Outcome In Ovarian Cancer Patients Research Articles

Association Between Risk of Malnutrition and Surgical Outcome in Ovarian Cancer Patients

Ovarian cancer is the fourth most cancer in Indonesia. Treatment of ovarian cancer is surgery. Malnutrition may complicate healing, so studying the association between malnutrition and surgical outcome in ovarian cancer patients is necessary. A cross-sectional study was conducted in Dr. Cipto Mangunkusumo General Hospital from July 2018 - March 2019. fromo 63 patients underwent surgery, four were excluded due to non-malignant ovarian pathology results. Parameters assessed were characteristic subjects and risk factors of malnutrition in ovarian cancer patients. Malnutrition was assessed using the Patient-Generated Subjective Global Assessment (PGSGA) and surgery factors assessed were the length of surgery, size of the tumor, and blood loss during surgery. The nutritional status was classified as well-nourished and malnourished. The receiver operating characteristic (ROC) curve is used to assess malnutrition, length of stay, size of the tumor, and blood loss during surgery. The result shows that the prevalence of malnutrition in ovarian cancer was 78% (moderate was 42.4% and severe was 35.6%), and the median length of stay was eight days. There is an association (chi-square test, p<0.05) between malnutrition and surgical outcome in ovarian cancer patients. Malnutrition is associated (chi-square test, p<0.05) with a length of stay and increased blood loss during surgery.

UCP1 modulates immune infiltration level and survival outcome in ovarian cancer patients

BackgroundThe uncoupling proteins (UCPs) are critical genes associated with tumorigenesis and chemoresistance. However, little is known about the molecular mechanism of the UCPs in ovarian cancer (OV).Material and methodsUCPs expression analysis was conducted using Gene Expression Profiling Interactive Analysis (GEPIA), and its potential in clinical prognosis was analyzed using Kaplan- Meier analyses. The influence of UCPs on immune infiltration was analyzed by TIMER. In addition, the correlation between UCPs expression and molecular mechanisms was investigated by TIMER and Cancer Single-cell State Atlas (CancerSEA).ResultsUCP1, UCP2, UCP3 and UCP5 expression levels correlated with a favorable prognosis and tumor progression. Moreover, UCP1 expression correlated to several immune cell markers and regulated tumorigenesis, such as tumor invasion, EMT, metastasis and DNA repair. In addition, UCP1 potentially involved in genes expression of SNAI2, MMP2, BRCA1 and PARP1.ConclusionsThese results implied a critical role of UCP1 in the prognosis and immune infiltration of ovarian cancer. In addition, UCP1 expression participated in regulating multiple oncogenes and tumorigenesis.

Ovarian cancer and KiSS-1 gene expression: A consideration of the use of Kisspeptin plus Kisspeptin aptamers in diagnostics and therapy

Gynaecological cancers continue to present a significant health burden upon the health of the global female population. This deficit is most prominent with ovarian cancer which possesses the lowest survival rate compared to all other cancers occurring within this anatomical region, with an annual UK-mortality of 7,300. The poor tolerability and selectively of the treatment options that are currently available is likely to have contributed to this high mortality rate thus, demonstrating the need for the development of enhanced therapeutic approaches. Aptamer technology would involve the engineering of specifically sequenced oligonucleotide chains, which bind to macromolecular targets with a high degree of affinity and selectively. Recent in-vitro studies conducted upon the clinical utility of this technique have supported its superiority in targeting individual therapeutic drug targets compared to various other targeting moieties currently within therapeutic use such as, monoclonal antibodies. For this reason, the employment of this technique is likely to be favourable in reducing the incidence of non-specific, chemotherapy-associated adverse effects. Kisspeptin is a naturally expressed polypeptide with an established role in the development of the reproductive system and other proposed roles in influencing the ability of ovarian cancer growths to exhibit the metastasis hallmark. This distinctive feature would indicate the potential for the manipulation of this pathway through the application of aptamer structures in developing a novel prophylactic strategy and improve the long-term outcome for ovarian cancer patients.

Integrative analysis deciphers the heterogeneity of cancer-associated fibroblast and implications on clinical outcomes in ovarian cancers

Accumulating evidence has recognized that cancer-associated fibroblasts (CAFs) are major players in the desmoplastic stroma of ovarian cancer, modulating tumor progression and therapeutic response. However, it is unclear regarding the signatures of CAFs could be utilized to predict the clinical outcomes of ovarian cancer patients. To fill in this gap, we explored the intratumoral compartment of ovarian cancer by analyzing the single-cell RNA-sequencing (scRNA-seq) datasets of ovarian carcinoma samples, and identified two distinct CAFs (tumor-promoting CAF_c1 subtype and myofibroblasts-like CAF_c2 subtype). The clinical significance of CAF subtypes was further validated in The Cancer Genomics Atlas (TCGA) database and other independent immunotherapy response datasets, and the results revealed that the patients with a higher expression of CAF_c1 signatures had a worse prognosis and showed a tendency of resistance to immunotherapy. This work uncovered the signatures of the CAF_c1 subtype that could serve as a novel prognostic indicator and predictive marker for immunotherapy.

Prevalence of BRCA1 and BRCA2 pathogenic sequence variants in ovarian cancer patients in the Gulf region: the PREDICT study

BackgroundPatients with pathogenic sequence variants (PSVs) in BRCA1/BRCA2 are at high risk of developing ovarian cancer (OC). However, genetic testing for BRCA1/BRCA2 PSVs is still not a routine practice in the Middle East. With the lack of epidemiological studies in the region, we aim to describe the prevalence of BRCA1/BRCA2 PSVs in patients with OC across different countries in the Gulf region.MethodsThe PREDICT study was an observational, prospective, epidemiological study, which consecutively recruited women with ovarian, primary peritoneal, and fallopian tube cancers from the following Gulf countries over the period from July 2017 to July 2019; United Arab Emirates (UAE), Kuwait, and Oman. The study was approved by the local ethics committee of participating centers. The BRCA1/BRCA2 PSVs were assessed by tissue genetic testing using next-generation sequencing (NGS).ResultsA total of 105 women were included with a median age at diagnosis of 52 years (IQR 44.5 – 61.0). Nearly 11.4% of patients reported a family history of ovarian or breast cancer, while 4.7% of patients reported a family history of other cancers. Most of the patients (70.3%) had advanced disease (FIGO stage III/IV) at presentation. Eighty-eight patients (84%) were successfully tested for somatic BRCA1/BRCA2 PSVs. Fifteen patients (17%) were found to have PSVs in either BRCA1, BRCA2, or both genes; of them, 10 patients (11.2%) had BRCA1 somatic PSVs alone, eight patients (9.1%) had BRCA2 somatic PSVs, while three patients (2.9%) had both PSVs. Five patients with BRCA1/BRCA2 somatic PSVs had germline PSVs tests, and three of them tested positive. Concerning treatment, 87.6% of patients received perioperative chemotherapy and 6.6% as first-line palliative chemotherapy. Eighty-seven (82.9%) patients underwent debulking surgery, with no residual disease in 42.5% of patients.ConclusionOur study showed that the prevalence of BRCA1/BRCA2 somatic PSVs in patients with OC is higher than the reported global figures (2-8%). However, more studies are warranted to further elucidate the prevalence of BRCA1/BRCA2 somatic and germline PSVs, as well as other relevant genetic alterations, to better understand their impact on OC patient outcomes in Gulf countries.Trial registrationNCT03082976.

The Platelet-Activating Factor Receptor's Association with the Outcome of Ovarian Cancer Patients and Its Experimental Inhibition by Rupatadine.

The platelet-activating factor receptor (PAFR) and its ligand (PAF) are important inflammatory mediators that are overexpressed in ovarian cancer. The receptor is an important player in ovarian cancer development. In this study, we aimed to evaluate the prognostic value of PAFR in epithelial ovarian cancer (EOC) and the potential use of its antagonist, rupatadine, as an experimental treatment. Tissue microarrays of ovarian cancer patients, most markedly those with a non-mucinous subtype, immunohistochemically overexpressed PAFR. Elevated cytoplasmic PAFR expression was found to significantly and independently impair patients’ overall and recurrence-free survival (OS: median 83.48 vs. 155.03 months; p = 0.022; RFS: median 164.46 vs. 78.03 months; p = 0.015). In vitro, the serous ovarian cancer subtypes especially displayed an elevated PAFR gene and protein expression. siRNA knockdown of PAFR decreased cell proliferation significantly, thus confirming the receptor’s protumorigenic effect on ovarian cancer cells. The clinically approved PAFR antagonist rupatadine effectively inhibited in vitro cell proliferation and migration of ovarian cancer cells. PAFR is a prognostic marker in ovarian cancer patients and its inhibition through rupatadine may have important therapeutic implications in the therapy of ovarian cancer patients.

Non-Surgical Management of Malignant Bowel Obstruction in Advanced Ovarian Cancer patients: A Systematic Review and Meta-Analysis.

Background:Malignant bowel obstruction is a common cause of morbidity and mortality in patients with advanced ovarian cancer. Many patients aren’t suitable for, or decline, surgical decompression. The outcomes for this frail group of patients are not well characterized.Aim:To evaluate survival outcomes of ovarian cancer patients who undergo non-surgical management of malignant bowel obstruction.Design:Systematic review and meta-analysis.Data Sources:Online literature search of Pubmed, Embase and Medline libraries up until December 2020. Searching abstracts of scientific meetings, reference lists of included studies and contacting experts in the field.Selection Criteria:Studies that investigated non-surgical management of confirmed bowel obstruction in advanced ovarian cancer patients were included. All levels of evidence including RCTs, cohort studies and case-series if they included greater than 5 patients.Data Collection and Analysis:The studies were independently chosen by two reviewers who extracted and analyzed the data separately through OpenMeta Analyst software. Study quality was assessed using the JADAD score and the Newcastle Ottawa Score.Results:24 studies met the eligibility criteria for the systematic review and 9 for the meta-analysis. Median survival of patients managed non-surgically for bowel obstruction was 44 days (95% CI 38-49 days, I 2 = 0%, P = 0.128).Conclusion:The quality of studies was relatively low, however the evidence shows that non-surgical management of bowel obstruction results in a short life expectancy but with controlled symptoms. Where quality of life is the main concern, this may be a feasible and effective strategy.

The Emerging Role of Non-coding RNAs in Drug Resistance of Ovarian Cancer.

Ovarian cancer is one of the most common gynecological malignancies with highest mortality rate among all gynecological malignant tumors. Advanced ovarian cancer patients can obtain a survival benefit from chemotherapy, including platinum drugs and paclitaxel. In more recent years, the administration of poly-ADP ribose polymerase inhibitor to patients with BRCA mutations has significantly improved the progression-free survival of ovarian cancer patients. Nevertheless, primary drug resistance or the acquisition of drug resistance eventually leads to treatment failure and poor outcomes for ovarian cancer patients. The mechanism underlying drug resistance in ovarian cancer is complex and has not been fully elucidated. Interestingly, different non-coding RNAs (ncRNAs), such as circular RNAs, long non-coding RNAs and microRNAs, play a critical role in the development of ovarian cancer. Accumulating evidence has indicated that ncRNAs have important regulatory roles in ovarian cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically highlight the emerging roles and the regulatory mechanisms by which ncRNAs affect ovarian cancer chemoresistance. Additionally, we suggest that ncRNAs can be considered as potential diagnostic and prognostic biomarkers as well as novel therapeutic targets for ovarian cancer.

Timing of intervention and complications of tunneled peritoneal catheter placement for recurrent malignant ascites in ovarian cancer patients

Objectives: In ovarian cancer patients, recurrent malignant ascites reduces quality of life and is associated with a poor prognosis. There is a lack of guidance in the literature regarding the placement of a tunneled peritoneal catheter in this patient population. We evaluated the outcomes of ovarian cancer patients who underwent tunneled peritoneal catheter placement for recurrent malignant ascites. Methods: We queried the institutional interventional radiology records from 5/2009 to 5/2020 for female patients with ovarian cancer who had a tunneled peritoneal catheter placed for malignant ascites. We evaluated patient characteristics, number of paracentesis procedures recorded prior to placement, complications, and the time between placement and death. Descriptive statistics were performed. Results: 30 patients were identified. The mean age was 68 (range, 42-88). 77% of patients were White and the average BMI was 26. 56.7% of patients had stage IIIC ovarian cancer and the 83.3% had papillary serous adenocarcinoma. Patients had a mean of four lines (range, 0-11) of chemotherapy before undergoing tunneled peritoneal catheter placement. The mean number of paracentesis performed prior to peritoneal catheter placement was two (range, 0-6). There were six minor complications (20%), including two catheter-related infections requiring removal and four instances of catheter dysfunction requiring revision. The median time of catheter placement to death was 44 days (range, 3-151). Conclusions: The complication rate of tunneled peritoneal catheter placement is low, as evidenced by no major complications found in this patient population. The short period from catheter placement until patient death suggests that tunneled peritoneal catheters should be pursued earlier in the disease course if patients have symptomatic, recurrent ascites.

An SNP at the 8q24 region (rs6983267) is associated with better survival and chemo-response in high-grade serous ovarian cancer

<h3>Objectives:</h3> 8q24 chromosomal region is strongly associated with risk of ovarian cancer and other cancers. One single-nucleotide polymorphisms SNP associated with ovarian cancer in this region is rs6983267, located within the long non-coding RNA Colon Cancer Associated Transcript2 (CCAT2). However, little is known about the association of this SNP with outcomes in ovarian cancer patients. Our aim was to assess the association between rs6983267 and clinical outcomes in patients with high-grade serous ovarian cancer (HGSC) <h3>Methods:</h3> This is a retrospective case-control study. Sanger sequencing was performed to determine the genotype at the rs6983267 locus (GG, GT, TT) in 99 HGSC patients. We compared survival and chemotherapy response between those with TT genotype and those with a genotype containing a G allele (GT, GG). Survival analysis was performed using Cox proportional hazard ratio analysis. Association with chemo-response was performed with logistic regression. <h3>Results:</h3> HGSC patients with TT genotypes at the rs6983267 locus had better survival than patients with genotypes containing a G allele (HR = 0.59; p=0.039) in the multivariate survival analysis. In the multivariate logistic regression, TT genotype was significantly associated with FIGO stage (OR = 5.34; p=0.014) and positive chemo-response (OR = 4.51; p=0.018). <h3>Conclusions:</h3> HGSC patients with a TT genotype at the rs6983267 locus had better survival than those with a G allele, despite being associated with more advanced disease (FIGO stage), possibly due to a better response to chemotherapy. Genetic variation may be key to decipher individual HGSC outcomes and chemotherapy response.

Abstract 2831: Exosome gene signatures characterize metastatic dynamicity

Abstract Early diagnosis and effective tumor monitoring can significantly alter clinical outcomes of ovarian cancer patients. Innovative tools are needed to enhance the sensitivity and specificity of current monitoring modalities. Extracellular vesicles, or exosomes, have shown to be promising conduits of diagnostic biomarkers to aid in tumor detection as evidenced by Exosome Diagnostics' new ExoDx Prostate (IntelliScore) test that uses exosomal markers to differentiate between benign prostate disease and early cancer (Tutrone, R., Donovan, M.J., Torkler, P. et al. Clinical utility of the exosome based ExoDx Prostate(IntelliScore) EPI test in men presenting for initial Biopsy with a PSA 2-10 ng/mL. Prostate Cancer Prostatic Dis 23, 607-614 (2020)). The potential of these vesicles however goes beyond simple diagnostic power of cancer detection. Due to the onco-specific contents packaged and the minimally invasive, low risk accessibility, exosomes have the capacity to be used as longitudinal monitoring tools to characterize early molecular changes at all stages of the disease. We hypothesized that the dynamicity of ovarian tumors during progression and metastatic development is reflected in exosomes. In order to test this we isolated exosomes and used qPCR to analyze exosomal gene signatures from a mouse model of ovarian cancer. SKOV3 ovarian cancer tumor cells were injected into mice and allowed to grow for 3 weeks. Plasma was collected from mice at 5-7 day increments and exosomes were extracted. Multiple established metastatic genes in ovarian cancer were evaluated and 4 genes, Lox, THBS1, TIMP3, and β-actin, were found to be differentially expressed in correlation with 3 translationally pertinent assessments: presence or absence of tumors, levels of metastatic burden, and longitudinal tumor progression. Gene expression patterns were compared with exosomal gene signatures extracted from human ovarian patient plasma and found to express similar patterns. These results support the diagnostic potential of using exosomal genetic signatures to detect early metastatic development and to facilitate longitudinal tracking of tumor progression. Citation Format: Amber Gonda, Jay V. Shah, Jake N. Siebert, Nanxia Zhao, Mi Jung Kwon, Prabhas V. Moghe, Nicola Francis, Vidya Ganapathy. Exosome gene signatures characterize metastatic dynamicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2831.

Abstract 3095: Targeting ALDH1A1 and regulatory networks that support stemness in ovarian cancer cells

Abstract Epithelial ovarian cancer (OC) is the deadliest amongst gynecologic cancers with the majority of deaths caused by cancer recurrence. A new paradigm explaining tumor relapse involves the persistence of cancer stem cells after chemotherapy. OC stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors, and we have previously shown that OCSCs contribute to recurrent, drug resistant high-grade serous OC (HGSOC) using ALDH (aldehyde dehydrogenase) activity as a robust functional marker to identify OCSCs. Of the ALDH isoforms, ALDH1A1 is an intracellular enzyme that oxidizes toxic aldehydes to carboxylic acids and plays a role in controlling cell differentiation pathways. High levels of ALDH1A1 expression have been associated with poor outcome in OC patients. Our group and others have demonstrated that OCSCs with high expression of ALDH1A1 have a greater ability to initiate ovarian tumors in vivo. However, the mechanism by which ALDH1A1 maintains stemness phenotype remains poorly understood. In the current study, we hypothesized that ALDH1A1 upregulation in OCSCs was associated with genetic changes that mediate the cellular signals needed for survival. To test this hypothesis, we used a novel ALDH1A1-specific small molecule inhibitor named compound 974. Treatment of HGSOC cell lines with compound 974 reduced ALDH enzyme activity (p&amp;lt;0.01) and inhibited stem-like properties including spheroid formation (p&amp;lt;0.01) and clonogenic survival (p&amp;lt;0.05). To further examine the effect of compound 974 to inhibit ALDH1A1 and consequently tumor initiation, mice were injected with 106, 105 and 104 OVCAR3 cells treated in vitro with compound 974 (5µM for 48h). Tumor initiation was delayed by 974 treatment compared to vehicle-treated group. Extreme limiting dilution analysis revealed that compound 974 reduced CSC frequency compared to control. Transcriptomic sequencing of ovarian cancer cells treated with compound 974 revealed significant inhibition of genes and pathways associated with stemness (NF-κB, KLF4, FZD7), chemoresistance (ABCB1) and senescence pathway genes (p15, p21). Furthermore, key genes associated with senescence associated secretory phenotype (SASP) such as IL6, IL8 and IL1α were significantly inhibited. Taken together, these data warrant further investigation into the mechanism of ALDH1A1 inhibition and loss of stemness in HGSOC. Citation Format: Vaishnavi Muralikrishnan, Kenneth P. Nephew, Thomas D. Hurley. Targeting ALDH1A1 and regulatory networks that support stemness in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3095.

Therapeutic Overcoming of Cancer Stem Cell-Featured Chemo-Resistant Ovarian Cancer via Photodynamic Therapy and Cascadic Chemotherapy Combined Hyaluronan Nanoparticles

In this study, we designed combination cancer therapeutic hyaluronan nanoparticles (NIR-responsive ROS-generating pheophorbide A and ROS-cleavable thioketal-linked SN38; PheoA-SN38-HC NPs). And the combined therapeutic effects of PheoA-SN38-HC NPs were investigated against HEY-T30 human ovarian cancer (OC) model which highly co-expresses cancer stem cell (CSC) markers and exhibits strong chemo-resistance. Clinical Proteomic Tumor Analysis Consortium (CPTAC) data showed that the expression of CSC markers (CD44, ALDH1A1, and CD117) rather than folic acid receptor is highly associated with poor clinical outcomes in OC patients. Western assay, migration and colony forming assay proved chemo-resistant HEY-T30 cells overexpress CSC markers and much more invasive than other cancer cells. Synthesized NPs were ~250 nm and spherical by DLS and TEM analysis. FACS and microscopic analysis revealed the active targeting property of PheoA-SN38-HC NPs in CD44+ HEY-T30 cells. Moreover, synergistic effects of the combination therapy of photodynamic ROS generation and ROS-triggered SN38 release were clearly demonstrated with in vitro HEY-T30 cells and an in vivo xenograft mouse model. In particular, the paracrine cytotoxic effect of SN38 released by ROS-trigger suggested that combination design could compensate for the clinical limitation of photodynamic therapy.

Zinc transporter SLC39A13/ZIP13 facilitates the metastasis of human ovarian cancer cells via activating Src/FAK signaling pathway

BackgroundZinc transporters have been found to be associated with the pathogenesis of numerous human diseases including cancer. As the most lethal gynecologic malignancy, ovarian cancer is characterized by rapid progression and widespread metastases. However, the function and underlying mechanism of zinc transporters in ovarian cancer metastasis remain unclear.MethodsThe relationship between zinc transporter gene expressions and clinical outcomes of ovarian cancer was assessed with the online database Kaplan-Meier plotter (http://kmplot.com/analysis/). Immunohistochemistry was performed to investigate the prognostic importance of ZIP13. The expression of ZIP13 in ovarian cancer cell lines was depleted to explore its effect on proliferation, adhesion, migration, and invasion both in vitro and in vivo assays. RNA-Seq, quantitative RT-PCR, and western blot analysis were performed to explore ZIP13-regulated downstream target genes.ResultsThe expressions of several zinc transporters were highly associated the clinical outcomes of ovarian cancer patients. Among them, high ZIP13 expression was an independent prognostic factor for poor survival in patients with ovarian cancer. ZIP13 knockout suppressed the malignant phenotypes of ovarian cancer cells both in vitro and in vivo. Further investigation revealed that ZIP13 regulated intracellular zinc distribution and then affected the expressions of genes involved in extracellular matrix organization and cytokine-mediated signaling pathway. This led to the activation of Src/FAK pathway with increased expressions of pro-metastatic genes but decreased expressions of tumor suppressor genes.ConclusionsZIP13 is shown to be a novel driver of metastatic progression by modulating the Src/FAK signaling pathway, which may serve as a promising biomarker for prognostic evaluation and targeted therapy in ovarian cancer.

An international, multicenter, real-world analysis of epithelial ovarian cancer treatment and outcomes.

5531 Background: Few major studies have examined and compared the management and outcomes of patients from diagnosis to death between countries. We have established an international collaboration across Europe and South Korea to compare treatment and outcomes in Epithelial Ovarian Cancer (EOC). Methods: Patients diagnosed with EOC between January 2012 and December 2018 (age ≥18), were included for analysis. Data from medical records from five European and a single South Korean treatment centre were extracted, standardised to a common data model and analysed at each centre using a common script developed in R. Time to each progression/recurrence event (defined as time to next treatment) and overall survival have been estimated using Kaplan Meier methodology and outcomes stratified by categories of interest. Changes in the use of anti-cancer therapies over time and the incidence of BRCA mutations and incidence/timing of second breast cancers have also been examined. Results: A total cohort of 2925 patients was identified with a median age at each centre of 53 to 67 years. Advanced disease (FIGO stage III - IV) (range 57% to 84%) and high-grade serous morphology (38% to 70%) were most common at each centre. The timing of surgery (primary, interval debulking or delayed) and the proportion of patients undergoing surgery varied with stage. Patients with stage I disease where most likely to undergo surgery (range 73% to 100%) and stage IV the least (range 39% to 84%). Median overall survival for high grade serous cancers ranged from 1.9 to 4.9 years, and for the whole cohort from 2.1 to 5.5 years. Median time to next treatment at first relapse for the whole cohort ranged from 14 to 22 months. Second breast cancers were noted in 6 to 17% of patients and the majority of these occurred before the diagnosis of EOC at a median time of 96 to 118 months prior to diagnosis of EOC. Additional data on treatment pathways, BRCA status and outcomes by line of therapy for each centre will be presented. Conclusions: Preliminary analysis of results across this network suggests a variation in patient populations between sites and substantial differences in both treatments and outcomes. The establishment of a common data model and the use of a common analytic script between sites across six different countries allows for detailed exploration of the factors influencing differences in patient management and treatment outcomes in ovarian cancer patients.

Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness.

Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.

Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound’s response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications.

Outcomes of ovarian cancer patients treated with platinum or non-platinum based chemotherapy after PARP inhibitor maintenance.

5563 Background: PARP inhibitors (PARPi) are approved for maintenance treatment of platinum sensitive ovarian cancers either after front-line therapy or after treatment for recurrence. Current recommendations include retreatment with platinum-based chemotherapy (PC) after progression on maintenance PARPi. There exists a theoretical concern that progression of disease (POD) on PARPi is indicative of the development of platinum resistance due to similar DNA targets of platinum chemotherapy and PARPi. Our objective was to evaluate the response to subsequent chemotherapy in patients who progressed on PARPi maintenance. Methods: All patients with ovarian, fallopian tube, or primary peritoneal cancer treated with PARPi treatment from 2017 to 2021 at two academic tertiary care centers were retrospectively identified. Patients were assessed for treatment time on PARPi, time to POD on PARPi (PFS), type of chemotherapy regimen following PARPi maintenance, and time to disease progression on subsequent therapy following PARPi (PFS2). Comparative statistical analyses were performed with appropriate two-sided statistical tests. Time to progression on chemotherapy after PARPi was calculated using the Kaplan-Meier method. Results: A total of 83 ovarian cancer patients treated with PARPi were identified, and of these, 61 (73.5%) were treated with PARPi in the maintenance setting. Among the patients treated with PARPi maintenance, 22 (36.1%) remain on treatment. 19 (31.1%) patients were started on PARPi maintenance after front-line chemotherapy. While on PARPi maintenance, 63.9% discontinued PARPi, the majority due to POD, and 26.2% due to patient intolerance of side effects. Following POD, 21/29 (72.4%) received subsequent PC and 8/29 (27.6%) received non-platinum based chemotherapy (NPC). Treatment time, PFS, and PFS2 are listed in Table. Of the patients who received PC, 14/21 (66.7%) had a PFS2 of over six months and 5/21 (23.8%) had a PFS2 of over 12 months. Of the patients who received NPC, 7/8 (87.5%) had a PFS2 of over six months and 2/8 (25.0%) had a PFS2 of over 12 months. Conclusions: Following POD on PARPi, patients responded to both PC and NPC. Time to progression on subsequent chemotherapy after treatment with PARPi does not differ significantly between PC and NPC regimens. Many patients continue to see benefit from PC after PARPi maintenance. Retreatment with PC following POD on PARPi maintenance should still be considered.[Table: see text]

Alternative splicing acts as an independent prognosticator in ovarian carcinoma

Alternative splicing (AS) events associated with oncogenic processes present anomalous perturbations in many cancers, including ovarian carcinoma. There are no reliable features to predict survival outcomes for ovarian cancer patients. In this study, comprehensive profiling of AS events was conducted by integrating AS data and clinical information of ovarian serous cystadenocarcinoma (OV). Survival-related AS events were identified by Univariate Cox regression analysis. Then, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to construct the prognostic signatures within each AS type. Furthermore, we established a splicing-related network to reveal the potential regulatory mechanisms between splicing factors and candidate AS events. A total of 730 AS events were identified as survival-associated splicing events, and the final prognostic signature based on all seven types of AS events could serve as an independent prognostic indicator and had powerful efficiency in distinguishing patient outcomes. In addition, survival-related AS events might be involved in tumor-related pathways including base excision repair and pyrimidine metabolism pathways, and some splicing factors might be correlated with prognosis-related AS events, including SPEN, SF3B5, RNPC3, LUC7L3, SRSF11 and PRPF38B. Our study constructs an independent prognostic signature for predicting ovarian cancer patients’ survival outcome and contributes to elucidating the underlying mechanism of AS in tumor development.

Multi-omics analysis of the prognosis and therapeutic significance of circadian clock in ovarian cancer.

Ovarian cancer (OV) is one of the most common female malignancies with high morbidity and mortality, but its mechanism is not fully understood. The circadian clock is involved in the regulation of the immune system and the tumor microenvironment, regulating biological processes and behaviors in multiple ways. Circadian rhythm disorders are considered a risk factor for tumorigenesis. Multi-omics analysis was performed to comprehensively illustrate the roles of circadian clock genes in OV, we found that most of circadian clock genes undergo epigenetic alterations in OV and are strongly correlated with overall and progression-free patient survival. These clock genes are mainly involved in the inhibition of Apoptosis pathway, Cell Cycle pathway and DNA Damage Response pathway, as well as the activation of RAS/MAPK pathway and RTK pathway. Drug sensitivity model indicate that the expression of core clock genes may associate with drug resistance. Further, immune infiltrates analysis shows that different mutant forms of core genes can not only suppress immune infiltration, but also affect clinical outcome of ovarian cancer patients. Overall, our results may provide novel insights for the potential selection of immunotherapeutic targets.