Association of Sialyl Tn antigen with cervical cancer lymph node status: An NRG oncology/GOG study.

OBJECTIVE: Detection of lymph node metastases in cervical cancer patients is important for guiding treatment decisions, however accuracies of current detection methods are limited. We evaluated associations of abnormal glycosylation, represented by Tn and STn antigens on mucin (MUC) proteins, in primary tumor specimens with lymph node metastasis or recurrence of cervical cancer patients. METHODS: Surgical specimens were prospectively collected from 139 patients with locally-advanced cervical cancer undergoing lymphadenectomy enrolled in a nation-wide clinical trial (NCT00460356). Of these patients, 133 had primary cervix tumor, 67 had pelvic lymph node (PLN) and 28 had para-aortic lymph node (PALN) specimens. Fixed tissue serial sections were immunohistochemically stained for Tn, STn, MUC1 or MUC4. Neuraminidase was used to validate Tn versus STn antibody specificity. Stain scores were compared with clinical characteristics. RESULTS: Primary tumor STn expression above the median was associated with negative PLN status (p-value: 0.0387; odds ratio 0.439, 95% CI: 0.206 to 0.935). PLN had higher STn compared to primary tumor, while primary tumor had higher MUC1 compared to PALN, and MUC4 compared to PALN or PLN (p = 0.017, p = 0.011, p = 0.016 and p < 0.001, respectively). Tn and STn expression correlated in primary tumor, PALN, and PLN, Tn and MUC1 expression correlated in primary tumors only (Spearman correlation coefficient [r] = 0.301, r = 0.686, r = 0.603 and r = 0.249, respectively). CONCLUSIONS: STn antigen expression in primary cervical tumors is a candidate biomarker for guiding treatment decisions and for mechanistic involvement in PLN metastases.

TP53 mutation and abnormal p53 expression in endometrial cancer: Associations with race and outcomes.

OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.

Cervical Stratified Mucin-Producing Intraepithelial Lesion: A Systematic Review of Diagnosis and Management.

OBJECTIVES: The aims of the study were to synthesize reported associations of stratified mucin-producing intraepithelial lesion (SMILE) of the cervix with other dysplasia lesions and immunohistochemical (IHC) stains, compare expected patterns of IHC staining to other lesions in the differential diagnosis, and assess follow-up pathology. METHODS: This systematic review includes all case reports and case series of cervical lesions consistent with SMILE based on the histologic diagnosis described in the original case series. MEDLINE, EMBASE, and Cochrane Database were searched through June 2019. Immunohistochemical analysis, concurrent lesions, and pathology on follow-up were compiled for comparison. Weighted averages of concurrent lesions were calculated. RESULTS: Nine case reports and case series were included, published between 2000 and 2019. Of 9 studies, 6 and 5 studies reported strong, diffuse staining of p16 and increased expression of Ki-67, respectively. Stratified mucin-producing intraepithelial lesion is associated with human papillomavirus, especially type 18. The weighted average risk of concurrent high-grade squamous intraepithelial lesion was 79% (range = 33%-93%), adenocarcinoma in situ 39% (2.9%-92%), adenocarcinoma 5% (1%-25%), and squamous cell carcinoma 6% (0%-11%). Patients underwent follow-up ranging from repeat Pap to radical hysterectomy, with pathology on follow-up infrequently and irregularly reported. CONCLUSIONS: Stratified mucin-producing intraepithelial lesion is a rare lesion with a paucity of research on necessary cytology and IHC stains for diagnosis, but p16 and Ki-67 IHC stains can be performed to rule out benign lesions. The lesion is associated with high risk of concurrent high-grade squamous intraepithelial lesion, adenocarcinoma in situ, and invasive carcinoma, but studies on the risk of pursuing fertility-preserving management are needed.

Extremes in body mass index affect overall survival in women with cervical cancer.

OBJECTIVE: To examine the effect of BMI on pathologic findings, cancer recurrence and survival in cervical cancer patients. METHODS: A retrospective cohort study of cervical cancer patients treated from July 2000 to March 2013 was performed. BMI was calculated, and patients were classified by BMI. The primary outcome was overall survival (OS). Secondary outcomes included stage, histopathology, disease-specific survival (DSS) and recurrence free survival (RFS). Kaplan-Meier survival curves were generated and compared using Cox proportional hazard ratios. RESULTS: Of 632 eligible patients, 24 (4%) were underweight, 191 (30%) were normal weight, 417 (66%) were overweight/obese. There was no difference in age (p=0.91), stage at presentation (p=0.91), grade (p=0.46), or histology (p=0.76) between weight categories. There were fewer White patients in the underweight (54%) and overweight/obese (58%) groups compared to the normal weight (71%) group (p=0.04). After controlling for prognostic factors, underweight and overweight/obese patients had worse median RFS than normal weight patients (7.6 v 25.0months, p=0.01 and 20.3 v 25.0months, p=0.03). Underweight patients also had worse OS (10.4 v 28.4months, p=0.031) and DSS (13.8 v 28.4months, p=0.04) compared to normal weight patients. Overweight/obese patients had worse OS than normal weight patients (22.2 v 28.4months, p=0.03) and a trend toward worse DSS (21.9 v 28.4months, p=0.09). CONCLUSION: Both extremes of weight (underweight and overweight/obesity) were associated with worse survival in patients with cervical cancer. Optimizing weight in cervical cancer patients may improve outcomes in these patients.

Adjuvant Treatment and Clinical Trials in Elderly Patients With Endometrial Cancer: A Time for Change?

OBJECTIVES: The aim of the study were to evaluate the gap between recommended and received adjuvant therapy in elderly patients with endometrial cancer (EC) and to determine the percent of women 70 years and older who would meet enrollment criteria for representative Gynecologic Oncology Group (GOG) trials. METHODS AND MATERIALS: An institutional review board approved retrospective chart review of all EC cases from a tertiary care institution from 2005 to 2010 was performed. Clinical, surgical, and pathologic data were abstracted from electronic medical records. Gynecologic Oncology Group protocols 249, 209, and 229L were selected as representative national EC trials. Patients were evaluated for eligibility by each protocol's criteria. RESULTS: Twenty-six percent (280/1064) of patients with EC were older than 70 years. More than 60% (181/280) of elderly patients with EC were recommended to undergo adjuvant therapy. By therapy type, 64% (48/75) of elderly patients who were recommended adjuvant radiation received it, 53% (49/92) of elderly patients who were recommended combination chemotherapy and radiation received it, and 29% (4/14) of elderly patients who were recommended chemotherapy received it. In evaluating enrollment criteria for GOG 249, 30% (40/134) of pathologically eligible patients would have been eliminated for medical clearance; for GOG 209, 31% (26/86) would have been eliminated, and for GOG 229L, 9% (4/45) would have been eliminated purely for medical reasons. CONCLUSIONS: More adjuvant treatment is recommended in the elderly patients because of a higher incidence of advanced disease and aggressive histopathology. Approximately half of the elderly patients who were recommended treatment actually received it. In addition, clinical trial data are limited for elderly patients because approximately one third of the women aged 70 years and older who meet pathologic enrollment criteria for trials were excluded because of complex medical disease.

Emerging therapies: angiogenesis inhibitors for ovarian cancer.

INTRODUCTION: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ∼ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC. AREAS COVERED: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib. EXPERT OPINION: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date.

Recurrence-free and 5-year survival following robotic-assisted surgical staging for endometrial carcinoma.

OBJECTIVE: The aim of this study is to report recurrence-free and overall survival for women with endometrial adenocarcinoma who were surgically staged using robotic-assisted laparoscopy. METHODS: A retrospective chart review was performed for all consecutive endometrial adenocarcinoma patients surgically staged with robotic-assisted laparoscopy at the University of North Carolina Hospital from 2005 to 2010. Demographic data, 5-year survival, and recurrence-free intervals were analyzed. Statistical analysis using Chi-square, t-test, and Kaplan-Meier curves were performed with SAS software. Study results were compared to endometrial cancer statistics from the Surveillance Epidemiology and End Results database from the National Cancer Institute. RESULTS: A total of 499 patients were identified and included in the study. Recurrence-free intervals after robotic-assisted surgical staging were 85.2% for stage IA, 80.2% for stage IB, 69.8% for stage II, and 69% for stage III. Projected 5-year survival was 88.7% for all patients included in the study. Nearly 82% of cases were endometrioid adenocarcinoma, with papillary serous, clear cell or mixed histology comprising 17.4% of cases. Median follow up time was 23 months, with a range of 0 to 80 months. Among stage IA, IB, II, and III patients, projected overall survival was 94.2%, 85.9%, 77.4%, and 68.6%, respectively. CONCLUSIONS: The results from this study demonstrate that robotic-assisted surgical staging for endometrial cancer does not adversely affect rates of recurrence or survival. These findings provide further evidence that robotic-assisted laparoscopic surgical staging is not associated with inferior results when compared to laparotomy or traditional laparoscopy.

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study.

PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

The importance of information, motivation, and behavioral skills (IMB): Healthcare provider perspectives on improving adherence to cervical cancer screening among at-risk women.

Objective: To understand the theoretical framework of how information, motivation, and behavioral skills (IMB) independently and collectively affect cervical cancer screening and testing adherence. Study design: Qualitative study. Methods: Data collected from three focus groups and seven individual interviews, with 33 healthcare providers, ranging from community health navigators, Ob-Gyn MD's, nurses, care coordinators, medical assistants, and outpatient managers, representing a grassroots community health agency, a large cancer center, and a public sector health clinic. We recruited providers over a five-month period in the summer to fall of 2019. Provider interviews and focus groups were structured with four to eleven participants per group and were audio-recorded. This study was rooted in grounded theory, analyzing data using the iterative process of Coding, Consensus, Co-occurrence, and Comparison to identify common themes. Results: Emerging qualitative findings include the relevance of information, the interaction between information and motivation, the role of behavioral skills, and the symbiotic relationship between information, motivation, and behavioral skills (IMB). Most notable is this interdependency between IMB components, with the core of this relationship being the critical link of coordinating adherence. Conclusion: This knowledge will help advance and expand IMB intervention components to improve time to cervical cancer screening and follow-up adherence among at-risk communities. Particularly given COVID-19 barriers, which disproportionately affect at-risk women, this study has practice implications that inform the development of cervical cancer screening practice interventions and strategies to improve adherence, while ensuring safety for both patients and providers.

Early diagnosis and treatment challenges of endodermal sinus tumors: A case report.

BACKGROUND: Ovarian endodermal sinus tumors (ESTs) are rapidly growing and highly malignant tumors that respond well to chemotherapy. They can be difficult to diagnose and delayed diagnosis can worsen prognosis. CASE: We present the case of a 20-year-old woman with an EST initially misdiagnosed as a tubo-ovarian abscess who then experienced rapid progression within weeks of initial presentation and was subsequently found to have unresectable advanced stage disease. CONCLUSION: ESTs are extremely aggressive and require prompt referral and early treatment with chemotherapy. Presenting symptoms of pain and a mass can lead to a broad range of differential diagnoses. In such patients, early consideration of tumor markers is warranted. This case report reviews the key aspects for prompt diagnosis and rapid treatment of these tumors, which significantly impacts the prognosis.

Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer.

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.

Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer.

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.

Buformin exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells.

OBJECTIVE: Biguanides are anti-diabetic drugs that are thought to have anti-tumorigenic effects. Most pre-clinical studies have focused on metformin for cancer treatment and prevention; however, buformin may be potentially more potent than metformin. Given this, our goal was to evaluate the effects of buformin on cell growth, adhesion and invasion in endometrial cancer cell lines. METHODS: The ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed by MTT assay. Apoptosis and cell cycle analysis was performed by FITC Annexin V assay and propidium iodide staining, respectively. Adhesion was analyzed using the laminin adhesion assay. Invasion was assessed using the transwell invasion assay. The effects of buformin on the AMPK/mTOR pathway were determined by Western immunoblotting. RESULTS: Buformin and metformin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines. IC50s were 1.4-1.6 mM for metformin and 8-150 µM for buformin. Buformin induced cell cycle G1 phase arrest in the ECC-1 cells and G2 phase arrest in the Ishikawa cells. For both ECC-1 and Ishikawa cells, treatment with buformin resulted in induction of apoptosis, reduction in adhesion and invasion, activation of AMPK and inhibition of phosphorylated-S6. Buformin potentiated the anti-proliferative effects of paclitaxel in both cell lines. CONCLUSION: Buformin has significant anti-proliferative and anti-metastatic effects in endometrial cancer cells through modulation of the AMPK/mTOR pathway. IC50 values were lower for buformin than metformin, suggesting that buformin may be more potent for endometrial cancer treatment and worthy of further investigation.

JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer.

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.

NT1014, a novel biguanide, inhibits ovarian cancer growth in vitro and in vivo.

BACKGROUND: NT1014 is a novel biguanide and AMPK activator with a high affinity for the organic cation-specific transporters, OCT1 and OCT3. We sought to determine the anti-tumorigenic effects of NT1014 in human ovarian cancer cell lines as well as in a genetically engineered mouse model of high-grade serous ovarian cancer. METHODS: The effects of NT1014 and metformin on cell proliferation were assessed by MTT assay using the human ovarian cancer cell lines, SKOV3 and IGROV1, as well as in primary cultures. In addition, the impact of NT1014 on cell cycle progression, apoptosis, cellular stress, adhesion, invasion, glycolysis, and AMPK activation/mTOR pathway inhibition was also explored. The effects of NT1014 treatment in vivo was evaluated using the K18 - gT121+/-; p53fl/fl; Brca1fl/fl (KpB) mouse model of high-grade serous ovarian cancer. RESULTS: NT1014 significantly inhibited cell proliferation in both ovarian cancer cell lines as well as in primary cultures. In addition, NT1014 activated AMPK, inhibited downstream targets of the mTOR pathway, induced G1 cell cycle arrest/apoptosis/cellular stress, altered glycolysis, and reduced invasion/adhesion. Similar to its anti-tumorigenic effects in vitro, NT1014 decreased ovarian cancer growth in the KpB mouse model of ovarian cancer. NT1014 appeared to be more potent than metformin in both our in vitro and in vivo studies. CONCLUSIONS: NT1014 inhibited ovarian cancer cell growth in vitro and in vivo, with greater efficacy than the traditional biguanide, metformin. These results support further development of NT1014 as a useful therapeutic approach for the treatment of ovarian cancer.

Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer.

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.

Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells.

High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis.

JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer.

Amplification and overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types. Using ovarian cancer cell lines, a transgenic mouse model, and primary cell cultures from human ovarian cancer tissues, we demonstrated that JQ1 significantly suppressed cellular proliferation and induced cell cycle arrest and apoptosis in ovarian cancer cells and mouse model via targeting c-Myc. In addition, JQ1 had multiple influences on cancer metabolism, particularly in the aerobic glycolysis pathway. JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors. Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.