Clear Cell Ovarian Cancer Research Articles

Capitalizing on the absence of TP53 mutations in low-grade serous and clear cell ovarian cancer with XPO1 inhibition

Capitalizing on the absence of TP53 mutations in low-grade serous and clear cell ovarian cancer with XPO1 inhibition

Abstract B177: Association between ethnicity and ovarian cancer tumor characteristics in Asian Americans in California

Abstract Background: Ovarian cancer is often associated with poor survival given that most patients are diagnosed at advanced stages when treatment is less effective. The disease is also very heterogeneous, consisting of various histologic subtypes that each have distinct epidemiologic and pathologic profiles. Given that some studies have noted ethnic-specific disparities in ovarian cancer survival when the Asian American population is disaggregated and certain tumor characteristics are associated with more favorable outcomes, we examined the relationship between Asian ethnic subgroup and ovarian cancer disease presentation. Methods: We included a total of 31,230 non-Hispanic White and Asian/Pacific Islander ovarian cancer cases diagnosed between 1996 and 2020 from the California Cancer Registry. Multivariable logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs) was used to examine the likelihood of being diagnosed with tumors of a certain stage, grade, and histologic subtype, for each Asian ethnic subgroup compared to non-Hispanic Whites. Demographic and socioeconomic factors were considered in the analyses. Results: Most, but not all, Asian ethnic subgroups were less likely to be diagnosed with advanced stage ovarian cancer and more likely to be diagnosed with clear cell ovarian cancer compared to non-Hispanic Whites. For South East Asians, the odds of having advanced stage tumors were 43% lower than non-Hispanic Whites (OR=0.57, 95% CI 0.41-0.79) and the odds of having clear cell tumors were almost 200% higher than non-Hispanic Whites (OR=2.97, 95% CI 1.92-4.61); only South Asians did not show lower odds of an advanced stage tumor diagnosis (OR=1.06, 95% CI 0.86-1.29) and higher odds of a clear cell tumor diagnosis (OR=0.93, 95% CI 0.63-1.37). Conclusion: There are clear differences in ovarian cancer disease presentation when each Asian ethnic subgroup is examined separately with South Asians constituting the only subgroup who did not show a lower likelihood of an advanced stage diagnosis and a higher likelihood of a clear cell diagnosis when compared to non-Hispanic Whites. Given that tumor stage and histologic subtype are considered important prognostic factors for ovarian cancer, identifying the underlying factors that may contribute to being diagnosed with certain tumor characteristics could provide clues to help us improve the survival of this highly fatal malignancy. Citation Format: Alice W. Lee, Jenny Chang, Sannia Siddiqui, Argyrios Ziogas, Robert E. Bristow. Association between ethnicity and ovarian cancer tumor characteristics in Asian Americans in California [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B177.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study

BackgroundPlatinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate...

753P Unlocking the circulating immune landscape of advanced clear-cell ovarian cancer: Insights from the MOCCA trial

753P Unlocking the circulating immune landscape of advanced clear-cell ovarian cancer: Insights from the MOCCA trial

Paired comparison of the analytical performance between the Oncomine™ Comprehensive Assay v3 and whole-exome sequencing of ovarian cancer tissue

BackgroundNext-generation sequencing (NGS) has been implemented in clinical oncology as a personalized medicine tool to identify targetable genetic alterations and to guide treatment decisions. However, the optimal NGS test strategy and target genes for clinical use are still being discussed. The aim was to compare the performance of the Oncomine™ Comprehensive Assay v3 (OCAv3) (targeted gene panel) and whole-exome sequencing (WES) to investigate somatic single and multiple nucleotide variants and small indels in ovarian cancer patients.Methods and resultsGenomic DNA was isolated from fresh frozen samples of five high-grade serous (HGSC) and three clear cell ovarian (oCCC) cancer patients. Exome sequencing libraries were prepared by using the Ion AmpliSeq Exome RDY kit, whereas libraries for OCAv3 were prepared using by Ion AmpliSeq™ Library Kit Plus. Sequencing was performed using the Ion S5XL System (Thermo Fisher Scientific). When including only variants classified as pathogenic, likely pathogenic or unknown significance based on ClinVar database verdicts and comparing overlapping regions covered both by the OCAv3 assay and WES, 23 variants were detected by both assays. However, OCAv3 detected additionally two variants: ARID1A: p.Gln563Ter and TP53: p.Ser261ValfsTer84 that have not passed WES filtering criteria due to low coverage.ConclusionsWith the present treatment possibilities, OCAv3 panel testing provided higher diagnostic yield due to better coverage. Our study emphasizes that WES, although offering the potential to identify novel findings in genes not covered by OCAv3, might overlook variants in genes relevant for OC.

Ovarian cancer risk factors in relation to family history.

Women with a family history of breast and/or ovarian cancer have an increased ovarian cancer risk. Yet it remains uncertain if common ovarian cancer risk factors-especially those which are modifiable-affect this high-risk population similarly to the general population. Using the Danish and Swedish nationwide registers, we established two nested case-control study populations in women with a family history of breast and/or ovarian cancer (2,138 ovarian cancers, 85,240 controls) and women without (10,730 ovarian cancers, 429,200 controls). The overall and histology-specific associations were assessed with conditional logistic regression. The country-specific estimates were combined based on a fixed-effect assumption. Multiparity, hysterectomy, tubal ligation, salpingectomy, and oral contraceptive (OC) use were associated with a reduced risk of ovarian cancer in both women with and without a family history, while endometriosis and menopausal hormone treatment (MHT) were associated with increased risk. Multiparity and OC use presented protective effects across all histologic subtypes except mucinous ovarian cancer which was not associated with OC use. MHT increased the risk of serous ovarian cancer but decreased the risk of the mucinous and clear cell cancers. Endometriosis was especially related to an increased risk of endometrioid and clear cell ovarian cancer. Factors associated with a decreased ovarian cancer risk were similar between women with and without a family history of breast and/or ovarian cancer. Given the higher baseline risk for women with a family history, special attention should be paid to risk factors like endometriosis and nulliparity in this high-risk population.

Final results of BrUOG 354: A randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas.

LBA5500 Background: Extra-renal clear cell cancer (CCC) are rare tumors that can arise from any organ. Gynecologic CCC can originate from the ovaries, endometrium, or cervix. Compared to serous carcinomas, ovarian CCC is associated with poorer outcomes to standard chemotherapy, warranting a focused evaluation for innovative therapies. We completed a two-stage two-arm phase 2 trial evaluating immunotherapy for extra-renal CCC and present the final results of treatment using nivolumab (N) monotherapy and in combination with ipilimumab (I) in this population. Methods: This is a randomized two-stage phase II study evaluating single-agent N (240mg IV every two weeks) or in combination with I (1mg/kg every six weeks) (N/I) in people with relapsed extra-renal CCC after at least one prior therapy (no prior immunotherapy). Measurable disease was required. In the first stage, volunteers were randomly assigned to N or N/I with stratification by tumor site (ovarian vs extra-ovarian). Treatment was continued until disease progression or unacceptable toxicity. Each arm was evaluated for overall response rate (ORR) separately at stage 1 using RECIST and iRECIST criteria. In January 2022, the N arm was closed, and subsequent volunteers were treated with N/I. The study completed enrollment in April 2023. Results: Between July 2018 and April 2023, 46 volunteers provided consent for the study and 44 were treated (14 N, 30 N/I). The median age was 57 (range, 18-75) years. Across the study, 75% were White, 9.1% Black, 4.5% were Asian, and 11.4% were Hispanic. All volunteers had a gynecologic primary, 36 (82%) with ovarian CCC. The median number of prior lines was 1 (range, 1-7). The Overall Response Rate (ORR) is 14.3% (2 Partial Responses) with N and 33% (4 Complete and 6 Partial Responses) with N/I. Four people continue on treatment with N/I as of December 2023. With a median follow up of 11.3 (range, 1.6-46.4) months, the median Progression-Free Survival is 2.2 (95% CI 1.2-3.4) months with N and 5.6 (95% CI 1.6-29.1) months with N/I. The median Overall Survival is 17 (95% CI 2.1-NR) and 24.6 (95% CI 5.9-NR) months, respectively. Serious treatment-related adverse events were recorded in 3 (21%) treated with N (all grade 3) and 14 (47%) treated with N/I (two of whom had grade 4 pancreatic enzyme elevations). No new safety signals were noted, and no treatment-related deaths were observed in either arm. Conclusions: Immunotherapy demonstrated important, meaningful, and durable activity in people with previously treated gynecologic CCC including four (12%) volunteers who achieved a complete response with N/I. N/I warrant further evaluation against standard treatment for people with ovarian CCC, given the historically chemotherapy-resistant nature of the disease. Clinical trial information: NCT03355976 .

Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

Genetically identification of endometriosis and cancers risk in women through a two-sample Mendelian randomization study

Endometriosis is a prevalent and chronic inflammatory gynecologic disorder affecting approximately 6–10% of women globally, and has been associated with an increased risk of cancer. Nevertheless, previous studies have been hindered by methodological limitations that compromise the validity and robustness of their findings. In this study we conducted a comprehensive two-sample Mendelian randomization analysis to explore the genetically driven causal relationship between endometriosis and the risk of cancer. We conducted the analysis via the inverse variance weighted method, MR Egger method, and weighted median method utilizing publicly available genome-wide association study summary statistics. Furthermore, we implemented additional sensitivity analyses to assess the robustness and validity of the causal associations identified. We found strong evidence of a significant causal effect of endometriosis on a higher risk of ovarian cancer via inverse-variance weighted method (OR = 1.19, 95% CI 1.11–1.29, p < 0.0001), MR-Egger regression, and weighted median methodologies. Remarkably, our findings revealed a significant association between endometriosis and an increased risk of clear cell ovarian cancer (OR = 2.04, 95% CI 1.66–2.51, p < 0.0001) and endometrioid ovarian cancer (OR = 1.45, 95% CI 1.27–1.65, p < 0.0001). No association between endometriosis and other types of cancer was observed. We uncovered a causal relationship between endometriosis and an elevated risk of ovarian cancer, particularly clear cell ovarian cancer and endometrioid ovarian cancer. No significant associations between endometriosis and other types of cancer could be identified.

Abstract CT111: Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial

Abstract Background NXP800 is an oral, small molecule that activates the integrated stress response through activation of the kinase GCN2. The drug causes growth inhibition and regression in various preclinical models, including ARID1A mutated ovarian and endometrial xenograft and cholangiocarcinoma PDX models. Methods We describe results of the dose-defining dose escalation cohort and the toxicity-pharmacokinetics and pharmacodynamic evaluation in a first-in-human phase I trial of NXP800. Dose escalation was guided by a Bayesian modified continual reassessment method that targeted a dose-limiting toxicity DLT probability (DLTp) closest to 30% but &amp;lt;33%. Toxicity was assessed using NCI.CTC.V5. Detailed sampling of blood for pharmacokinetic analysis and blood for mRNA and protein analysis in peripheral blood mononuclear cells was conducted on C1D-3 to -7 (run in prior to continuous dosing) and C2D1. Two schedules (once per day [QD] and twice per day [BID] and a dose range of 50 to 150 mg/day were evaluated. Results Eighteen patients were treated: at baseline, the median age was 65 years (range 42-77), 9 (50%) were female and 14/18 (78%) had an ECOG score of 1. The most common treatment emergent adverse events (more than 20% of patients) were nausea, vomiting, diarrhea, fatigue, decreased appetite, AST increase and thrombocytopenia. All these side effects were grade 1-2 except grade 3 nausea and grade 3 diarrhea reported in one patient each and grade 3 thrombocytopenia in 2 patients. The MTD for the QD schedule was 100 mg (DLTp=26%), no doses in the BID schedule had estimated DLTp of &amp;lt;33%. The average Cmax at 50 mg and 75 mg OD was 190 nM and 384 nM during the run-in and 495 nM and 656 nM in cycle 2 reached by 3 hours. ATF4 protein in PBMCs was elevated in 57% and 80% of patients during run in and Cycle 2 respectively, 6 hours after 50 mg and 75 mg treatment. The mRNA biomarkers in blood most consistently elevated included ATF4 transcriptional targets NUPR1, ULBP1 and TRIB3 at 2 - 24 hours after 50 mg and 75 mg treatment. Further, mRNA levels for these biomarkers were elevated in post-treatment biopsy samples in one of the two patients tested. It is envisaged that NXP800 will need to be dosed continuously and although the protocol defined MTD at 28 days at 100 mg QD, it was decided to take a dose of range of 50 mg and 75 mg OD which caused biomarker modulation, forward for further evaluation. Conclusions A tolerable dose/schedule of continuous dosing of NXP800 has been established with biomarker modulation in blood. Patients will be randomized to two dose levels 50 and 75 mg/day in a QD schedule to evaluate response in a population of ARID1A mutated, platinum-resistant, clear cell ovarian cancer (NCT05226507). Citation Format: Simon Pacey, Ching Leung, Simon Rodney, Ana Filipa Palma DosReis, Ruth Ruddle, Matthew Tall, Karen Swales, Robert te Poele, Paul Workman, Diane Marsolini, Megan Sardone, Enrique Poradosu, Shay Shemesh, Udai Banerji. Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT111.

Endometriosis-associated ovarian cancer: a different clinical entity

ObjectiveTo compare survival outcomes and patterns of recurrence between endometriosis-associated ovarian cancer patients and non-endometriosis-associated ovarian cancer patients.MethodsThis retrospective study included data of consecutive patients with endometrioid or clear cell...

Abstract 3647: Digital spatial transcriptomic reveals different epithelial and immune cells signatures across endometriosis-related diseases: From simple ovarian endometriosis to ovarian cancer

Abstract Endometriosis represents a pressing medical concern, imposing a relevant burden on patients including potential malignant transformation into endometriosis-associated ovarian cancer (EAOC). Despite the process of cancer development remains unclear, immune cells abnormalities arose as putative biomarkers in the neoplastic progression. One-third of ovarian endometriosis cases exhibit PD-1/PD-L1 expression levels comparable to those observed in cancer. To substantiate the biological basis of these findings, this study aimed to elucidate the spatial transcriptomic profile of epithelial and immune components from different endometriosis-related conditions, along with their genetic interplay. Formalin-fixed paraffine embedded (FFPE) specimens from 4 ovarian endometriosis (OE) cases, two of which displayed elevated levels of PD-1/PD-L1 expression and were referred to as cancer-like endometriosis (CLE), 1 Clear Cell Ovarian Cancer (CCOC) and 1 Endometrioid Ovarian Cancer (EOC) were cut in 5um section for spatial transcriptomic analysis using GeoMX Human Whole Transcriptome Atlas (WTA) probe-set (&amp;gt;18000 genes). For all sections, the regions of interest (ROIs) were identified using a set of morphology markers: anti-human CD3, CD68 and PanCK antibodies. Spatial transcriptomic analysis revealed condition-specific gene enrichment of epithelial and immune cells across the different conditions. In spite of similar H&amp;E findings, PanCKpos epithelial cells from CLE showed an increased expression of genes involved in stress response and defense regulation pathways (e.g. CXCL6, S100A9, and PECAM-1), when compared to OE, in which PanCKpos cells were enriched in DUSP1/2 and VIM. Interestingly, in CCOC, location-specific gene-enrichment was found in PanCKpos cells, with a significant up regulation of tumor suppressor genes (e.g. EGR-1, NR4A1) in normal-looking peri-tumoral epithelium compared to cancerous intra-tumoral PanCKpos cells. Similarly, in the immune compartment, spatial transcriptomic analysis revealed that CD3pos cells from CLE displayed an up-regulation of genes involved in IL-17 signaling, response to oxydative stress and complement activation (e.g. CXCL6, HMOX1, S100A9, and PECAM-1), when compared to OE. Moreover, in CCOC, CD68pos cells of the tumoral mass showed over-expression of tumor growth and progression markers (e.g. SPP1) compared to their counterpart in the outer area of the tumoral mass. In this first comprehensive spatial transcriptomic study of endometriosis-related diseases with GeoMx WTA, our findings uncovered remarkable differences in epithelial and immune cells among different stages and tissue locations. Importantly, CLE emerged as a transitional entity with a unique immune profile. Ongoing analysis of six additional samples will further refine our results. Citation Format: Valentina Iacobelli, Camilla Nero, Stefano Alivernini, Giulia Scaglione, Floriana Camarda, Francesca Sillano, Rita Trozzi, Alessia Piermattei, Barbara Tolusso, Giulia Mantini, Luciano Giacò, Gloria Anderson, Gian Franco Zannoni, Elisa Gremese, Anna Fagotti, Giovanni Scambia. Digital spatial transcriptomic reveals different epithelial and immune cells signatures across endometriosis-related diseases: From simple ovarian endometriosis to ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3647.

Abstract 524: Using acquired resistance to explore the mechanism of action of the integrated stress response/GCN2 activator NXP800 - A new developmental agent for platinum-resistant ARID1A mutant ovarian cancer

Abstract Background: NXP800 is a potent, oral activator of the Integrated Stress response (ISR), inhibitor of heat shock factor 1 (HSF1) activation and tumor cell proliferation, which is in early clinical studies in ARID1A-mutated, platinum resistant, clear cell ovarian cancer (NCT05226507). We discovered NXP800 using multiparameter medicinal chemistry optimization of a hit identified from a cell-based phenotypic screen. Owing to the unbiased nature of phenotypic screening, target identification is crucial to understand the biological and therapeutic activity of hit compounds. Methods and Results:: By RNAseq profiling human cancer cells treated with NXP800 we identified changes in expression of genes regulated by HSF1 or ATF4 - effects accompanied by eIF2alpha (eIF2a) phosphorylation and resulting activation of the ISR. To further understand this response, we explored whether NXP800 resistance models could inform on its mechanism of action (MoA). We used ARID1A mutant SK-OV-3 human ovarian carcinoma cells that are 1) highly sensitive to NXP800, 2) model the target patient population and 3) MSI-high so likely to have an elevated mutation rate contributing to acquisition of resistance. We generated two independent NXP800-resistant SK-OV-3 cell lines in which NXP800-mediated ATF4 induction and concomitant inhibition of global translation were abolished. By whole exome sequencing, we identified a heterozygous L99P mutation in the alpha subunit of eIF2B (eIF2Ba), the nucleotide exchange factor for eIF2a. Expression of eIF2BaL99P, but not wild-type, in parental SK-OV-3 cells reduced sensitivity to NXP800 to the same level as cells with NXP800-induced resistance. Using fluorescence recovery after photobleaching to monitor the dynamic association of the eIF2B:eIF2a complex, we elucidated that the eIF2BaL99P mutation reduces NXP800-mediated inhibition of eIF2a-GFP recycling through eIF2B bodies. Phosphorylation of eIF2a is regulated by four stress-controlled kinases GCN2, HRI, PKR and PERK. Using systematic siRNA knockdown or small-molecule inhibitors, we showed that GCN2 alone is required for ISR activation by NXP800 and that ISR induction inhibited HSF1 activation. Furthermore, inactivation of GCN2 reduced the antiproliferative activity of NXP800 to the same extent observed in NXP800-resistant SK-OV-3 cells. In contrast, exposure of resistant or parental SK-OV-3 cells expressing eIF2BaL99P to GCN2 inhibitors did not cause further reduction in NXP800 sensitivity - confirming the importance of the eIF2BaL99P mutation in the resistance mechanism. Conclusions: We have used acquired resistance to understand the MoA of NXP800 as a potent activator of GCN2 and the ISR pathway. Further studies are underway to determine the exact proximal molecular target of NXP800 and the mechanism of GCN2/ISR activation. Citation Format: Marissa V. Powers, Rachel Hodgson, Swee Y. Sharp, Toby Roe, K. Elizabeth Allen, Susan Campbell, Robert te Poele, Matthew Cheeseman, Keith Jones, Paul A. Clarke, Paul Workman. Using acquired resistance to explore the mechanism of action of the integrated stress response/GCN2 activator NXP800 - A new developmental agent for platinum-resistant ARID1A mutant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 524.

Abstract 2096: A novel, orally available ferroptosis inducer targeting Fe-S assembly with significant in vivo anti-tumor efficacy

Abstract Background: Ferroptosis is a novel form of cell death driven by iron-dependent lipid peroxidation, which disrupts cellular membranes resulting in immune-activating death. A variety of tumor types, particularly those associated with enhanced lipid and/or iron content, or which experience increased oxidative stress (including drug tolerant persister cells), are sensitive to ferroptosis, rendering ferroptosis a promising therapeutic strategy for cancer. However, currently available ferroptosis inducers show limited activity in vivo, suggesting a need for novel molecular targets to validate the clinical utility of ferroptosis induction. Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of VHL resulting in constitutive activation of HIF-1α and HIF-2α, which contribute to disease progression, including by promoting lipid accumulation that sensitizes ccRCC cells to ferroptosis. Methods: We performed a high-throughput screen to identify small molecule inhibitors of HIF-2α followed by structure-activity-relationship studies for validation. The molecular target of these inhibitors was identified using the Drug Affinity Responsive Target Stability assay, and target validation was confirmed using siRNA and NMR. In vitro efficacy was determined in a panel of cancer cell lines and in vivo anti-tumor efficacy was verified using mouse models of cancer. Results: We identified a novel molecule, KD061, which decreases HIF-1/2α and induces ferroptosis in vivo through oral administration by targeting Iron Sulfur Cluster Assembly 2 (ISCA2). ISCA2 is a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex and ISCA2 inhibition either pharmacologically or using siRNA triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 inhibition also decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation. These studies reveal a novel function of ISCA2 in extra-mitochondrial Fe-S assembly that may be limiting in cancer due to the increased need for these proteins in DNA replication and maintenance. Outside of ccRCC, a 92-cell line screen reveals a variety of tumor types sensitive to ISCA2 inhibition including melanoma and clear cell ovarian cancer. Treatment of tumor-bearing mice with KD061 resulted in &amp;gt; 65% tumor growth inhibition, associated with significantly increased lipid peroxidation, thus confirming ferroptosis in vivo, and with decreased HIF-1/2α. The anti-tumor efficacy of KD061 exceeded that of α-PD1 and was well tolerated at the therapeutic dose. Conclusions: We describe the first orally available inducer of ferroptosis with significant anti-tumor efficacy in ccRCC and other tumor types. Citation Format: Yangsook Song Green, Maria Ferreira dos Santos, Simone Ciofi-Baffoni, Xiaohui Liu, Mei Yee Koh. A novel, orally available ferroptosis inducer targeting Fe-S assembly with significant in vivo anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2096.

Abstract B055: Identifying compounds to promote apoptotic cell death in clear cell ovarian cancer

Abstract B055: Identifying compounds to promote apoptotic cell death in clear cell ovarian cancer

Abstract A037: Exploring the therapeutic effectiveness of EO3001 in the treatment of clear cell ovarian cancers with ARID1A mutations

Abstract A037: Exploring the therapeutic effectiveness of EO3001 in the treatment of clear cell ovarian cancers with ARID1A mutations

A case series of four women with clear cell ovarian cancer, with unexpected atypical endometriosis as precursor lesions

A case series of four women with clear cell ovarian cancer, with unexpected atypical endometriosis as precursor lesions

Association of Four Interleukin-8 Polymorphisms (-251 A>T, +781 C>T, +1633 C>T, +2767 A>T) with Ovarian Cancer Risk: Focus on Menopausal Status and Endometriosis-Related Subtypes.

Interleukin-8 (IL-8) is involved in the regulation of inflammatory processes and carcinogenesis. Single-nucleotide polymorphisms (SNPs) within the IL-8 gene have been shown to alter the risks of lung, gastric, or hepatocellular carcinomas. To date, only one study examined the role of IL-8 SNPs in ovarian cancer (OC), suggesting an association between two IL-8 SNPs and OC risk. In this study, we investigated four common IL-8 SNPs, rs4073 (-251 A>T), rs2227306 (+781 C>T), rs2227543 (+1633 C>T), and rs1126647 (+2767 A>T), using the restriction fragment length polymorphism (PCR-RFLP) technique. Our study included a cohort of 413 women of Central European descent, consisting of 200 OC patients and 213 healthy controls. The most common (73.5%) histological type was high-grade serous OC (HGSOC), whereas 28/200 (14%) patients had endometriosis-related (clear cell or endometrioid) OC subtypes (EROC). In postmenopausal women, three of the four investigated SNPs, rs4073 (-251 A>T), rs2227306 (+781 C>T), and rs2227543 (+1633 C>T), were associated with OC risk. Furthermore, we are the first to report a significant relationship between the T allele or TT genotype of SNP rs1126647 (+2767 A>T) and the EROC subtype (p = 0.02 in the co-dominant model). The TT homozygotes were found more than twice as often in EROC compared to other OC subtypes (39% vs. 19%, p = 0.015). None of the examined SNPs appeared to influence OC risk in premenopausal women, nor were they associated with the aggressive HGSOC subtype or the stage of disease at the initial diagnosis.

Causal effect analysis of estrogen receptor associated breast cancer and clear cell ovarian cancer.

Evidence indicates that the risk of developing a secondary ovarian cancer (OC) is correlated with estrogen receptor (ER) status. However, the clinical significance of the relationship between ER-associated breast cancer (BC) and clear cell ovarian cancer (CCOC) remains elusive. Independent single nucleotide polymorphisms (SNPs) strongly correlated with exposure were extracted, and those associated with confounders and outcomes were removed using the PhenoScanner database. SNP effects were extracted from the outcome datasets with minor allele frequency > 0.01 as the filtration criterion. Next, valid instrumental variables (IVs) were obtained by harmonizing exposure and outcome effects and further filtered based on F-statistics (> 10). Mendelian randomization (MR) assessment of valid IVs was carried out using inverse variance weighted (IVW), MR Egger (ME), weighted median (WM), and multiplicative random effects-inverse variance weighted (MRE-IVW) methods. For sensitivity analysis and visualization of MR findings, a heterogeneity test, a pleiotropy test, a leave-one-out test, scatter plots, forest plots, and funnel plots were employed. MR analyses with all four methods revealed that CCOC was not causally associated with ER-negative BC (IVW results: odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.66-1.20, P = 0.431) or ER-positive BC (IVW results: OR = 0.99, 95% CI = 0.88-1.12, P = 0.901). F-statistics were computed for each valid IV, all of which exceeded 10. The stability and reliability of the results were confirmed by sensitivity analysis. Our findings indicated that CCOC dids not have a causal association with ER-associated BC. The absence of a definitive causal link between ER-associated BC and CCOC suggested a minimal true causal influence of ER-associated BC exposure factors on CCOC. These results indicated that individuals afflicted by ER-associated BC could alleviate concerns regarding the developing of CCOC, thereby aiding in preserving their mental well-being stability and optimizing the efficacy of primary disease treatment.

MiRNA Expression Profiles in Ovarian Endometriosis and Two Types of Ovarian Cancer-Endometriosis-Associated Ovarian Cancer and High-Grade Ovarian Cancer.

Endometriosis-associated ovarian cancer (EOC) consisting of endometrioid cancer and clear-cell ovarian cancer could be promoted by many factors. miRNAs, which are small, non-coding molecules of RNA, are among them. The aim of this study was to detect miRNAs connected with the malignant transformation of endometriosis. FFPE (formalin-fixed, paraffin-embedded) samples of 135 patients operated on for endometriosis and different types of ovarian cancer (EOC and HGSOC-high-grade serous ovarian cancer) were studied. Healthy ovarian tissue was used as a control group. From the expression panel of 754 miRNAs, 7 were chosen for further tests according to their ROC (receiver operating characteristic) curves: miR-1-3p, miR-125b-1-3p, miR-31-3p, miR-200b-3p, miR-502-5p, miR-503-5p and miR-548d-5p. Furthermore, other potentially important clinical data were analysed, which included age, BMI, Ca-125 concentration, miscarriages and deliveries and concomitant diseases such as hypertension, type 2 diabetes and smoking. Among the miRNAs, miR200b-3p had the lowest expression in neoplastic tissues. miR31-3p had the highest expression in women without any lesions in the ovaries. miR-502-5p and miR-548-5p did not differ between the studied groups. The examined miRNA panel generally distinguished significantly normal ovarian tissue and endometriosis, normal ovarian tissue and cancer, and endometriosis and cancer. The malignant transformation of endometriosis is dependent on different factors. miRNA changes are among them. The studied miRNA panel described well the differences between endometriosis and EOC but had no potential to differentiate types of ovarian cancer according to their origin. Therefore, examination of a broader miRNA panel is needed and might prove itself advantageous in clinical practice.