A University of Kentucky Markey Cancer Center study reveals how prostate cancer cells adapt their metabolism to thrive in bone tissue, offering a potential new treatment target for patients with advanced disease.
The research, led by Ka Wing Fong, Ph.D., and published in Molecular Cancer Research, identifies a biological pathway that helps prostate cancer cells produce the energy they need to grow in bone. The findings could lead to new therapies for patients with bone metastases, which occur in approximately 90% of men who die from metastatic prostate cancer.
When prostate cancer spreads to the bones, current treatments often provide limited relief from pain and other complications. Patients with bone metastases face a five-year survival rate of just 33%.
The research team found that a protein called TRIM28 activates a metabolic enzyme known as LDHA. LDHA helps cancer cells convert glucose into energy through a process called glycolysis. The study showed that blocking this TRIM28-LDHA pathway reduced tumor growth in lab models.
"By targeting how these tumors generate energy, researchers may be able to develop more targeted therapies that work alongside existing treatments to control disease in bone more effectively," said Fong, an assistant professor in the UK College of Medicine's Department of Toxicology and Cancer Biology.
Using tissue samples from patients with advanced prostate cancer, the researchers detected pS473-TRIM28, which is a transcription activator in bone metastases. They then used mouse models to test whether disrupting the TRIM28-LDHA pathway could slow tumor growth in bone tissue.
The experiments showed that cancer cells with reduced TRIM28 or LDHA produced less lactate, consumed less glucose, and grew more slowly in bone. Treatment with an experimental drug that blocks LDHA activity also reduced tumor growth in mouse models.
Analysis of patient data also revealed that people with high levels of both TRIM28 and LDHA had worse outcomes than those with lower levels of these proteins.
The current study builds on Fong's research into TRIM28's role in prostate cancer. In a study published in the Journal of Clinical Investigation earlier this year, his team showed that a protein called RSK1 activates TRIM28, which then works with another protein called E2F1 to help cancer cells grow and resist hormone therapy.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R03CA256230, and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121327. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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