Scientists at Cedars-Sinai, a non-profit, tertiary 958-bed hospital and multi-specialty academic health science center located in the Beverly Grove neighborhood of Los Angeles, California, have discovered how prostate cancer can sometimes withstand and even outwit a standard hormone therapy. This may cause the cancer to spread.
Their findings also point to a simple blood test that may help doctors predict when this type of hormone therapy resistance will occur.
Located just below the bladder in men, the prostate is a gland approximately the size of a walnut. It promotes proper sexual function by contributing fluid to the ejaculate.
According to the American Cancer Society, prostate cancer is the second-leading cause of cancer death in men, behind lung cancer, killing nearly 30,000 in the U.S. each year. In its early stages, the most common type, adenocarcinoma, is curable and generally responds well to therapies, including those that target androgen – a male sex hormone that stimulates tumor growth.
Because prostate cancer is usually a slow growing cancer, most men diagnosed with the disease generally die from causes unrelated to their prostate cancer.
However, in certain patients, the cancer becomes resistant to androgen-targeted therapy, and the cancer recurs or spreads. One possible reason for that resistance, the study indicated, appears to be that the therapy causes some adenocarcinoma cells to become neuroendocrine cancer-type cells – a rare type that normally appears in fewer than 1 percent of prostate cancer patients.
“This transformation is a problem because neuroendocrine prostate cancer is especially aggressive, metastasizes more readily and is more resistant to both androgen-targeted therapy and chemotherapy,” explained Neil Bhowmick, PhD, co-director of the Cancer Biology Program at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai.
Bhowmick is senior author of the study, published in The Journal of Clinical Investigation, and Rajeev Mishra, PhD, former project scientist in his laboratory, is the lead author.
The study was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) and the U.S. Department of Veterans Affairs.
About one-fourth of the patients who receive androgen-targeted therapy may relapse with tumors that show features of neuroendocrine prostate cancer and develop treatment-resistant disease, according to published research.
Treatment-resistant disease means that the cancer does not, or no longer, respond to, or resist, treatment. This is also called refractory disease or refractory cancer.
To learn more about this process, the investigators examined the interactions between the tumor epithelia and its microenvironment and how cancer cells interact with the non-cancerous supporting cells near the tumor, referred to as the cancer microenvironment or tumor microenvironment, in laboratory mice. This microenvironment include fibroblasts, immune cells and cells that comprise the blood vessels. It also includes proteins produced by cells present in the tumor that support the growth of tumor cells.
The researchers epigenetic changes in cancer-associated prostatic fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. These interactions, they noted, raised the level of the amino acid glutamine, turning the supporting cells into “factories” that supplied fuel for the cancer cells.
Glutamine is the most abundant amino acid in the blood and tissues. It is essential for tumor growth and marked changes in organ glutamine metabolism are characteristic of the host with cancer.
“While glutamine is known to spur cancer growth, its role in prostate cancer cells to trigger reprogramming of adenocarcinoma cells into neuroendocrine cancer cells is a new and important finding,” explained Roberta Gottlieb, MD, professor of Medicine and vice chair of translational medicine in the Department of Biomedical Sciences at Cedars-Sinai.
Gottlieb was a co-author of the study.
The team also examined how androgen-targeted therapy affected the cancer microenvironment.
“To our surprise, we found this type of therapy further changed the cellular environment in a way that caused adenocarcinoma cells in the prostate to transform into neuroendocrine cancer-type cells,” observed Bhowmick, professor of Medicine and Biomedical Sciences.
As the final step in validating the findings in mice, investigators compared levels of glutamine in the plasma of small groups of patients – one with treatment-responsive prostate cancer and the other with treatment-resistant prostate cancer. They found that levels of glutamine were higher in the second group.
This finding has potential implications for treating prostate cancer patients, said Edwin Posadas, MD, co-director of the Translational Oncology Program at the cancer institute and associate professor and clinical chief of the Division of Hematology/Oncology in the Department of Medicine at Cedars-Sinai.
Simple blood test
The study raises the possibility that a simple blood test measuring glutamine might be able to pinpoint when androgen-targeted therapy is failing in a prostate cancer patient and even predict when therapy resistance will occur,” Posadas said, who co-authored the study.
He said the team is designing a new study to test this hypothesis.
 Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P, Duong F, Angara B, et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018 Jul 26. pii: 99397. doi: 10.1172/JCI99397. [Pubmed][Full Text]
 Souba WW Glutamine and cancer. Ann Surg. 1993 Dec;218(6):715-28. [Pubmed][Full Text]
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Featured Image: Hands holding blue prostate cancer awareness ribbon. Courtesy: © 2010 – 2018 Fotolia. Used with permission. Illustration 1.0: Research conducted by a team of physicians at Cedars-Sinai raises the possibility that a simple blood test measuring glutamine might pinpoint when androgen-targeted therapy is failing in a prostate cancer patient. Courtesy: © 2010 – 2018 Getty Images. Used with permission.
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