Treatment Options For Cervical Cancer Research Articles

Vaccination and modern therapy of cervical cancer

Cervical cancer is the fourth most common cancer in women worldwide and is responsible for over 300 thousand deaths worldwide. The causative agent of cervical cancer is persistent infection with high-risk human papillomavirus subtypes, and viral oncoproteins E 5, E 6, and E 7 interact with human factors to induce and maintain a malignant phenotype. This review describes the mechanisms behind the onset and development of cervical cancer and discusses in detail promising and effective new treatment options for cervical cancer, including immunotherapy, targeted therapy and combination therapy.

Piperlongumine induces apoptosis and autophagy via the PI3K/Akt/mTOR pathway in KB human cervical cancer cells.

Natural products are continuously being researched to develop safe and effective treatment options for cervical cancer, the fourth most common cancer in women. Piperlongumine (PL), an amide alkaloid mainly present in long pepper, exhibits neuroprotective and anti-cancer properties. However, the specific effect of PL in cervical cancer and the relationship between the anti-cancer pathway and autophagy remain unclear. Therefore, we aimed to investigate PL-induced apoptosis in KB human cervical cancer cells and the relationship between apoptosis and autophagy therein. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays showed that PL treatment suppressed KB cell viability and proliferation. Apoptosis was identified through 4',6-diamidino-2-phenylindole and annexin V-propidium iodide staining, increased cleaved-poly (ADP-ribose) polymerase and Bcl-2 associated X levels, and decreased B cell lymphoma 2 levels. Acridine orange staining and increased microtubule-associated protein 1A/1B-light chain 3-II and Beclin-1 levels confirmed autophagy. We determined that KB cell-related autophagy exerted cytoprotective effects using the autophagy inhibitors 3-methyladenine and hydroxychloroquine. PL treatment promoted apoptosis by inhibiting the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway in KB cells; inhibiting the pathway using PI3K inhibitors increased autophagy. We suggest that PL is a potential natural anticancer agent for cervical cancer treatment.

Genome-wide perturbations of A-to-I RNA editing dysregulated circular RNAs promoting the development of cervical cancer

Cervical cancer, the second most common female malignant tumor, seriously threatens women's health and lives. Despite the availability of the HPV vaccine, effective treatment options for cervical cancer are still lacking. New research perspectives now clarify that RNA editing dysregulation and changes in circRNA expression are jointly involved in disease pathogenesis, so molecular changes associated with circRNA and RNA editing may provide clues for the development of new therapeutic strategies for cervical cancer. In this study, we designed a series of pipelines to identify and analyze dysregulated RNA editing events in circRNAs. Our findings indicate a decrease in A-to-I RNA editing levels in cervical cancer compared to normal tissues, and editing may influence the back-splicing process of circRNAs through structural modifications of Alu elements. Moreover, our research reveals that RNA editing could modulate circRNA biogenesis by influencing RNA binding protein (RBP) binding on a transcriptome-wide scale, as well as influence the expression and coding potential of circRNAs. Importantly, we identified three RNA editing sites that could serve as potential biomarkers. In summary, our study presents a comprehensive landscape of RNA editing perturbations in circRNAs, providing new insights into the complex relationship between RNA editing and circRNA dysregulation in cervical cancer.

Gambogic Acid Lysinate-induced Cervical Cancer SiHa Cells Apoptosis in vitro and in vivo.

Surgical resection and chemotherapy are the primary treatment options for cervical cancer; however, efficacy of chemotherapy drugs is limited by drug resistance. There is an urgent need to find new compounds. Gambogic acid lysinate (GAL), a new compound made from gambogic acid and lysine, has good anti-tumor activity, however, the effect of GAL on cervical cancer remains undetermined. The present study sought to explore the anti-tumor activity of GAL in SiHa cells. Cell viability was detected by means of an MTT assay, a cell growth curve was drawn with Microsoft Excel 2010, the cell cycle and cell apoptosis were evaluated by flow cytometry, and Western blotting was employed to explore the mechanism of GAL. Additionally, the in vivo anti-tumor activity of GAL was studied through a xenograft tumor model in nude mice. GAL inhibited the proliferation of both SiHa cells (IC50 was 0.83 μmol/l and 0.77 μmol/l respectively for 48 h and 72 h) and HeLa cells (IC50 did not reach). In SiHa cells, GAL (1 and 2 μmol/l) inhibited cell proliferation and 2 μmol/l GAL could also induce cell apoptosis and decrease the number of S phase. Both 1 and 2 μmol/l GAL inhibited SiHa cells invasion and increased the number of G0/G1 phase. The results of Western blot assay demonstrated that P53 and P21 were involved in SiHa cells S phase arrest and BCL-2 and BAX were involved in SiHa cells apoptosis. In vivo study showed that the growth of SiHa cell xenograft tumors was inhibited via cell apoptosis induced by GAL (2.5 mg/kg body weight), however, GAL (2.5 mg/kg body weight) had no significant effect on weight gain of mice. GAL induced SiHa cells apoptosis by BCL-2 and BAX pathway and SiHa cells S phase arrest by P53 and P21 pathway in vitro and inhibited the growth of SiHa cell xenograft tumors.

Cervical cancer benefits from trabectedin combination with the β-blocker propranolol: in vitro and ex vivo evaluations in patient-derived organoids.

Background: Cervical cancer (CC) is characterized by genomic alterations in DNA repair genes, which could favor treatment with agents causing DNA double-strand breaks (DSBs), such as trabectedin. Hence, we evaluated the capability of trabectedin to inhibit CC viability and used ovarian cancer (OC) models as a reference. Since chronic stress may promote gynecological cancer and may hinder the efficacy of therapy, we investigated the potential of targeting β-adrenergic receptors with propranolol to enhance trabectedin efficacy and change tumor immunogenicity. Methods: OC cell lines, Caov-3 and SK-OV-3, CC cell lines, HeLa and OV2008, and patient-derived organoids were used as study models. MTT and 3D cell viability assays were used for drug(s) IC50 determination. The analysis of apoptosis, JC-1 mitochondrial membrane depolarization, cell cycle, and protein expression was performed by flow cytometry. Cell target modulation analyses were carried out by gene expression, Western blotting, immunofluorescence, and immunocytochemistry. Results: Trabectedin reduced the proliferation of both CC and OC cell lines and notably of CC patient-derived organoids. Mechanistically, trabectedin caused DNA DSBs and S-phase cell cycle arrest. Despite DNA DSBs, cells failed the formation of nuclear RAD51 foci and underwent apoptosis. Under norepinephrine stimulation, propranolol enhanced trabectedin efficacy, further inducing apoptosis through the involvement of mitochondria, Erk1/2 activation, and the increase of inducible COX-2. Notably, trabectedin and propranolol affected the expression of PD1 in both CC and OC cell lines. Conclusion: Overall, our results show that CC is responsive to trabectedin and provide translational evidence that could benefit CC treatment options. Our study pointed out that combined treatment offset trabectedin resistance caused by β-adrenergic receptor activation in both ovarian and cervical cancer models.

17P Impact of adjuvant chemoradiotherapy on survival outcome compared to other treatment modalities for cervical cancer stage IIIc

Cervical cancer is very common among females. Surgery, chemotherapy and radiotherapy are different treatment options for cervical cancer. In 2018, the FIGO staging system has implemented lymph node status in the staging criteria but didn’t consider the number of positive lymph nodes. The current guidelines recommends primary chemoradiotherapy to treat the advanced stages but combined treatment regimens for node positive cervical cancer remains controversial, so this study aims to evaluate the survival outcome of different treatment modalities with further stratification by the positive lymph node number. We used Surveillance, Epidemiology, and End Results (SEER) database to extract the data of 3146 patients with node positive cervical cancer diagnosed from 2000 to 2018, they were treated with different approaches: adjuvant chemoradiotherapy, adjuvant radiotherapy, surgery without systemic treatment, adjuvant chemotherapy and primary chemoradiotherapy. We divided patients into four groups according to the number of involved lymph nodes: one node, two to three nodes, four to 10 nodes, more than 10 nodes. We used SPSS for data analysis. The overall 5-year survival outcome was higher for adjuvant chemoradiotherapy compared to adjuvant radiotherapy, surgery, primary chemoradiotherapy and adjuvant chemotherapy (68.7%, 63.4%, 59.1%, 47.5%, 40.7% ; P-value >0.00). Out of adjuvant chemoradiotherapy showed better 5-year overall survival outcome in patients with one lymph node involvement 73.1% and in patients with 2-3 positive lymph nodes 63.9%. These results highlighted adjuvant chemo-radiotherapy as the treatment of choice for node cervical cancer stage IIIc, surgery and adjuvant chemoradiotherapy has have qiuet similar survival outcome. We also recommend the number of positive lymph nodes to be implemented in the upcoming FIGO system as a predictor for survival outcome and a factor for the treatment plan. Further evaluation is necessary to weigh the benefit versus side effects of the best regimen for each patient.

Angiogenesis-related gene signatures reveal the prognosis of cervical cancer based on single cell sequencing and co-expression network analysis.

Cervical cancer ranks first in female reproductive tract tumors in terms of morbidity and mortality. Yet the curative effect of patients with persistent, recurrent or metastatic cervical cancer remains unsatisfactory. Although antitumor angiogenic drugs have been recommended as the first-line treatment options for cervical cancer, there are no comprehensive prognostic indicators for cervical cancer based on angiogenic signature genes. In this study, we aimed to develop a model to assess the prognosis of cervical cancer based on angiogenesis-related (AG) signature genes, and to provide some reference for the comprehensive treatment of cervical cancer in the clinical setting. First we screened the AG gene set from GeneCard website, and then performed angiogenesis-related scores (AGS) per cell from single cell sequencing dataset GSE168652, followed by performing weighted gene co-expression network analysis (WGCNA) for cervical cancer patients according to angiogenesis phenotype. Thus, we established a prognostic model based on AGS by taking the intersection of WGCNA angiogenic module gene and differential gene (DEGs) of GSE168652. The GSE44001 was selected as an external validation set, followed by performing ROC curve analysis to assess its accuracy. The results showed that we successfully constructed a prognostic model related to the AG genes. Patients in the high-AGS group in both the train, test and the validation sets had a worse prognosis than those in the low-AGS group, had lower expression of most immune checkpoint-associated genes and lower tumor mutational burden as well. Patients in the low-AGS group were more sensitive to AMG.706, Bosutinib, and Lenalidomide while Imatinib, Pazopanib, and Sorafenib were more recommended to patients in the high-AGS group. Finally, TXNDC12 and ZC3H13, which have high hazard ratio and poor prognosis in the model, were highly expressed in cervical cancer cell lines and tissue. Meanwhile, the results showed that TXNDC12 promoted the migration of cervical cancer cells and the tubule-forming ability of endothelial cells. In conclusion, our model based on genes with AG features can effectively assess the prognosis of cervical cancer, and can also provide reference for clinicians to choose immune-related treatments.

LINC00707 Promotes Cell Proliferation in Cervical Cancer via the miR-374c-5p/SDC4 Axis.

Cervical cancer (CC) is the second main reason of cancer-related deaths in women around the world. Long intergenic nonprotein coding RNA 707, which is known as LINC00707, has been elucidated to facilitate the progression of multifarious tumors, but how it may exert functions in CC has not been elucidated yet. By using quantitative real-time RT-PCR (RT-qPCR), we identified the expression pattern LINC00707 may possess in CC. Loss-of-function assays including Cell Counting Kit-8 (CCK-8), colony formation, and transferase-mediated dUTP nick-end labeling (TUNEL) assays were taken to verify the effects of LINC00707 inhibition on CC cell proliferation and apoptosis. The downstream RNAs were selected through bioinformatics prediction, and their interaction with LINC00707 was verified through mechanism assays including the luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay. According to results, LINC00707 was upregulated in CC cells, and LINC00707 insufficiency inhibited cell proliferation while facilitating cell apoptosis. MicroRNA (miRNA) miR-374c-5p interacted with LINC00707, and syndecan-4 (SDC4) was verified to be the downstream target gene. Data of rescue assays proved that LINC00707 could promote CC cell malignancy via the miR-374c-5p/SDC4 axis, which revealed a potential treatment option for CC.

Identification of Novel Tumor Microenvironment Regulating Factor That Facilitates Tumor Immune Infiltration in Cervical Cancer.

Cervical cancer is one of the most common gynecologic malignancies and one of the leading causes of cancer-related deaths in women worldwide. There are more than 30 categories of human papillomavirus infections in the genital tract. The recently discovered immune checkpoint suppression is a potential approach to improve clinical outcomes in these patients by altering immune cell function. However, many questions remain unanswered in terms of this method. For example, the proportion of responders is limited and the exact mechanism of action is uncertain. The tumor microenvironment (TME) has long been regarded as having nonnegligible influence on effectiveness of immunotherapy. The programmed cell death protein 1 (PD-1) pathway has received much attention due to its involvement in activating T-cell immune checkpoint responses. Since tumor cells may evade immune detection and become highly resistant to conventional treatments, anti-PD-1/PD-L1 antibodies are preferred as a kind of cancer treatment and many have just been licensed. To provide a theoretical basis for the development of new therapies, investigating the effect of tumor microenvironment on the prognosis of cervical cancer is necessary. In this work, immunological scores obtained from the ESTIMATE algorithm were used to differentiate between patients with high and low immune cell infiltration. We identified 11 immunologically significant differentially expressed genes (DEGs). For example, CXCR3 was found to be an important factor in CD8+ T cell recruitment and tumor immunological infiltration in cervical cancer. These results may lead to novel directions of understanding complex interactions between cancer cells and the tumor microenvironment, as well as new treatment options for cervical cancer.

Role of NRF2 cascade in determining the differential response of cervical cancer cells to anticancer drugs: an in vitro study.

Cervical cancers are usually treatable if detected in early stages by a combination of therapies. However, the prognosis of cervical cancer patients with metastasis remains unfavorable due to the fact that most of the cervical carcinomas are either resistant to anticancer drugs or show signs of relapse after initial treatment. Therefore, it is important to control the chemoresistance as it is the key to develop effective treatment options for cervical cancer. The current study aimed at evaluating the differential responses of cervical cancer cells to anti-cancer drugs and assessed whether the differences in the expression profiles of antioxidant genes regulated by nuclear factor erythroid-2-related factor 2 (NRF2), led to the variations in the sensitivities of the cancer cells to treatment. Three cervical cancer cell lines were investigated for their differences in NRF2 pathway by measuring the gene expression and enzyme activity. The differences in the sensitivity to anti-cancer drugs and variation in ROS profile was also evaluated. The addition of exogenous drugs to manipulate the intracellular ROS and its effect on NRF2 pathway genes was also investigated. HeLa and SiHa cells were more sensitive to cisplatin and oxaliplatin treatment than C33A cells. HeLa and SiHa cells had significantly lower NRF2 gene levels, NQO1 enzyme activity and basal GSH levels than C33A cells. Levels of ROS induced were higher in HeLa than C33A cells. Overall, the differences in the cellular levels of antioxidant regulatory genes led to the differential response of cervical cancer cells to anti-cancer drugs.

Low-dose naltrexone plays antineoplastic role in cervical cancer progression through suppressing PI3K/AKT/mTOR pathway

The incidence of cervical cancer is increasing annually worldwide. Low-dose naltrexone (LDN) has been reported to delay tumor progression, but the mechanism remains unclear. Here, we found that low-dose naltrexone could upregulate the expression of OGFr. Additionally, LDN could suppress the abilities of colony formation, migration and invasion in cervical cancer cells. LDN could also inhibit cervical cancer progression in mice model. Moreover, LDN indirectly reduced the expressions of PI3K, pAKT and mTOR in vitro and in vivo. Therefore, LDN may be considered a potential treatment option for cervical cancer.

FAM83A as a Potential Biological Marker Is Regulated by miR-206 to Promote Cervical Cancer Progression Through PI3K/AKT/mTOR Pathway

Background and Objective: Chemotherapy and radiotherapy are effective treatment options for cervical cancer (CC), but their efficacy is limited by short survival rate of about 5 years particularly for advance stage CC. Bioinformatics analysis combined with experimental in vivo and in vitro data can identify potential markers of tumorigenesis and cancer progression to improve CC prognosis and survival rate of the patients. This study aims to investigate the prognostic value of family with sequence similarity 83, member A (FAM83A) gene and miR-206 in promoting CC progression and the involved genetic signaling pathways.Method: This was a bioinformatic analysis study based on RNA sequencing data of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and verification by in vivo and in vitro experimental data. It was designed to evaluate whether the aberrantly expressed gene signatures could serve as new potential biomarker to improve prognosis prediction in CC. The TCGA RNA sequencing data [306 cervical squamous cell carcinoma (SCC) and endocervical adenocarcinoma samples and 13 adjacent samples] and GEO data (GSE9750 and GSE52903 datasets) were integrated and performed a bioinformatics analysis.Results: The results showed that CC-associated FAM83A gene serves as a key regulator of CC development and progression. Functionally, we observed that FAM83A is significantly overexpressed in CC, which is linked to poor overall survival as well as disease-free survival in CC patients. The in-vitro and in-vivo assessments performed after silencing FAM83A revealed that cell proliferation was significantly inhibited and the S-phase cell cycle arrest was induced. Mechanistically, FAM83A plays a role in PI3K/AKT signaling, and its downstream molecules could promote CC cell proliferation. Furthermore, functionality assessments by in-vitro luciferase reporter system and immunoblot analysis showed that miR-206 was the upstream of FAM83A and negatively correlated with FAM83A.Conclusion: The miR-206/FAM83A/PI3K/AKT signaling pathway possibly serves as a critical effector in CC progression indicating the potential prognostic value of FAM83A gene as a novel biomarker for CC progression.

Recent advances in the contribution of noncoding RNAs to cisplatin resistance in cervical cancer.

Cervical cancer (CC) remains a major disease burden on the female population worldwide. Chemotherapy with cisplatin (cis-diamminedichloroplatinum (II); CDDP) and related drugs are the main treatment option for CC; however, their efficacy is limited by the development of drug resistance. Noncoding RNAs (ncRNAs) have been found to play critical roles in numerous physiological and pathological cellular processes, including drug resistance of cancer cells. In this review, we describe some of the ncRNAs, including miRNAs, lncRNAs and circRNAs, that are involved in the sensitivity/resistance of CC to CDDP-based chemotherapy and discuss their mechanisms of action. We also describe some ncRNAs that could be therapeutic targets to improve the sensitivity of CC to CDDP-based chemotherapy.

Outcomes of External-Beam Radiation Therapy Boost with Conventional Fractionation in Cervical Cancer: A Retrospective Analysis about 133 Cases

Introduction: External-beam radiation therapy boost is a treatment option in cervical cancer when brachytherapy is not feasible. Though less effective than brachytherapy, some encouraging results have been reported from some institutions experiences. We conducted this study to assess outcomes of EBRT boost for our patients at National Institute of Oncology in Rabat. Patients and Methods: We collected data from patients treated for cervical cancer between January 2012 and December 2015. Patients, tumor and treatment characteristics were collected. Overall survival (OS), disease-free survival (DFS) and prognostic factors influencing DFS were assessed. Results: One hundred and thirty-three patients were enrolled. Median age was 52 years. Patient haemoglobin level ranged from 3.9 to 15.5 g/dl [mean: 11.2 g/dl]. Most tumors were classified stage III/IVA (63.2%) according to the FIGO classification. Regional lymph node metastases (pelvic and or para-aortic) were observed in 45.1%. Median total dose to tumor was 69.6 Gy (ranging from 66 to 70 Gy). Overall treatment time was protracted, with a median of 60 days. Most of patients received concurrent chemotherapy (94.7%) and the number of cycle ranged from 2 to 7 (median = 5). The follow-up median was 31.3 months, ranging from 6.2 to 96.8 months. At the first visit, most patients achieved complete response (80.5%). Five years OS and DFS were 47% and 44% respectively. In univariate and multivariate analysis, regional lymph nodes metastasis (presence or absence) and haemoglobin level (≤11 g/dl and >11 g/dl) were the two significant and independent prognostic factors influencing DFS (HR: 1.86; p = 0.01 for the former) (HR: 0.59; p = 0.03 for the latter). Conclusion: Our study showed that EBRT boost in conventional fractionation was an acceptable treatment option for cervical cancer unamenable to brachytherapy, especially in the two subgroups of patients that are those without pelvic and/or para-aortic lymph node metastasis and those with haemoglobin level above 11 g/dl.

Long non-coding RNA TP73-AS1 predicts poor prognosis and regulates cell proliferation and migration in cervical cancer.

IntroductionCervical cancer is one of the most common malignant tumors in women, which seriously affects women’s health, especially in developing countries. This study aims to investigate novel molecular markers for poor prognosis of cervical cancer to achieve correct guidance of clinical treatment, accurate assessment of prognosis, and provide a new basis for the choice of reasonable treatment options for cervical cancer patients.Material and methodsQRT-PCR was employed to investigate the expression of lncRNA TP73-AS1 in cervical cancer tissues and cell lines. COX multivariate analysis showed the relationship between TP73-AS1 expression and clinicopathological features of patients with cervical cancer. Colony formation and MTT assay detected the effect of TP73-AS1 on proliferation of cervical cancer cells. The effect of TP73-AS1 on migration and invasion of cervical cancer cells was determined by the wound-healing assay and transwell assay. Western blot was performed to assess the expression of EMT markers.ResultsThis study showed that lncRNA TP73-AS1 was up-regulated in cervical cancer tissues and cell lines (p < 0.001), and high expression of TP73-AS1 could be considered as an independent prognostic factor (p < 0.05). Moreover, lncRNA TP73-AS1 promotes cervical cancer cell migration and invasion, and knockdown of TP73-AS1 inhibits the growth of cervical cancer cells (p < 0.001).ConclusionsOur results indicated that lncRNA TP73-AS1 was up-regulated in cervical cancer tissues and cell lines, predicting poor prognosis of cervical cancer and regulating cell proliferation and migration.

Effect of radiotherapy on the survival of cervical cancer patients: An analysis based on SEER database.

Cervical cancer is among the most frequent cancer types in women worldwide. Radiotherapy, including external beam radiation and brachytherapy, is one of the commonly used treatment options for cervical cancer. However, the adverse effects of radiation therapy on cervical cancer survival have been poorly investigated with inconclusive results. Therefore, the aim of this study was to determine the suitable radiotherapy modality according to patients' characteristics. A retrospective survival analysis of 44,602 patients was performed using the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate proportional hazard Cox model was used to evaluate the prognostic impact of different radiotherapy modalities, primary surgery, age, TNM stage, and tumor size. Our results indicated that patients without primary surgery, diagnosed at older age (≥45 years' old), at advanced TNM stages (III/IV) or with larger tumor size (≥3 cm) could benefit from radiotherapy. However, radiotherapy was detrimental in patients with primary surgery, diagnosed at younger age (<45 years' old), at earlier TNM stages (I/II) or with smaller tumor size (<3 cm). In addition, external beam radiation was in most cases less effective compared with combined external beam and brachytherapy. These results highlighted the necessity of realizing personalized radiotherapy treatments for patients with cervical cancer.

Patient characteristics associated with treatment of cervical cancer in the United States.

e17020 Background: Treatment options for cervical cancer include surgery, radiation therapy, chemotherapy, and immunotherapy depending upon the disease stage. There is limited real-world evidence providing us with a clinical profile for a treated cervical cancer patient. The objective of this study was to compare cervical cancer patients who were currently receiving treatment versus those not receiving treatment. Methods: This was a retrospective, cross-sectional analysis of Medical Expenditure Panel Survey (MEPS) data (2006-2015). Cervical cancer cases were identified using ICD-9 CM code 180 or clinical classification software code 26. Patients receiving only chemotherapy, radiation therapy, undergoing surgery, or a combination of these treatments in a given year were regarded as “currently receiving treatment”. The comparator cohort included patients “not currently receiving treatment”. The two cohorts were compared in terms of patient clinical characteristics using bivariate analyses. Results: The analytic cohort consisted of 275,246 cervical cancer cases (mean age: 42 years, Caucasian: 88.0%, having private insurance: 55.3%) of which 115,639 (42.01%) were “currently receiving treatment”. The most common treatment option was undergoing surgery only (88.21%), followed by combination therapy (6.82%), chemotherapy only (3.84%), and radiation therapy only (1.12%). The “currently receiving treatment” cohort had a significantly higher proportion of patients having a history of myocardial infarction (4.21% vs 3.50%), congestive heart failure (2.73% vs 1.42%), chronic obstructive pulmonary disorder (29.5% vs 23.2%), connective tissue disease (20.5% vs 11.6%), renal disease (2.49% vs 0.48%), and diabetes (17.7% vs 11.7%) compared to those “not currently receiving treatment”. The latter cohort had a higher proportion of patients with moderate/severe liver disease (0.46% vs 5.32%). Conclusions: The observed real-world patient characteristics and treatment patterns were indicative of a cohort of largely early stage cervical cancer patients. Patients receiving treatment appeared to have a higher comorbidity burden which may subsequently result in poorer quality of life and activity limitations.

A single arm, phase 2, multicenter, international trial of tisotumab vedotin (HuMax-TF-ADC) in previously treated, recurrent or metastatic cervical cancer.

TPS5601Background: Cervical cancer treatment options are limited for patients with recurrent and/or metastatic cervical cancer. Tisotumab vedotin (TV) is an antibody-drug conjugate (ADC) composed o...

Tumor necrosis factor-related apoptosis inducing ligand overexpression and Taxol treatment suppresses the growth of cervical cancer cells in vitro and in vivo.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a member of tumor necrosis factor (TNF) superfamily and functions to promote apoptosis by binding to cell surface death receptor (DR)4 and DR5. Cancer cells are more sensitive than normal cells to TRAIL-induced apoptosis, and TRAIL-based therapeutic strategies have shown promise for the treatment of cancer. The present study investigated whether enforced overexpression of TRAIL in cervical cancer cells promoted cell death in the presence or absence of Taxol, an important first-line cancer chemotherapeutic drug. Hela human cervical cancer cells were transfected with a TRAIL expression plasmid, and the effects of the combination treatment with Taxol on apoptosis was investigated in vitro and in tumor xenografts in vivo. The results indicated that Taxol treatment and TRAIL overexpression enhanced apoptosis compared with either treatment alone. The present data indicate that Taxol may enhance the pro-apoptotic effects of TRAIL overexpression in HeLa cells by increasing cleaved caspase-3 and DR5 expression levels and decreasing Bcl-2 expression levels. Furthermore, the findings suggest a possible novel treatment option for cervical cancer and uncovers a potential mechanism of the enhancing effects of Taxol on TRAIL-induced apoptosis.

Abstract B44: Radiation therapy induced a supra-additive cytotoxic effect in cervical cancer cell line when combined with mTOR inhibitors

Abstract The PI3K/AKT/mTOR signaling pathway is frequently activated in HPV-positive squamous cell carcinomas, such as cervical (CC) and head and neck tumors. This study aimed to investigate the biologic effects of mTOR inhibitors associated with radiation therapy (RT) in a cervical cancer cell line (HeLa). A human keratinocytes cell line (HaCaT) was used as control. Temsirolimus, everolimus, resveratrol, curcumin, and epigallocatechin gallate (EGCG) were the mTOR inhibitors used as treatment. MTT cell viability assay was performed to obtain dose-response curves. A nonlinear regression was applied to dose-response curves, in order to calculate the 50% cell cytotoxicity rate (CC50) for each treatment. To evaluate radiosensitization, cells were pretreated with mTOR inhibitors at CC50 followed by RT at 2Gy dose. Mann-Whitney test was used to compare the irradiated and nonirradiated groups. Cell death profile after treatment with temsirolimus, resveratrol, and curcumin was also assessed with flow cytometry. Kruskal-Wallis test with Dunn's post-test was applied on flow cytometry results to compare the control to the treated groups within each cell death profile. Everolimus, temsirolimus, EGCG, resveratrol, and curcumin were cytotoxic to the cervical cancer cell line. The lowest CC50 values after both 24 and 48 hours of treatment were seen in the groups of everolimus with HeLa (28.31 µM and 22 µM, respectively) and temsirolimus with HaCaT (26.54 µM and 12.85 µM). Resveratrol resulted in the highest CC50 values for both cell lines (325.8 µM and 144.6 µM for 24 and 48 hours in HeLa and 355.3 µM and 260.3 µM for 24 and 48 hours in HaCaT). An additive effect was observed when RT was associated with mTOR inhibitors. Cell viability at CC50 for the drug alone and combined to RT were: 64.44% and 33.88% for EGCG; 63.28% and 33.41% for resveratrol; 52.62% and 36.55% for curcumin; 54.06% and 35.04% for temsirolimus; 50.06% and 37.37% for everolimus. These results showed that radiation induced a statistically significant (p &amp;lt; 0.01) supra-additive cytotoxic effect in the cervical cancer cell line when combined with mTOR inhibitors. A Tumor Selectivity Index (TSI) was calculated for each mTOR inhibitor. After a 24-hour treatment, only EGCG and resveratrol were more cytotoxic to HeLa than to HaCaT, with TSIs of 1.41 and 1.09, respectively. After 48 hours of treatment, resveratrol, curcumin, and everolimus were also more cytotoxic to HeLa when compared to HaCaT, with TSIs of 1.8, 3.25, and 3.77, respectively. The TSI results showed that resveratrol was selective for the cancer cell line in both 24 and 48 hours, even though its CC50 was very high. After 24 hours, temsirolimus induced late apoptosis or necrosis in HeLa cells. Based on these data, new studies with mTOR inhibitors as treatment options for cervical cancer are recommended, mainly combined to radiotherapy. Diet-derived mTOR inhibitors may be powerful strategies for the treatment of cervical cancer, particularly if its selectivity for cancer cell lines is confirmed in further studies. Considering the role of HPV oncoproteins and the activation of the PI3K/AKT/mTOR pathway in the pathogenesis of cervical cancer, mTOR inhibitors could be an important therapy in the drug armamentarium for cervical cancer. Citation Format: Daniele Xavier Assad, Gabriel Alvares Borges, Samuel Avelino, Eliete Neves da Silva Guerra. Radiation therapy induced a supra-additive cytotoxic effect in cervical cancer cell line when combined with mTOR inhibitors [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B44.