Low estrogen 'improves efficacy' of PARP inhibitors on womb cancer

13/11/2013

Researchers have discovered that low hormone levels may make endometrial cancer tumors more sensitive to a class of medication called PARP inhibitors - drugs that induce cancer cell death. This is according to a study published in the journal Molecular Cancer Therapeutics.

Endometrial cancer, also known as womb cancer, forms in the tissue lining of the uterus. According to the National Cancer Institute, 49,560 new cases of womb cancer are expected in the US this year, including 8,190 deaths from the disease.

Investigators from the University of California-Los Angeles (UCLA) say that previous research on endometrial cancer cell lines has shown that poly ADP-ribose polymerase (PARP) inhibitors are able to promote cancer cell death in the absence of a protein called phosphatase and tensin homolog (PTEN) - a tumor suppressor.

Missing PTEN is a defect found in 80% of endometrial cancers, the researchers say. The deletion is believed to cause damage to DNA by impairing the cell signaling pathway.

For this pre-clinical trial, the researchers wanted to see whether PARP inhibitors would be effective in a laboratory model within a tumor microenvironment that closely resembled human womb cancer.

PARP 'not reliant' on PTEN mutation

A PARP inhibitor was given to the model in two hormonal extremes - high and low estrogen.

The researchers saw a reduction in tumor size when low estrogen was administered. However, to their surprise, there was no response to the PARP inhibitor at all in the high estrogen environment.

Dr. Daniel Paik, a 3rd year fellow in gynecologic oncology at UCLA and an investigator in the study, explains:

"We wanted to see if the inhibitors were effective in endometrial tumors that had PTEN loss, on the premise that PTEN is involved in DNA repair and its loss interfered with this process.

In our experiments, we found that tumors treated with the inhibitors did show decreased growth, but that this did not rely solely on the loss of PTEN."

Low estrogen levels 'determine drug's effectiveness'

On repeating the experiment, the researchers did not administer any estrogen alongside the PARP inhibitor, meaning the tumors were within a low-level hormonal environment. This caused the tumors to shrink significantly.

Explaining why this happened, the investigators say that estrogen levels affected the metabolism of the PARP inhibitor, and a low estrogen level caused a significant increase in the amount of the drug that was detected in the blood stream. This meant there was more of the PARP inhibitor available to fight the cancer.

They discovered that a high estrogen environment caused less of the drug to circulate the system. However, they were still able to see signs of drug activity within the tumors.

On further investigation, they found that a high estrogen environment caused the tumors to better repair cell damage, and DNA repair built up resistance to the PARP inhibitor. But a low estrogen environment meant the tumors were less able to repair cell damage, meaning the PARP inhibitors could induce tumor cell death.

Commenting on their findings, Dr. Sanaz Memarzadeh, an assistant professor of obstetrics and gynecology at UCLA and study investigator, says:

"This study showed us that endometrial cancers that have defects in PTEN are sensitive to PARP inhibition, but the response hinges on low levels of estrogen.

And we learned that the hormonal milieu may significantly impact tumor response to this therapy. The difference in the response was remarkable. It was like night and day."

The researchers say their findings could lead to an alternative treatment option for womb cancer as opposed to conventional treatments that can have limited efficacy, particularly in the late stages.

They note that extension of this research to clinical trials "could personalize the therapy of women afflicted with advanced endometrial cancer using well-tolerated orally administered therapeutic agents."

Dr. Memarzadeh adds that their findings could also be relevant to other hormone-driven cancers, such as breast, ovarian and prostate cancers.

Earlier this year, Medical News Today reported on a study suggesting that women could reduce the risk of womb cancer through healthy eating, coffee drinking and exercising.

 

Source: Medical News Today: http://www.medicalnewstoday.com/articles/268702.php

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