Amy Skubitz

Pilot Study of Daily Exemestane in Women with Endometrial Intraepithelial Neoplasia or Low-Grade Endometrial Cancer

Abstract Purpose: To evaluate exemestane, an aromatase inhibitor, as a preventive intervention for endometrial cancer. Experimental Design: This is a multicenter, single-arm, “window of opportunity” pilot study of exemestane (25 mg daily for 21–42 days) in postmenopausal individuals undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer. The primary objective is to determine the change in proliferation, measured by Ki-67 expression, in pre- and posttreatment endometrial tissue specimens. Secondary outcomes include measurement of circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety, and adverse effects. Results: Forty participants were accrued to the study. The mean body mass index was 40.3 (range, 22.8–60.5, SD = 9.8). Preoperative diagnoses included EIN (n = 11, 27.5%), grade 1 endometrial cancer (n = 26, 65%), and grade 2 endometrial cancer (n = 3, 7.5%). Median Ki-67 score decreased from 40.7% [IQR (33.9, 50.3)] at baseline to 18.1% [IQR (8.8, 31.8)] at surgery, representing a median absolute change from baseline of 20.4% [IQR (−29.9, −6.7), P < 0.001]. In a matched historic control cohort, participants also had a decrease in Ki-67 score with a median absolute change from baseline of −6.7% [IQR (−12.7, −1.3), P< 0.001]. However, the decrease in Ki-67 was greater in the study participants than the historic controls, with a median difference between the groups of −13.4% [IQR (−23.3, 6.9), P ≤ 0.01]. Both tissue estrogen receptor and progesterone receptor expression declined significantly with exemestane treatment (P < 0.001). However, serum estradiol levels did not change between baseline and after treatment (P = 0.16). Conclusions: In this pilot study, exemestane demonstrated antiproliferative effects in EIN and low-grade endometrial cancer. This agent warrants further evaluation for the prevention of endometrial cancer.

Inhibition of Ovarian Cancer Cell Spheroid Formation by Synthetic Peptides Derived from Nectin-4

The formation of 3D multicellular spheroids in the ascites fluid of ovarian cancer patients is an understudied component of the disease progression. Spheroids are less sensitive to chemotherapy, in part due to the protection afforded by their structure, but also due to their slower proliferation rate. Previous studies suggest that the cell adhesion molecule Nectin-4 plays a key role in the formation of ovarian cancer spheroids. In this study, we further examined the role of Nectin-4 at early time points in spheroid formation using real-time digital photography. Human NIH:OVCAR5 ovarian cancer cells formed aggregates within 8 h, which further contracted into compact spheroids over 24 h. In contrast, Nectin-4 knockdown cells did not form tightly compacted spheroids. Synthetic peptides derived from Nectin-4 were tested for their ability to alter spheroid formation in two ovarian cancer cell lines. Nectin-4 peptide 10 (N4-P10) had an immediate effect on disrupting ovarian cancer spheroid formation, which continued for over 24 h, while a scrambled version of the peptide had no effect. N4-P10 inhibited spheroid formation in a concentration-dependent manner and was not cytotoxic; suggesting that N4-P10 treatment could maintain the cancer cells as single cells which may be more sensitive to chemotherapy.