Sensitizing endometrial tumors to PARP inhibitors

Modulating the hormonal environment in which endometrial cancers grow could make tumors significantly more sensitive to a new class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors, according to new research. The findings could lead to a novel one-two punch therapy to fight endometrial cancers and provide an alternative option for conventional treatments that, particularly in advanced disease, have limited efficacy.

Studies on endometrial cancer cell lines have shown that PARP inhibition induces cell death when tumor suppressor phosphatase and tensin homolog (PTEN) is missing, a defect found in about 80% of human endometrial cancers. However, the research team, from the University of California at Los Angeles, wanted to test the inhibitors in a laboratory model with a tumor microenvironment that closely resembles human endometrial cancer to see if this therapy would be effective, said study senior author Sanaz Memarzadeh, MD, PhD, and an assistant professor of obstetrics and gynecology and director of the Gynecologic Oncology (G.O.) Discovery Lab at UCLA.

“A PARP inhibitor was given orally in two hormonal extremes—high and low estrogen,” Memarzadeh said. “The treatment achieved a significant reduction in tumor size in a low estrogenic milieu. In striking contrast, no response to the inhibitor was seen in tumors exposed to high levels of estrogen.”

The G.O. Discovery research team began their work testing PARP inhibitors in endometrial cancer after clinical testing in breast and ovarian cancers showed that the drugs were only harmful to cells if they had a defect in DNA double strand repair, which is common in some cancers. The BRCA gene mutations that can cause breast and ovarian cancers interfere with the cell's DNA homologous recombination repair pathway. PTEN mutation or deletion is also thought to cause DNA damage by interfering with this cell-signaling pathway.

“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,” said third-year fellow Daniel Paik, MD. “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.”

The researchers found that the PTEN-null tumors did not respond to PARP inhibitors in high-level estrogen environments. When the experiment was repeated in the absence of estrogen, the tumors shrank significantly. Estrogen levels affected the metabolism of the PARP inhibitor.

“Results of this pre-clinical trial suggest that orally administered PARP inhibitors in a low estrogenic hormonal milieu can effectively target PTEN-null endometrial tumors,” the study concluded. “Extension of this work to clinical trials could personalize the therapy of women afflicted with advanced endometrial cancer using well-tolerated orally administered therapeutic agents.”

The study appeared in Molecular Cancer Therapeutics (2013; doi:10.1158/1535-7163.MCT-13-0572).

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