Estrogen Levels Affect the Efficacy of PARP Inhibitors in PTEN-Deficient Endometrial Tumors
PARP inhibition appears to be an effective way to shrink PTEN-deficient endometrial tumors with low levels of estrogen but is ineffective in those with high levels of estrogen, according to preclinical study results reported by Janzen et al in Molecular Cancer Therapeutics. The findings suggest that modulating the hormonal environment may render PTEN-deficient endometrial tumors more sensitive to PARP inhibitors such as olaparib.
Preclinical Study Findings
Investigators at the University of California, Los Angeles, established an in vivo mouse model to evaluate the therapeutic efficacy of PARP inhibitors in endometrial tumors driven by the loss of PTEN. This laboratory model had a tumor microenvironment that closely resembled human endometrial cancer. The orally bioavailable PARP inhibitor olaparib was given to mice with PTEN-deficient endometrial tumors in two hormonal conditions: high or low levels of estrogen.
The hormonal milieu was the key factor in the response to olaparib. A measurable response to PARP inhibition was not demonstrated in tumors exposed to high estrogen levels. Furthermore, there appeared to be no significant effect on tumor size or mass of the PTEN-deficient tumors with high estrogen levels. The investigators indicated that high estrogen levels may induce resistance to PARP inhibition.
In contrast, low levels of circulating estrogen seemed to sensitize these same PTEN-deficient endometrial tumors to the antitumor effects of olaparib. A significant reduction in the size of these tumors and a sustained inhibition of activity of the PARP enzyme in the tumor bed were noted. Although there was evidence of residual cancer in these tissues after treatment with olaparib, there was a sixfold decrease in tumor mass.
Difference in Peak Serum Drug Concentrations
The investigators also reported a difference in serum drug concentrations related to estrogen levels. Serum concentrations of olaparib peaked at 2 hours in mice supplemented with estrogen, which coincided with maximal PARP inhibition in the tumor. The drug levels steadily declined after 2 hours, which again was associated with decreased PARP inhibition in the tumor. As for the mice with low estrogen levels, serum drug concentrations peaked at 30 minutes and were 20-fold higher than those in the mice with higher levels of estrogen.
To shed more light on the difference in circulating drug levels in each hormonal milieu, the investigators examined the expression of CYP3A41; this is a mouse homologue of CYP3A4, the primary enzyme that metabolizes olaparib in humans and may be regulated by estrogen. They found significantly higher levels of CYP3A41 transcript in estrogen-treated vs estrogen-depleted mice.
In addition, endogenous estrogen levels may impact the function of Rad51, which the investigators called a critical protein involved in homologous recombination. In a high estrogenic milieu, the function of Rad51 may promote resistance to PARP inhibition in PTEN-deficient endometrial tumors, they added.
Clinical Implications
Based on the findings of this preclinical study, the investigators suggested that PARP inhibition be tested in conjunction with hormonal ablation in clinical trials treating women with PTEN-deficient endometrial tumors. In addition, they noted, their study results may be relevant to other hormone-driven cancers, such as breast, prostate, and ovarian tumors.
Both the bioavailability of olaparib and the efficiency of cell death induced by PARP inhibition seemed to be affected by estrogen levels. A patient’s hormonal status could alter the optimal dosing of olaparib required to achieve a therapeutic response, according to the authors. Therefore, the use of PARP inhibitors in combination with hormonal therapy may prove to be a novel approach to treating women with PTEN-deficient endometrial cancers.
In closing, the investigators concluded, “Extension of this work to clinical trials could personalize the therapy for women afflicted with advanced endometrial cancer using well-tolerated orally administered therapeutic agents.”
Sanaz Memarzadeh, MD, PhD, of the University of California, Los Angeles, is the corresponding author of the article in Molecular Cancer Therapeutics.
This study was funded by the Concern Foundation, National Cancer Institute, UCLA’s Scholars in Translational Medicine Program, Mary Kay Foundation, STOP Cancer, Broad Stem Cell Research Center Research Award, Sidney Kimmel Foundation, National Center for Research Resources, and the University of California Research Coordinating Committee.
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