Androgen Deprivation Therapy Can Make Prostate Cancer More Aggressive, Study Finds

Androgen Deprivation Therapy Can Make Prostate Cancer More Aggressive, Study Finds

While androgen deprivation therapy (ADT) is an important treatment for prostate cancer, a new study has found that it sometimes promotes the transformation of prostate cancer cells into a more aggressive type resistant to treatment. However, the findings also suggested that a simple blood test could help predict when ADT resistance would occur.

The study, “Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming,” appeared in The Journal of Clinical Investigation.

Prostate adenocarcinoma, the most common type of prostate cancer, generally responds well to ADT. The therapy aims to reduce levels of the male sex hormone androgen or stop it from stimulating tumor growth. Prostate adenocarcinoma is curable in its early stages.

However, certain patients develop resistance to the hormone therapy, which causes cancer to return or spread. Possible explanations for this include the expansion of a resistant cell population as other cells die and the support of tumor survival by cells from the tumor microenvironment.

Epigenetic changes — which are changes in gene expression rather than in the gene itself — in prostatic cancer-associated fibroblasts (CAFs) can be used to predict disease progression. CAFs are cells that are responsible for generating connective tissue and are able to induce tumor development.

A research team at Cedars-Sinai assessed ADT-related epigenetic changes in cells from the tumor’s surrounding environment to understand how they could affect tumor growth and treatment resistance.

Using fibroblasts from prostate cancer patients and mouse prostates, researchers found that ADT changes the epigenetics of cells in the tumor environment, and the therapy’s interaction with cancer cells led some adenocarcinoma cells to become neuroendocrine cancer cells, a rare type that appears in less 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 [ADT] and chemotherapy,” Neil Bhowmick, PhD, the study’s senior author, said in a press release.

Bhowmick said that about one-fourth of patients on ADT may relapse, with tumors showing characteristics of neuroendocrine prostate cancer, and develop treatment-resistant disease.

By observing the interaction between CAFs and cancer cells, the team found that ADT caused CAFs to produce high levels of the amino acid glutamine. This rise in glutamine supported the high energy requirements of cancer cells, favoring their survival and proliferation.

“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,” said Roberta Gottlieb, MD, a co-author of the study.

The team found that blocking the uptake of glutamine restored sensitivity to ADT in mice with castration-resistant prostate cancer.

An analysis of prostate cancer patients confirmed these findings, with glutamine levels being higher in treatment-resistant patients than in those who responded to ADT.

“Our data suggested that plasma glutamine can be used as a prognostic marker following ADT response and development of resistance,” the scientists wrote.

“The study raises the possibility that a simple blood test measuring glutamine might be able to pinpoint when [ADT] is failing in a prostate cancer patient and even predict when therapy resistance will occur,” said Edwin Posadas, MD, study co-author and co-director of the Translational Oncology Program at Cedars-Sinai. He added that the team will test this hypothesis in a new study.


  1. will Emes Jr. says:

    In the Cedar’s Sinai study regarding stromal epigenetic alterations, why were there two modalities used? What is the value of predicting the time at which ADT fails if the following therapy has to be more agressive and thus more harmful. Is the assumption that there will be developed a therapy which is just slightly more harmful than ADT? Or does that therapy already exist?…….I’m fully aware that we’re not discussing my particular case……..I was diagnosed with a t3, gleason 3/4 prostate cancer just over ten years ago. After a gallium 68/ct scan, it was determined that I had too many lesions,5, to benefit from SBRT. I started ADT 13 months ago. I have no side effects from the ADT.
    My PSA has risen to .7 and I accept my physicians advice to have a PSA
    test every 2 months and to resume ADT when my PSA is between 5 and 10……..I don’t have as keen in interest in the study of prostate cancer as many of the members of my support group…….However, as I have followed my care, my q

    • will Emes Jr. says:

      my question is: After looking at my case, there seems to be an infinite number of things to study. How do you decide what to investigate? there is a limited amount of time and money. do you think that the greater utilization of Bid Data woulds accelerate the discovery of a cure for cancer?
      Will Emess Jr.

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