the tumor, as these enzymes’ activity differs depending on the type of cancer.
The team analyzed 125 kinases identified in metastatic prostate cancer tissue samples, and then focused their analysis on five kinases that seemed to be more expressed in prostate cancer tissue when it spreads to the bone. Researchers noted these five kinases were not present in benign tumors and early-stage prostate cancer tissue.
“Our findings show that non-mutated protein kinases can drive prostate cancer bone metastasis,” said Claire Faltermeier, the study’s first author and a medical and doctoral student in Witte’s lab. “Now, we can investigate if therapeutic targeting of these kinases can block or inhibit the growth of prostate cancer bone metastasis.”
Dr. Witte’s lab has been trying to understand how cancer develops at the cellular level. He has revealed that a particular type of kinase activity, called tyrosine kinase, can play a role in certain types of leukemia, which was the basis for the design of Gleevec, the first targeted therapy for chronic myelogenous leukemia.
“Cancer-causing kinase activity has been successfully targeted and inhibited before. As a result, chronic myelogenous leukemia is no longer fatal for many people,” said Witte, who also is a member of the UCLA Jonsson Comprehensive Cancer Center and a professor of microbiology, immunology and molecular genetics at the UCLA David Geffen School of Medicine. “I believe we can accomplish this same result with advanced stages of prostate cancer with a fundamental understanding of the cellular nature of the disease.”
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