WIH Researchers Examine Role of Hormone HE4 in Patient Responses to Ovarian Cancer Treatment

Researchers at Women & Infants’ Hospital of Rhode Island recently published the results of an investigation into the role of hormone HE4 in patient responses to ovarian cancer treatment.

Researchers at Women & Infants’ Hospital of Rhode Island recently published the results of an investigation into how we might better tailor therapy for ovarian cancer.

The work comes out of the molecular therapeutic laboratory directed by Richard G. Moore, M.D., of Women & Infants’ Program in Women’s Oncology. Entitled “HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation,” the research was recently published in the international science journal Scientific Reports, a Nature publishing group.

The goal of the study was to investigate the role of the hormone HE4 (Human epididymis protein 4) in modulating ovarian cancer’s response to hormones and hormonal therapies. HE4 is a biomarker that is elevated in ovarian cancer and is known to play a role in resistance to chemotherapy.

Richard G. Moore, M.D.

“There is little known about the biologic functions of HE4 but we did know that there were hormonal responsive elements within the promoter region of the HE4 gene, which regulates gene expression. For this reason, we hypothesized that steroid hormones could influence expression of HE4 in ovarian cancer,” Moore explains.

The study resulted in multiple findings:

• Hormonal therapies like tamoxifen (Nolvadex) and fulvestrant (Faslodex) are effective because they bind the estrogen receptor. If cells have less estrogen receptor expression, these drugs can’t do their job. This, the researchers believe, is due to epigenetic modifications which modify the DNA structure but not the DNA sequence itself. Overexpression led to the epigenetic modification known as decreased DNA methylation in cell culture and in human tissue samples.

• Treatment of ovarian cancer cells with tamoxifen and fulvestrant all cause HE4 to translocate to the cell nucleus, where it can then effect further gene expression in cancer cells.

• Using the drug ivermectin (broad-spectrum antiparasitic agent), the researchers were able to inhibit the protein import in-4, which then inhibited HE4 from translocating to the nucleus. If HE4 can’t enter the nucleus, it cannot affect gene expression. The ability to block HE4 from entering the nucleus restored sensitivity to hormonal therapy.

“We are not certain but believe this might mean there could be a subset of women whose tumors are more likely to respond to hormonal therapy. Moreover, we might be able to eventually identify which tumors these are and target treatment,” Moore says.

Dr. Moore’s lab will continue to investigate the expression of estrogen receptors in both primary and recurrent ovarian cancers and how that relates to HE4 expression. In addition, Dr. Moore and other researchers will investigate how importin inhibitors may play a role in addressing chemoresistance to standard therapeutics, particularly in HE4 overexpressing tumors.

About Women & Infants Hospital

Women & Infants’ Hospital of Rhode Island, a Care New England hospital, is one of the nation’s leading specialty hospitals for women and newborns. The primary teaching affiliate of The Warren Alpert Medical School of Brown University for obstetrics, gynecology and newborn pediatrics, as well as a number of specialized programs in women’s medicine, Women & Infants’ is the eighth largest stand-alone obstetrical service in the country with nearly 8,400 deliveries per year.In 2009, Women & Infants opened the country’s largest, single-family room neonatal intensive care unit.

New England’s premier hospital for women and newborns, Women & Infants’ and Brown offer fellowship programs in gynecologic oncology, maternal-fetal medicine, urogynecology and reconstructive pelvic surgery, women’s mental health, neonatal-perinatal medicine, pediatric and perinatal pathology, gynecologic pathology and cytopathology, and reproductive endocrinology and infertility. It is home to the nation’s only mother-baby perinatal psychiatric partial hospital, as well as the nation’s only fellowship program in obstetric medicine.

Women & Infants’ Hospital has been designated as a Breast Center of Excellence from the American College of Radiography; a Center for In Vitro Maturation Excellence by SAGE In Vitro Fertilization; a Center of Biomedical Research Excellence by the National Institutes of Health; and a Neonatal Resource Services Center of Excellence. It is one of the largest and most prestigious research facilities in high risk and normal obstetrics, gynecology and newborn pediatrics in the nation, and is a member of the National Cancer Institute’s Gynecologic Oncology Group and the National Institutes of Health’s Pelvic Floor Disorders Network.

Sources:

• WIH Researchers Examine Role of Hormone in Patient Responses to Ovarian Cancer Treatment, Women & Infants Hospital Press Release, September 8, 2014.

• Lokich E et al. “HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation.” Sci Rep. 2014 Jun 30;4:5500. doi: 10.1038/srep05500. [PMID:24975515] [PMCID:PMC4074789]

Related Posts:

• Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer (March 15, 2009).

• European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer (February 24, 2009).

• Working Smarter, Not Harder: Use of Anti-Estrogen Therapy to Battle Recurrent Ovarian Cancer (August 18, 2008).

Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer

… University of Minnesota researchers evaluated the use of fulvestrant [Faslodex®] in women with recurrent ovarian or primary peritoneal cancer. …Using modified-RECIST criteria 13 patients (50%) achieved SD …[T]he University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

It is well-known that the goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Previously, Fulvestrant (Faslodex®), a novel estrogen receptor (ER) antagonist, was proven clinically beneficial and well-tolerated in treating recurrent breast cancer. If a pathologist determines that a women’s ovarian cancer biopsy is estrogen receptor positive (ER+), there is a possibility that she may respond to anti-estrogen therapy.

On this basis, University of Minnesota researchers evaluated the use of fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Patients with ER+, multiply recurrent ovarian or primary peritoneal carcinoma were eligible for trial enrollment if (i) they had measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, or (ii) an abnormal and rising CA-125 blood test measurement. Treatment consisted of single agent fulvestrant, 500 mg IM (intramuscular) on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until the patient experienced intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as bimonthly CT scans. The clinical trial primary endpoint was “clinical benefit” (CB) (i.e., CB=complete response (CR) + partial response (PR) + stable disease (SD)) at 90 days).

Pursuant to the phase II fulvestrant clinical trial, the study researchers reported the following:

• Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose;
• Patients received a median of 5 prior chemotherapeutic regimens (range: 2-13) prior to enrollment;
• One patient experienced CR (4%), one patient experienced PR (4%), and 9 patients experienced SD (35%) using modified-Rustin criteria (CA-125 level);
• Using modified-RECIST criteria 13 patients (50%) achieved SD;
• The median time to disease progression was 62 days (mean 86 days); and
• Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients).

Based upon the foregoing results, the University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

Primary Source:  A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer; Argenta PA, Thomas SG, Judson PL et. al., Gynecol Oncol. 2009 Feb 22. [Epub ahead of print]