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Endometrial cancer (EC) shares risk factors (e.g. obesity) with cardiovascular disease (CVD), yet little research has investigated CVD diagnoses among EC survivors. We aimed to describe the burden of CVD diagnoses among older women with EC compared to women without a cancer history.Women aged 66+ years with an EC diagnosis during 2004-2017 (N = 44,386) and matched women without cancer (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the cancer diagnosis date of the EC case in that matched set. ICD-9/10 diagnosis codes were used to define CVD outcomes in the Medicare claims. Prevalent CVD was identified using diagnosis codes in the year before the index date. Hazard ratios (HRs) for incident CVD diagnoses after the index date were estimated using multivariable Cox proportional hazards regression. Women with a prevalent CVD were excluded from incidence analyses for that outcome.Compared to women without cancer, women with EC had a higher prevalence of CVD diagnoses at the index date. In analyses beginning follow-up at 1 year post-index date, EC survivors had an increased risk of incident CVD diagnoses including ischemic heart diseases (HR = 1.73; 95% CI: 1.69-1.78), pulmonary heart disease (HR = 1.95; 95% CI: 1.88-2.02), and diseases of the veins and lymphatics (HR = 2.71; 95% CI: 95% CI: 2.64-2.78). Risk of CVD diagnoses among women with EC was also elevated within the first year post-index date.Management of pre-existing CVD and monitoring for incident CVD may be critical during EC treatment and throughout long-term survivorship.

Uterine abnormalities resulting from neonatal exposure to GEN or DES.

Purpose Although paclitaxel is a promising first-line chemotherapeutic drug for ovarian cancer, acquired resistance to paclitaxel is one of the leading causes of treatment failure, limiting its clinical application. Asparagus officinalis has been shown to have anti-tumorigenic effects on cell growth, apoptosis, cellular stress and invasion of various types of cancer cells and has also been shown to synergize with paclitaxel to inhibit cell proliferation in ovarian cancer. Methods Human ovarian cancer cell lines MES and its PTX-resistant counterpart MES-TP cell lines were used and were treated with Asparagus officinalis and paclitaxel alone as well as in combination. Cell proliferation, cellular stress, invasion and DMA damage were investigated and the synergistic effect of a combined therapy analyzed. Results In this study, we found that Asparagus officinalis combined with low-dose paclitaxel synergistically inhibited cell proliferation, induced cellular stress and apoptosis and reduced cell invasion in paclitaxel-sensitive and -resistant ovarian cancer cell lines. The combined treatment effects were dependent on DNA damage pathways and suppressing microtubule dynamics, and the AKT/mTOR pathway and microtubule-associated proteins regulated the inhibitory effect through different mechanisms in paclitaxel-sensitive and -resistant cells. Conclusion These findings suggest that the combination of Asparagus officinalis and paclitaxel have potential clinical implications for development as a novel ovarian cancer treatment strategy.

Background: We investigated excess mortality after endometrial cancer using conditional relative survival estimates and standardized mortality ratios (SMR). Methods: Women diagnosed with endometrial cancer during 2000–2017 (N = 183,153) were identified in the Surveillance Epidemiology and End Results database. SMRs were calculated as observed deaths among endometrial cancer survivors over expected deaths among demographically similar women in the general U.S. population. Five-year relative survival was estimated at diagnosis and each additional year survived up to 12 years post-diagnosis, conditional on survival up to that year. Results: For the full cohort, 5-year relative survival was 87.7%, 96.2%, and 97.1% at 1, 5, and 10 years post-diagnosis, respectively. Conditional 5-year relative survival first exceeded 95%, reflecting minimal excess mortality compared with the general population, at 4 years post-diagnosis overall. However, in subgroup analyses, conditional relative survival remained lower for Black women (vs. White) and for those with regional/distant stage disease (vs. localized) throughout the study period. The overall SMR for all-cause mortality decreased from 5.90 [95% confidence interval (CI), 5.81–5.99] in the first year after diagnosis to 1.16 (95% CI, 1.13–1.19) at 10+ years; SMRs were consistently higher for non-White women and for those with higher stage or grade disease. Conclusions: Overall, endometrial cancer survivors had only a small survival deficit beyond 4 years post-diagnosis. However, excess mortality was greater in magnitude and persisted longer into survivorship for Black women and for those with more advanced disease. Impact: Strategies to mitigate disparities in mortality after endometrial cancer will be needed as the number of survivors continues to increase.

Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

The aim of this study was to investigate survival differences between equivalent residual disease [complete gross resection (CGR), minimal residual disease (MRD), suboptimal] at the time of primary debulking surgery (PDS) and interval debulking surgery (IDS). The National Cancer Database was used to identify patients from 2010 to 2015 with stage IIIC/IV primary peritoneal or ovarian cancer who had residual disease recorded. Propensity score matching (PSM) was used to correct for differences in characteristics between the PDS and IDS groups. Of 8683 patients with advanced ovarian cancer, 4493 (52%), 2546 (29%), and 1644 (19%) had CGR, MRD, or suboptimal resection, respectively. From 2010 to 2015, the number of patients undergoing IDS increased 27% (ptrend

Over the last decade, there has been a dramatic surge in research exploring the human gut microbiome and its role in health and disease. It is now widely accepted that commensal microorganisms coexist within the human gastrointestinal tract and other organs, including those of the reproductive tract. These microorganisms, which are collectively known as the "microbiome", contribute to maintaining host physiology and to the development of pathology. Next generation sequencing and multi-'omics' technology has enriched our understanding of the complex and interdependent relationship that exists between the host and microbiome. Global changes in the microbiome are known to be influenced by dietary, genetic, lifestyle, and environmental factors. Accumulating data have shown that alterations in the gut microbiome contribute to the development, prognosis and treatment of many disease states including cancer primarily through interactions with the immune system. However, there are large gaps in knowledge regarding the association between the gut microbiome and gynecologic cancers, and research characterizing the reproductive tract microbiome is insufficient. Herein, we explore the mechanisms by which alterations in the gut and reproductive tract microbiome contribute to carcinogenesis focusing on obesity, hyperestrogenism, inflammation and altered tumor metabolism. The impact of the gut microbiome on response to anti-cancer therapy is highlighted with an emphasis on immune checkpoint inhibitor efficacy in gynecologic cancers. We discuss dietary interventions that are likely to modulate the metabolic and immunologic milieu as well as tumor microenvironment through the gut microbiome including intermittent fasting/ketogenic diet, high fiber diet, use of probiotics and the metabolic management of obesity. We conclude that enhanced understanding of the microbiome in gynecologic cancers coupled with thorough evaluation of metabolic and metagenomic analyses would enable us to integrate novel preventative strategies and adjunctive interventions into the care of women with gynecologic cancers.

Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre‐ and post‐metformin‐treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalTrials.gov: NCT01911247) were analyzed by mass spectrometry (MS)‐based proteomic and immunohistochemical analyses. Jupiter microtubule‐associated homolog 1 (JPT1) was significantly elevated in metformin responders (n = 13) vs nonresponders (n = 7), and found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for JPT1. Metformin response and loss of JPT1 were assessed in RL95‐2 and ACI‐181 endometrial cancer (EC) cell lines. We further identified that silencing of JPT1 abundance does not alter cellular response to metformin or basal cell proliferation, but that JPT1 abundance does decrease in response to metformin treatment in RL95‐2 and ACI‐181 EC cell lines. These data suggest that JPT1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable preoperative EEC patient stratification to metformin treatment and the ability to monitor patient response., We report JPT1 (Jupiter microtubule‐associated homolog 1) as a predictive and pharmacodynamic biomarker candidate of metformin response in endometrial cancers.

Background: Endometrial cancer and its treatment may impact urinary system function, but few large-scale studies have examined urinary diagnoses among endometrial cancer survivors. We investigated the risk of several urinary outcomes among older women with endometrial cancer compared with similar women without a cancer history. Methods: Women aged 66+ years with an endometrial cancer diagnosis during 2004–2017 (N = 44,386) and women without a cancer history (N = 221,219) matched 1:5 on exact age, race/ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to define urinary outcomes in the Medicare claims. HRs for urinary outcomes were estimated using multivariable Cox proportional hazards regression models. Results: Relative to women without cancer, endometrial cancer survivors were at an increased risk of several urinary system diagnoses, including lower urinary tract infection [HR, 2.36; 95% confidence interval (CI), 2.32–2.40], urinary calculus (HR, 2.22; 95% CI, 2.13–2.31), renal failure (HR, 2.28; 95% CI, 2.23–2.33), and chronic kidney disease (HR, 1.85; 95% CI, 1.81–1.90). Similar associations were observed in sensitivity analyses limited to 1+ and 5+ years after endometrial cancer diagnosis. Black race, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often significant predictors of urinary outcomes among endometrial cancer survivors. Conclusions: Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer. Impact: Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history.

Endometrial cancer (EC) is a highly obesity-driven cancer, with limited treatment options. ONC201 is an imipridone that selectively antagonizes the G protein-coupled receptors dopamine receptor D2 and D3 (DRD2/3) and activates human mitochondrial caseinolytic protease P (ClpP). It is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through induction of the integrated stress response (ISR) as well as through stimulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and subsequent induction of apoptosis. ONC201 is being evaluated in Phase II clinical trials for solid tumors and hematological malignancies, including EC. ONC206 is an analog of ONC201 with nanomolar potency in Phase I clinical trials. This study evaluated the anti-tumor efficacy of ONC206 in EC cell lines and the Lkb1(fl/fl)p53(fl/fl) genetically engineered mouse model of endometrioid EC. ONC206 revealed greater potency than ONC201 in the inhibition of proliferation in EC cell lines, with IC50 concentration ranges of 0.21-0.32 µM for ONC026 versus 2.14-3.53 µM for ONC201. ONC206 induced cellular stress, apoptosis and cell cycle G1 arrest, accompanied by inhibition of the AKT/mTOR/S6 pathways in EC cells. Diet-induced obesity accelerated tumor growth in Lkb1(fl/fl)p53(fl/fl) mice. ONC206 inhibited EC tumor size and weight in both obese and lean mice after 4 weeks of treatment. Treatment with ONC206 led to a decrease in expression of Ki67, BCL-XL and phosphorylation of S6, as well as an increase in ClpP in endometrial tumors under both obese and lean conditions. Overall, the pre-clinical efficacy of ONC206 is promising and worthy of further exploration in clinical trials for endometrioid EC.

Objective This study was aimed to measure the effects of a high-fat diet and metformin on placental mechanistic target of rapamycin (mTOR) signaling in mice. Study Design Pregnant friend virus B (FVB)-strain mice were allocated on embryonic day (e) 0.5 to one of four groups; group 1: control diet (CD, 10% fat) + control treatment (CT), group 2: CD + metformin treatment (MT), group 3: high-fat diet (HFD, 60% fat) + CT, and group 4: HFD + MT. Metformin (2.5 mg/mL) was provided in water; CT mice received water. Fetuses and placentas were collected. Western blot measured placental p-Akt and p-S6 expression. Results 20 dams (five/group) and 192 fetuses were studied. Compared with CD-fed, HFD-fed dams had higher placental p-Akt protein expression (p Conclusion Increased placental mTOR signaling and metformin inhibition of placental mTOR signaling only occurred in the presence of an HFD exposure. These findings suggest that metformin may modulate placental mTOR signaling in the presence of metabolic exposures during pregnancy.

Objectives Evaluate association between obesity and angiogenic-related gene expression in endometrial cancer (EC). Evaluate interaction between diet and metformin on angiogenic-related gene expression. Methods We evaluated the association between 168 human angiogenic-related genes and body mass index (BMI) in the TCGA Uterine Corpus Endometrial Carcinoma cohort (endometrioid endometrial cancer (EEC) cohort n = 290, and copy number high cohort n = 55), an independent validation cohort from Gynecologic Cancer Center of Excellence (GYN-COE) (n = 62) and corresponding 185 homologous mouse genes in an LKB1fl/flp53fl/fl mouse model of EC (n = 20). Mice received 60% of calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% of calories from fat in a low-fat diet (LFD). After tumor growth, HFD (n = 5) and LFD (n = 5) mice were treated with metformin (200 mg/kg/day) or control. Whole transcriptome analysis of mouse tumors was performed using RNA-Seq. Results At a false-discovery rate of 10%, twenty-one angiogenic-related genes were differentially expressed with respect to BMI when adjusting for grade in the TCGA EEC cohort. Evaluation of these genes in the mouse model control group revealed association between increased Edil3 expression in HFD versus LFD mice (2.5-fold change (FC); unadjusted p = 0.03). An interaction was observed for expression of Edil3 between diet and metformin treatment (unadjusted p = 0.009). Association between BMI and increased expression of EDIL3 was validated in one of four EDIL3 probesets in the GYN-COE cohort (p = 0.0011, adjusted p = 0.0342). Conclusions Obesity may promote tumor progression via differential modulation of angiogenic pathways in EEC. Our exploratory findings demonstrated that EDIL3 may be a candidate gene of interest.

Background: ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). Methods: Our objective was to evaluate the effect of the ONC201 on (1) proliferation, cellular stress, apoptosis and invasion in human serous ovarian cancer (OC) cell lines, and (2) inhibition of tumor growth in a genetically engineered mouse model of high grade serous OC (K18-gT121+/-;p53fl/fl;Brca1fl/fl; KpB) under obese (high fat diet) and lean (low fat diet) conditions. Findings: ONC201 inhibited cell proliferation and induced G1 cell cycle arrest, cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in the mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5. Interpretation: These results suggest that ONC206 may be a promising therapeutic agent to be explored in future clinical trials in high grade serous OC. Funding Statement: This work is supported by: (1) VLB: American Cancer Society (ACS) Research Scholar Grant - RSG CCE 128826. (2) VLB: NIH/NCI - R37CA226969. (3) JW: Beijing health system high-level health personnel training program fund (2014-3-073) Declaration of Interests: VP and JEA are employees and stockholders of Oncoceutics. No potential conflicts of interest were disclosed by the other authors. Ethics Approval Statement: All mice were handled according to protocols approved by the UNC-CH Institutional Animal Care and Use Committee (IACUC).

Objectives: Ipatasertib (IPAT) is an orally administered selective protein kinase B (AKT) inhibitor that has demonstrated clinical activity in triple-negative breast and metastatic prostate cancer. Given that the AKT/mTOR pathway is altered in the vast majority of endometrioid endometrial cancers (ECs), it is logical that IPAT may also have efficacy in EC. Thus, we aimed to evaluate the anti-proliferative effects of IPAT in human endometrioid cell lines as well as in the LKB1fl/flp53fl/fl genetically engineered mouse model of endometrioid EC. Methods: The human endometrioid EC cell lines ECC-1 (PTEN mutant) and HEC-1A (PTEN wild type, PIK3CA mutant, KRAS mutant) were exposed to varying concentrations of IPAT (Genentech). Cell proliferation was assessed by MTT and colony assays. Cell cycle progression was measured by Cellometer. Apoptosis was assessed by cleaved caspase-3 assay. Cellular stress was assessed using tetra-methylrhodamine ester (TMRE) and DCFDA assays. Western immunoblotting determined effects of IPAT on BCL-2, MCL-1, Bip, CDK4, CDK6, cyclin D1, pAKT, pS6, PERK, calnexin, and PDI in both cell lines.LKB1fl/flp53fl/fl mice were used to evaluate the effect of IPAT on endometrial tumor growth. The mice were treated with placebo or IPAT (15mg/kg daily intraperitoneally for 4 weeks) starting 8 weeks after tumor induction via AdCre injection. Results: IPAT inhibited cellular proliferation in a dose dependent fashion in both cell lines after 72 hours of treatment. Median IC50 was 0.18µM in ECC-1 and 3.5µM in HEC-1A. IPAT induced the activity of cleaved caspase 3 by 15.6-fold in ECC-1 and 1.41-fold in HEC-1A (p Conclusions: IPAT significantly inhibited cell proliferation and induced apoptosis and cellular stress via inhibition of the AKT/mTOR pathway in human endometrioid EC cell lines. Furthermore, IPAT reduced tumor growth in a transgenic mouse model of endometrioid EC. These results suggest that IPAT is worthy of further exploration in clinical trials for EC.

Objectives: Ipatasertib (IPAT) is an orally administered selective protein kinase B (AKT) inhibitor that has demonstrated clinical activity in triple-negative breast and metastatic prostate cancer. Given that the AKT/mTOR pathway is altered in the vast majority of endometrioid endometrial cancers (ECs), it is logical that IPAT may also have efficacy in EC. Thus, we aimed to evaluate the anti-proliferative effects of IPAT in human endometrioid cell lines as well as in the LKB1fl/flp53fl/fl genetically engineered mouse model of endometrioid EC. Methods: The human endometrioid EC cell lines ECC-1 (PTEN mutant) and HEC-1A (PTEN wild type, PIK3CA mutant, KRAS mutant) were exposed to varying concentrations of IPAT (Genentech). Cell proliferation was assessed by MTT and colony assays. Cell cycle progression was measured by Cellometer. Apoptosis was assessed by cleaved caspase-3 assay. Cellular stress was assessed using tetramethylrhodamine ester (TMRE) and DCFDA assays. Western immunoblotting determined effects of IPAT on BCL-2, MCL-1, Bip, CDK4, CDK6, cyclin D1, pAKT, pS6, PERK, calnexin, and PDI in both cell lines. LKB1fl/flp53fl/fl mice were used to evaluate the effect of IPAT on endometrial tumor growth. The mice were treated with placebo or IPAT (15mg/kg daily intraperitoneally for 4 weeks) starting 8 weeks after tumor induction via AdCre injection. Results: IPAT inhibited cellular proliferation in a dose dependent fashion in both cell lines after 72 hours of treatment. Median IC50 was 0.18µM in ECC-1 and 3.5µM in HEC-1A. IPAT induced the activity of cleaved caspase 3 by 15.6-fold in ECC-1 and 1.41-fold in HEC-1A (p Conclusions: IPAT significantly inhibited cell proliferation and induced apoptosis and cellular stress via inhibition of the AKT/mTOR pathway in human endometrioid EC cell lines. Furthermore, IPAT reduced tumor growth in a transgenic mouse model of endometrioid EC. These results suggest that IPAT is worthy of further exploration in clinical trials for EC.

Objectives: Obesity is associated with higher risk and worse outcomes for endometrial cancer (EC) as well as chemoresistance. The gut microbiome affects metabolic/immune pathways central to obesity and cancer, impacting efficacy of chemotherapy/immunotherapy; however, the effects of the uterine microbiome upon the progression and treatment of EC remain unknown. Given these complex relationships, we assessed the efficacy of paclitaxel/carboplatin (P/C) in the LKB1fl/flp53fl/fl mouse model of obesity-driven endometrioid EC and explored the microbiotic and metabolomic impact of this treatment. Methods: Starting at 3 weeks of age, mice were fed a control low fat diet (LFD; 10% calories from fat) versus a high fat diet (HFD; 60% calories from fat) to mimic diet-induced obesity. AdCre was injected at 6 weeks to induce invasive EC. Mice were treated with paclitaxel (20 mg/kg intraperitoneally [IP] weekly) and carboplatin (50 mg/kg IP weekly) in combination for 4 weeks. The microbiota profiles were characterized by bacterial 16S rRNA high throughput sequencing, and the data was analyzed using QIIME2 and MicrobiomeAnalyst. Global, unbiased metabolomics was used to identify the metabolic effects of P/C in the ECs. Results: Diet-induced obesity led to a >30% increase in tumor size (p Conclusions: Diet-induced obesity led to distinct microbiotic and metabolomic effects in the ECs of LKB1fl/flp53fl/fl mice. The efficacy of P/C was similar between obese versus lean mice; however, impact of this treatment on intra-tumoral metabolic and bacterial pathways aligned with obesity status. These findings suggest that different metabolic and microbial adjuvant interventions may be warranted in the setting of obesity to improve chemotherapeutic response.

OBJECTIVES: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. METHODS: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. RESULTS: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P=0.68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P

Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers.

Objectives: Endometrial cancer (EC) survivors are often overweight or obese and may benefit from increased physical activity. Increases in daily step count of 2,000 steps per day has been shown to improve cardiovascular health. We sought to assess a fitness intervention (fitness tracker + tailored feedback messages) for EC survivors. Methods: A prospective trial of EC survivors was undertaken from September 2018 to December 2019. Thirty-nine survivors were approached for enrollment with 36 randomized (18 intervention, 18 control). All participants received a fitness tracker. Survivors were randomized 1:1 to receipt or non-receipt of weekly tailored feedback messages. The primary outcome was change in average daily step count from baseline (week 1) to study completion (week 12). Secondary outcomes included acceptability, and changes in metabolic lab parameters (serum glucose, LDL, and insulin levels), body mass index (BMI) and waist to hip ratio (W/H). The trial was powered to detect a clinically significant change in daily step count of 2,000 steps. Comparisons of baseline to study completion labs were made using the Wilcoxon Two-sample test. Student's T-test was used for comparisons of control and intervention groups. Results: At baseline, there was no difference in BMI (35.9 vs 36.7, p=0.81) or W/H ratio (0.9 vs 0.89, p=0.40) between control and intervention arms. Baseline daily step count was 5291 steps in the control arm and 4295 in the intervention arm (p=0.16). There was no difference in baseline metabolic labs including glucose (100 vs 103, p=0.85), serum insulin (13.1 vs 16.8, p=0.78), and LDL (150 vs 113, p=0.07). The intervention group saw a statistical change in average daily step count (4295 to 5332, p=0.02). The control group did not have a statistically significant change (5291 to 5600, p=0.40). For the primary outcome of average daily step count change, there was no statistically significant difference between the two groups (+309 control vs +1037 intervention, p=0.21). There was no difference in change in BMI (-0.27 vs -0.02, p=0.7), glucose (+1 vs -3, p=0.29), LDL (-9.1 vs -3.5, p=0.95) or insulin (-2.15 vs -1.95, p=0.32) between the control and intervention arms. Regarding acceptability, survivors found the feedback to be helpful (87%) and easy to understand (87%). Two-thirds of survivors found the messages to be motivating, 47% desired increased frequency of messaging, and 53% thought the weekly message was adequate. Overall, 33% of intervention survivors versus 22% of control survivors had decline in fitness tracker use during the intervention, resulting in missing step data (p=0.46). Conclusions: A fitness intervention using fitness trackers and tailored feedback messaging may improve physical activity as measured by daily step count in EC survivors, however, significant noncompliance with fitness tracker use was seen in both groups by study end. Tailoring the frequency of feedback messages to survivor preference may be important to optimizing this intervention.

Objectives: The inclusion of palliative care (PC) across the cancer continuum has been identified as a marker of high-quality cancer care. With limited PC specialists, integrated approaches may be necessary with the primary oncologist providing this care. However, recurrent ovarian cancer patients often have significant physical and/or emotional needs that may be best addressed by PC specialists. Our primary objective was to test the effect of a structured PC intervention on quality of life (QOL) for patients with recurrent ovarian cancer. Secondary objective was to assess the effect of the structured PC approach on overall survival. Methods: This was an IRB approved prospective randomized controlled trial at 2 academic institutions and was registered with clinicaltrials.gov (NCT02090582). Eligible patients included those with platinum resistant ovarian cancer or platinum sensitive cancer with a sentinel clinical event (recent bowel obstruction, liver metastases, pleural effusion or ascites). Subjects were randomized 1:1 to usual care versus a structured palliative care intervention (see Figure 1). Quality of life was assessed using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) and Functional Assessment of Chronic Illness Therapy-Palliative Care (FACIT-PAL) at baseline and 12-week intervals. Wilcoxon tests were used to detect differences between arms. Overall survival was analyzed using Kaplan-Meyer curves. Results: A total of 54 subjects were enrolled from 5/2014-4/2016; 26 in the intervention arm and 28 in the control arm. Median follow up was 6.5 months (Range: 2-12months). Median age of subjects was 63 with an ECOG performance status of 1. The majority of patients were Caucasian (44; 81.5%) and had platinum resistant disease (37; 68.5%). Most patients had received between 1-3 prior lines of chemotherapy (34/54; 63%); 5 patients (9.2%) had received ≥6 lines of therapy. There was no difference in overall or subset QOL in patients receiving usual care compared to those in the structured PC arm (p=0.14). There were no differences in hospital admissions (p=0.96), days from last chemo to hospice admission (p=1.0), days from hospice admission to death (p=0.41), place of death (p=0.68) or number of PC appointments (p=0.30) between the two arms. Patients enrolled in the 2nd half of the cohort were more likely to die at home rather than in the hospital or inpatient hospice (p=0.01) compared to subjects enrolled early in the study period. 81% of subjects randomized to the intervention arm completed at least 1 QDACT assessment (range 1-17). Similarly, there was no overall survival difference between the 2 arms (9.3m vs 10.1m; p=0.21). Download : Download high-res image (146KB) Download : Download full-size image Conclusions: Structured integrated approaches between gynecologic oncology providers and PC specialists are feasible. The QDACT tool may be an effective, standardized measure to assess cancer symptom burden over time in this population. Further study is needed to identify interventions and collaborations that may have the greatest impact on QOL for recurrent ovarian cancer patients.

Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease.

// Helen J. MacKay 1 , Douglas A. Levine 2 , Victoria L. Bae-Jump 3 , Daphne W. Bell 4 , Jessica N. McAlpine 5 , Alessandro Santin 6 , Gini F. Fleming 7 , David G. Mutch 8 , Kenneth P. Nephew 9 , Nicolas Wentzensen 10 , Paul J. Goodfellow 11 , Oliver Dorigo 12 , Hans W. Nijman 13 , Russell Broaddus 14 and Elise C. Kohn 15 1 Division of Medical Oncology & Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 2 Division of Gynecologic Cancer, Department of OB/GYN, NYU Langone Laura and Isaac Perlmutter Cancer Center, New York, NY, United States 3 Division of Gynecologic Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, CA, United States 4 Reproductive Cancer Genetics Section, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute/NIH, MSC 8000, Bethesda, ML, United States 5 University of British Columbia & BC Cancer Agency, Division of Gynecologic Oncology, Vancouver, British Columbia, Canada 6 Department of Gynecology, Obstetrics and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States 7 Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, IL, United States 8 Department of Obstetrics & Gynecology, Washington University School of Medicine, St. Louis, MO, United States 9 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, United States 10 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, ML, United States 11 James Comprehensive Cancer Center and The Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH, United States 12 Division Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford, CA, United States 13 Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 14 Department of Pathology, Unit 85, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States 15 Clinical Investigations Branch of The Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, ML, United States Correspondence to: Elise C. Kohn, email: kohne@mail.nih.gov Keywords: endometrial cancer, molecular targets Received: March 03, 2017 Accepted: May 15, 2017 Published: August 03, 2017 ABSTRACT The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials.

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges., Diagnostics: Dual selection improves circulating tumor cell assay Using two selection markers, instead of one, can improve the sensitivity of a blood test for circulating tumor cells (CTCs). Steven A. Soper from the University of Kansas in Lawrence, USA, and colleagues analyzed blood samples from patients with cancers of the pancreas, colon, breast, ovaries and prostate, as well blood from healthy donors and those with benign disease. They ran each patient’s blood through two microfluidic devices, one chip targeting the established marker epithelial cell adhesion molecule (EpCAM) and another targeting a new marker, fibroblast activation protein alpha (FAPα). Doing so detected CTCs in nearly all the cancer patients—a substantial improvement over testing for EpCAM CTCs alone. Molecular and genetic analyses of the CTCs showed that those expressing EpCAM and FAPα are distinct subpopulations, and testing for both could prove valuable for clinical management.

// Li Sun 1, 3, * , Yajie Yin 1, 2, 3, * , Leslie H. Clark 3 , Wenchuan Sun 3 , Stephanie A. Sullivan 3 , Arthur-Quan Tran 3 , Jianjun Han 4 , Lu Zhang 1 , Hui Guo 1 , Esther Madugu 3 , Tommy Pan 3 , Amanda L. Jackson 5 , Joshua Kilgore 6 , Hannah M. Jones 3 , Timothy P. Gilliam 3 , Chunxiao Zhou 3, 7 and Victoria L. Bae-Jump 3, 7 1 Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China 2 School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China 3 Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 4 Department of Surgical Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China 5 Division of Gynecologic Oncology, University of Cincinnati, Cincinnati, OH, USA 6 Houston Methodist Gynecologic Oncology Associates, Houston, TX, USA 7 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA * These authors have contributed equally to this work Correspondence to: Victoria L. Bae-Jump, email: victoria_baejump@med.unc.edu Chunxiao Zhou, email: czhou@med.unc.edu Keywords: glycolysis, glutaminolysis, ovarian cancer, AMPK/mTOR Received: April 19, 2017 Accepted: June 04, 2017 Published: June 29, 2017 ABSTRACT Cancer cell metabolism is required to support the biosynthetic demands of cell growth and cell division, and to maintain reduction oxidaton (redox) homeostasis. This study was designed to test the effects of glucose and glutamine on ovarian cancer cell growth and explore the inter-relationship between glycolysis and glutaminolysis. The SKOV3, IGROV-1 and Hey ovarian cancer cell lines were assayed for glucose, pyruvate and glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis and ATP production. As determined by MTT assay, glucose stimulated cell growth while the combination of glucose, glutamine and pyruvate resulted in the greatest stimulation of cell proliferation. Furthermore, 2-deoxy-glucose (2-DG) and 3-bromopyruvate (3-BP) induced apoptosis, caused G1 phase cell cycle arrest and reduced glycolytic activity. Moreover, 2-DG in combination with a low dose of aminooxyacetate (AOA) synergistically increased the sensitivity to 2-DG in the inhibition of cell growth in the ovarian cancer cell lines. These studies suggest that dual inhibition of glycolysis and glutaminolysis may be a promising therapeutic strategy for the treatment of ovarian cancer.

A study of cancer-associated mutations in normal endometrial glands of the uterus has now been performed using whole-genome sequencing. The analysis sheds light on the early changes that lead to invasive disease. Whole-genome sequences from normal human endometrial tissue.

Significance Uterine carcinosarcoma (UCS) is an aggressive endometrial cancer variant distinguished from endometrial adenocarcinoma (EC) by admixed malignant epithelial and mesenchymal components (carcinoma and sarcoma). The molecular events underlying UCS are enigmatic, as cancer gene mutations are generally shared among UCS/EC. We take advantage of genetic approaches in mice to show that inactivation of Fbxw7 and Pten results in UCS through spontaneous acquisition of mutations in a third gene (Tp53), arguing for strong biological selection and synergism in UCS. We used this UCS model including tumor-derived cell lines to show that Fbxw7 loss drives epithelial–mesenchymal transition, explaining Fbxw7’s role in UCS. This model system argues that simultaneous genetic defects in 3 distinct pathways (Fbxw7, Pten/PI3K, Tp53) converge in UCS genesis., Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

Highlights • TP53 mutations are common in serous endometrial tumors. • Endometrial tumors with micro and macrometastasis are more likely than tumors with ITC only to have LVSI. • No patient with ITC only disease had a recurrence in the study time frame., Objectives Lymph node (LN) metastasis and genomic profiles are important prognostic factors in endometrial cancer (EMCA). However, the prognostic significance of low volume metastasis found in sentinel lymph nodes (SLN) is unknown. We sought to determine if genomic mutations were associated with metastatic volume. Methods Surgically staged women with EC who were enrolled in both a SLN clinical trial and tumor sequencing protocol were eligible. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Three specific gene mutations were evaluated, TP53, PTEN and PIK3CA in the primary tumor of patients with LN negative, LN positive and ITC disease. Results 42 patients were eligible; of these, 7 (16.7%) had ITC only and 7 (16.7%) had micrometastatic or macrometastatic (LN positive) disease. No differences were seen in TP53, PIK3CA or PTEN between groups. All ITC patients with TP53 mutations were of non-endometrioid histology (2/7). Deeper myometrial invasion and lymph vascular space invasion were more likely to occur in the LN positive group (p

Objectives: Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for patients with homologous recombination (HR) deficient tumors. While HR mutations are rare in endometrial cancers (ECs), emerging data suggests that loss of function of the tumor suppressor gene PTEN, which is mutated in 80% of endometrioid ECs, may also sensitize tumors to PARP inhibition. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist that has anti-tumorigenic effects in EC via induction of apoptosis, activation of the integrated stress response and modulation of Akt signaling. Both PARP inhibitors and imipridones are being evaluated in EC clinical trials, but have yet to be explored in combination. We sought to examine the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid EC cell lines and in a mouse model of endometrioid EC. Methods: The ECC-1 and HEC-1 EC cell lines were used. Cell proliferation was assessed after exposure to varying doses of olaparib (MedChemExpress) and ONC206 (Oncoceutics) via the MTT assay. Synergy between olaparib and ONC206 was assessed by the combination index (CI) method of Chou-Talalay. Cellular stress was evaluated using the DCFH-DA assay. Apoptosis was assessed using the cleaved caspase-3 assay. Western immunoblotting was performed to determine effects of olaparib and ONC206 on apoptosis and the mTOR pathway. LKB1fl/flp53fl/fl mice were fed either a low-fat diet (10% of calories from fat, lean) or high-fat diet (60% of calories from fat, obese). Following EC onset, the mice were treated with ONC206 (100 mg/kg weekly orally), olaparib (25 mg/kg daily orally), or the combination for 4 weeks. Immunohistochemistry was used to assess Ki-67 expression in EC. Results: Both drugs inhibited cell proliferation in a dose-dependent manner (IC50 for olaparib of 15 µM for ECC-1 and 25 µM for HEC-1; IC50 for ONC206 of 3.3 µM for ECC-1 and 0.9 µM for HEC-1). Simultaneous exposure of EC cells to ONC206 and olaparib resulted in synergistic anti-proliferative effects (CI Citation Format: Sarah E. Paraghamian, Gabrielle M. Hawkins, Wenchuan Sun, Yali Fan, Xin Zhang, Hongyan Suo, Varun Vijay Prabhu, Joshua E. Allen, Chunxiao Zhou, Victoria Bae-Jump. A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO044.

Objectives: Obesity is associated with increased risk of and mortality from endometrial cancer (EC). Previous studies have shown that omega-3 polyunsaturated fatty acid (PUFA) supplementation may counteract the detrimental effects of obesity-driven cancers, but this has not been thoroughly investigated in EC. We aimed to assess the effect of omega-3 PUFAs on cell proliferation and tumor growth in endometroid EC cell lines and an LKB1fl/flp53fl/fl mouse model of endometroid EC. Methods: The human endometrioid EC cell lines ECC-1 and KLE were exposed to varying concentrations of the omega-3 PUFA, docosahexaenoic acid (DHA). Cell proliferation was assessed by MTT assay. Apoptosis was assessed by Annexin V-FITC assay. Reactive oxygen species (ROS) were measured using the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay. Western immunoblotting was performed to determine the effects of DHA on the anti-apoptotic proteins BCL-2 and MCL-1 and the cellular stress proteins PERK, Bip, and PDI. LKB1fl/flp53fl/fl mice were fed either a low fat diet (10% of calories from fat, lean) or high fat diet (60% of calories from fat, obese). Following EC onset, the mice were treated with placebo or DHA (15mg/kg weekly for 4 weeks, IP). Immunohistochemistry (IHC) was performed on tumors in the treated and untreated mice to assess for proliferation and apoptosis. Global, unbiased metabolomics was used to identify the metabolic effects of DHA in the endometrial tumors. Results: DHA inhibited cell proliferation in a dose-dependent manner in both cell lines (ECC-1 IC50 of 60µM; KLE IC50 of 35µM). DHA increased the expression of annexin V (p Conclusions: DHA robustly inhibits EC proliferation and tumor growth in vitro and in vivo. This suggests that omega-3 PUFA supplementation may be a promising dietary strategy for EC prevention and treatment. Citation Format: Jillian A. O'Donnell, Lindsey K. Buckingham, Stuart R. Pierce, Lindsay West, Yiajie Yin, Wenchuan Sun, Ziwei Fang, Douglas P. Lee, Chunxiao Zhou, Victoria L. Bae-Jump. Docosahexaenoic acid demonstrates anti-tumorigenic effects in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO031.

// Haifeng Qiu 1, 2 , Jing Li 3 , Leslie H. Clark 2 , Amanda L. Jackson 2 , Lu Zhang 2, 4 , Hui Guo 2, 4 , Joshua E. Kilgore 2 , Paola A. Gehrig 2 , Chunxiao Zhou 2, 5 , Victoria L. Bae-Jump 2, 5 1 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China 2 Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 3 Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China 4 Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China 5 Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Correspondence to: Victoria L. Bae-Jump, email: vbae@unch.unc.edu Chunxiao Zhou, email: czhou@med.unc.edu Keywords: endometrial cancer, JQ1, BRD4 inhibitor, PTEN/PI3K/AKT signal pathway, intrinsic resistance Received: April 15, 2016 Accepted: August 10, 2016 Published: August 26, 2016 ABSTRACT Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.

Fatty acid synthase (FAS) is a key lipogenic enzyme that is highly expressed in endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines. The endometrial cancer cell lines ECC-1 and KLE were used. Cell proliferation was assessed by MTT assay after treatment with orlistat. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression, and the AMPK/mTOR pathways. Orlistat inhibited cell proliferation by 61 % in ECC-1 cells and 57 % in KLE cells at a dose of 500 μM. Treatment with orlistat at this concentration resulted in G1 arrest (p

// Hui Guo 1, 2, 4 , Yan Zhong 2, 3 , Amanda L. Jackson 2 , Leslie H. Clark 2 , Josh Kilgore 2 , Lu Zhang 1, 2, 4 , Jianjun Han 2, 5 , Xiugui Sheng 1 , Timothy P. Gilliam 2 , Paola A. Gehrig 2, 6 , Chunxiao Zhou 2, 6 , Victoria L. Bae-Jump 2, 6 1 Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan University, Jinan, P.R. China 2 Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA 3 Department of Gynecologic Oncology, Linyi Cancer Hospital, Linyi, P.R. China 4 School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Shandong, P.R. China 5 Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Jinan, P.R. China 6 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA Correspondence to: Victoria L Bae-Jump, e-mail: victoria_baejump@med.unc.edu Chunxiao Zhou, e-mail: czhou@med.unc.edu Keywords: ovarian cancer, everolimus, proliferation, mTOR, metabolon Received: October 13, 2015 Accepted: January 24, 2016 Published: March 05, 2016 ABSTRACT Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo . Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro . Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers.

Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer. TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30–40 mg/m2 IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling. There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R 2 = 0.61, p = 0.02), particularly in patients receiving PLD alone (R 2 = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands. TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

OBJECTIVE. To evaluate the association between body mass index (BMI) and mortality in women with endometrial cancer. METHODS. A systematic review was performed utilizing a Medline search with Mesh keywords ‘endometrial neoplasms’ and (‘body mass index’ or ‘obesity’) and (‘survival analysis’ or ‘mortality’ or ‘survivor’ or ‘survival’) for studies published prior to June 2013. Inclusion criteria included studies that assessed associations between BMI and survival in endometrial cancer patients. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were adjudicated by a third reviewer. A random-effects model was constructed that was comparable to the standard random-effects models used in the meta-analysis of odds ratios. The model was fitted using SAS PROC NLMIXED. RESULTS. 1451 studies were identified and reviewed in duplicate, 18 met inclusion criteria. A random-effects meta-analysis demonstrated significantly higher odds of mortality with increasing BMI in endometrial cancer patients. Specifically the odds ratios were 1.01, 1.17, 1.26, and 1.66 for BMI categories of 25–29.9, 30–34.9, 35–39.9, and 40+, respectively. The odds ratio for all-cause mortality in endometrial cancer patients with a BMI ≥ 40 compared to those with a BMI < 25 was 1.66 (CI: 1.10–2.51, p = 0.02). A single dose–response model indicated that a 10% increase in BMI resulted in a 9.2% increase in the odds of all-cause mortality (p = 0.007). CONCLUSION. Increased BMI is significantly associated with increased all-cause mortality in women with endometrial cancer, with the highest risk for those with a BMI ≥ 40.

Introduction: African American (AA) women suffer a higher mortality from endometrial cancer (EC) than non-Hispanic white (NHW) women. Potential biological causes for this disparity in AA women include a higher risk of more lethal histologic/molecular subtypes and greater rates of obesity. We hypothesize that another biological factor driving his racial disparity is the uterine microbiome. Thus, we evaluated the microbiota of human ECs and assessed for variations by race. Methods: Banked tumor specimens of post-menopausal patients undergoing hysterectomy for early stage endometrioid ECs were identified. Tumors were analyzed from AA and NHW women and stratified as obese (BMI≥30kg/m2) or non-obese (BMI Citation Format: Gabrielle M. Hawkins, Amber N. McCoy, Andrew Olshan, Russell Broaddus, Wendy R. Brewster, Jeffrey Roach, Temitope Keku, Victoria L. Bae-Jump. Impact of race on the uterine microbiome in women with early stage endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR07.