bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A68: Increasing intracellular glucose levels decreased expression of Enolase-I promoting cisplatin resistance in ovarian cancer cells
Authors: Rabelo-Fernandez Robert J. , Santana Yasmarie , Grafals Nilmary , Quiñones Blanca , Santiago Ginette , Lozada Eunice , Reyes Jeyshka , Vivas-Mejía Pablo E. 
Published: September 2020

Abstract
Cytoreductive surgery in combination with platinum-based chemotherapy has been used for more than four decades for treat ovarian cancer. Although initially most ovarian tumors respond well to cisplatin treatment, many of those tumors become resistant to chemotherapy. Although many mechanisms of cisplatin resistance have been proposed, the molecular mechanism leading to the cisplatin resistance in ovarian cancer tumors has not been fully understood. In this study, we sought to identify novel proteins associated with the cisplatin resistance of ovarian cancer cells. A proteomic analysis showed 48 proteins differentially abundant in cisplatin-resistant (A2780CP20) compared to their counterpart cisplatin-sensitive (A2780) ovarian cancer cells. The quantitative analysis revealed low protein levels of Enolase-1 (ENO1) in A2780CP20 cells. Small-interference RNA (siRNA)-targeted ENO1 showed a reduction in the sensitivity of ovarian cancer cells to cisplatin treatment. In contrast, ectopic expression of ENO1 in cisplatin-resistant ovarian cancer cells reduced the sensitivity of these cells to cisplatin treatment. Since ENO1 is an enzyme involved in glucose metabolism, we evaluated ovarian cancer cells’ metabolic state by measuring their glucose consumption. Intracellular glucose uptake was measured in pairs of cisplatin-sensitive and cisplatin-resistant cells. The glucose content levels were higher in all cisplatin-resistant cells compared with their -sensitive counterparts. Overall, these results suggest that low levels of ENO1 are associated with the cisplatin resistance of ovarian cancer cells. Therefore, targeting the glycolytic pathways could be a strategy to overcome the cisplatin resistance of women with advanced and drug-resistant ovarian cancer.
Citation Format: Robert J. Rabelo-Fernandez, Yasmarie Santana, Nilmary Grafals, Blanca Quiñones, Ginette Santiago, Eunice Lozada, Jeyshka Reyes, Pablo E. Vivas-Mejía. Increasing intracellular glucose levels decreased expression of Enolase-I promoting cisplatin resistance in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A68.
Abstract A75: Serine auxotrophy: A novel metabolic vulnerability of platinum-resistant ovarian cancer?
Authors: Van Nyen Tom , Duarte Joao A.G. , Rossi Matteo , Planque Mélanie , Zaal Esther , Talebi Ali , Moens Stijn , Eelen Guy , Horlings Hugo , Swinnen Johan , Berkers Celia , Carmeliet Peter , Agami Reuven , Fendt Sarah-Maria , Lambrechts Diether , Annibali Daniela , Amant Frederic 
Published: September 2020

Abstract
Ovarian cancer accounts for the highest number of gynecologic-associated deaths in the developed world, and resistance to platinum-based therapy represents a major clinical and societal challenge in patients’ management. Since metabolism is intertwined with signaling pathways controlling cell death, we aimed to investigate to what extent metabolic adaptations could contribute to the development of the resistant phenotype. By performing isotope-labeled 13C-glucose tracer analysis in vitro, we found that, when they become resistant to platinum, ovarian cancer cells stop to synthetize serine and are characterized by significantly lower intracellular levels of this amino acid compared to sensitive cells. However, serine is required for cellular growth and survival, and resistant cells increase its uptake from the medium, becoming exquisitely vulnerable to serine starvation. We showed that, although resistant cells accumulate DNA damage upon platinum treatment, they have a higher capacity of repairing it because of increased poly(ADP)-ribose polymerase (PARP) activity, compared to the sensitive ones. Since PARP enzymes are major oxidized nicotinamide adenine dinucleotide (NAD+)-consuming enzymes, we collected evidence that serine synthesis downregulation, as a consequence of central carbon metabolic reshuffling, provides resistant cells with the advantage of sparing NAD+, thus sustaining PARP activation and allowing a more efficient DNA repair. We confirmed that downregulation of serine synthesis is a peculiar trait of resistant tumors also in vivo, using patient-derived xenografts (PDX) ovarian cancer models subjected to serine/glycine free diet. Moreover, analysis of The Cancer Genome Atlas Consortium (TCGA) ovarian cancer dataset revealed that tumors from platinum-resistant patients are characterized by a downregulation of serine biosynthetic enzymes, suggesting that serine auxotrophy could represent a novel and exploitable vulnerability of platinum-resistant ovarian cancers.
Citation Format: Tom Van Nyen, Joao A.G. Duarte, Matteo Rossi, Mélanie Planque, Esther Zaal, Ali Talebi, Stijn Moens, Guy Eelen, Hugo Horlings, Johan Swinnen, Celia Berkers, Peter Carmeliet, Reuven Agami, Sarah-Maria Fendt, Diether Lambrechts, Daniela Annibali, Frederic Amant. Serine auxotrophy: A novel metabolic vulnerability of platinum-resistant ovarian cancer? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A75.
Abstract B02: miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling
Authors: Knarr Matthew , Kwiatkowski Lily J. , Dziubinski Michele , McAnulty Jessica , Skala Stephanie , Avril Stefanie , Drapkin Ronny , DiFeo Analisa 
Published: September 2020

Abstract
Genomic instability predisposes cells to malignant transformation; however, the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells—the precursor cell type for the majority of high-grade serous ovarian cancers—through the inhibition of RB1 and simultaneously drives a cell-protective inhibition of the stimulator-of-interferon-genes (STING) in order to maintain a microenvironment conducive to the propagation of cells with a high-degree of genomic instability. We found that miR-181a inhibition of RB1 leads to profound nuclear defects, genomic instability, and nuclear rupture resulting in a persistence of genomic material in the cytoplasm. While normally, this persistence of genomic material in the cytoplasm induces interferon response through STING to drive cell death, miR-181a directly downregulates STING and prevents apoptosis. The most common mechanism by which oncogenic miRNAs promote tumorigenesis is through the direct inhibition of tumor suppressor genes; however, our studies highlight a new mechanism of oncomiR transformation through the combination of tumor suppressor gene inhibition and abrogation of immune surveillance that initiates and propagates tumor cell survival. Importantly, we found that miR-181a induction in human ovarian tumors is tightly associated with decreased IFNg response and downregulation of lymphocyte infiltration and leukocyte fraction. To date, DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation; thus, our findings are the first to identify a genetic factor, miR-181a, that can downregulate STING expression and impair signaling in cancer cells, creating a survival advantage. Our studies support the notion that the induction of STING-mediated signaling in cancer cells could lead directly to cancer cell death; however, these effects are abrogated by miR-181a. Given the recent interest in the development of STING agonists as a strategy to harness the immune system to treat cancer, this study introduces a novel patient-selective biomarker as well as potent therapeutic target for development of the most effective combination treatments.
Citation Format: Matthew Knarr, Lily J. Kwiatkowski, Michele Dziubinski, Jessica McAnulty, Stephanie Skala, Stefanie Avril, Ronny Drapkin, Analisa DiFeo. miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B02.
Abstract B20: Endometrial cancer molecular risk stratification in endometrioid ovarian cancers: A novel application of precision medicine
Authors: Krämer Pauline , Talhouk Aline , Bosse Tjalling , Heitz Florian , Singh Naveena , Kommoss Felix , Brucker Sara , McAlpine Jessica , Kommoss Stefan , Koebel Martin , Anglesio Michael 
Published: September 2020

Abstract
Objective: Endometrioid ovarian carcinoma (ENOC) is associated with a generally more favorable prognosis compared to other ovarian carcinoma histotypes. Nonetheless, patients are still treated with a “one size fits all” approach. While tumor staging offers some stratification, the development of personalized treatment concepts remains elusive. Our group has recently validated the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), to distinguish clinically relevant prognostic groups amongst endometrial carcinomas. ENOC shares risk factors, genomics, and histology with its endometrial counterpart. The aim of our study was to apply and test ProMisE on ENOC.
Methods: ProMisE was applied to 509 ENOC after biomarker-assisted review of ENOC histotype. Cases were aligned into low-risk POLE mutant (POLE), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and a final moderate-risk category lacking these biomarkers (p53wt). Kaplan-Meier and multivariate survival analysis were performed.
Results: 4% of cases were POLE, 16% MMRd, 71% p53wt, and 10% p53abn. Groups showed distinct progression-free and overall survival (p &lt;0.001), near identical to profiles of endometrial cancers. 5-year PFS was 54% in p53abn, 82% in MMRd, 85% in p53wt, and 100% in POLEmut cases. Median overall survival was reached in p53 mutant cases only. ProMisE classes of ENOC were independent of stage and residual disease in multivariable analysis.
Conclusion: ProMisE risk classification provides additional prognostic information in a large cohort of ENOC. Our findings support introduction of ProMisE-stratified treatment strategies to improve patient care across ENOC. Further, ENOC may benefit from parallel efforts under investigation in endometrial carcinoma.
Citation Format: Pauline Krämer, Aline Talhouk, Tjalling Bosse, Florian Heitz, Naveena Singh, Felix Kommoss, Sara Brucker, Jessica McAlpine, Stefan Kommoss, Martin Koebel, Michael Anglesio. Endometrial cancer molecular risk stratification in endometrioid ovarian cancers: A novel application of precision medicine [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B20.
Abstract B43: A serum protein biomarker signature for the detection of early stages of ovarian cancer
Authors: Skubitz Amy P. , Boylan Kristin L. , Starr Timothy K. , Pu Xuan , Cao Qing , Geschwind Kate , Bast Robert C. , Lu Karen H. , Celestino Joseph , Petersen Ashley J. 
Published: September 2020

Abstract
The two bes- known ovarian cancer biomarkers, CA125 and HE4, are neither adequately sensitive nor specific to be used to screen the general population for early stages of ovarian cancer. The purpose of this study was to develop a multiprotein classifier that would combine additional protein biomarkers with CA125 and HE4 in order to increase their sensitivity and specificity. We used the Olink Proseek Multiplex Oncology II panel to simultaneously quantify the expression levels of 92 cancer-related proteins using proximity extension assay technology. We analyzed serum from two institutions: 143 women with early-stage (I/II) ovarian cancer (serous, endometrioid, clear-cell, mucinous, and others) and compared the values obtained to 341 age-matched healthy women. We identified 24 proteins whose relative expression between cancers and controls was significantly different between the samples from the two institutions; therefore, we removed these proteins from downstream analysis. Principle Component Analysis and T-distributed Stochastic Neighbor Embedding separated the ovarian cancer samples from the healthy controls, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with previously measured clinical values for CA125 (correlation coefficient of 0.81). CA125 and HE4 were detected at low levels in samples from healthy women, while higher levels were observed in the early-stage ovarian cancer cases. We identified 31 proteins that differed significantly (p &lt; 0.001) between ovarian cancer and healthy samples, several of which are novel serum biomarkers for ovarian cancer. In total, 11 proteins had an estimated area under the ROC curve of 0.70 or greater. CA125 alone achieved a sensitivity of 81.0% at a specificity of 98%. However, by adding three proteins to CA125, we increased the assay sensitivity to 86.2%, while holding the specificity fixed at 98%. In conclusion, our data demonstrate that the inclusion of several protein biomarkers can improve the sensitivity and specificity of CA125 alone for the detection of early stages of ovarian cancer. Validation of this multiprotein classifier is currently under way using serum samples from other institutions.
Citation Format: Amy P. Skubitz, Kristin L. Boylan, Timothy K. Starr, Xuan Pu, Qing Cao, Kate Geschwind, Robert C. Bast, Jr., Karen H. Lu, Joseph Celestino, Ashley J. Petersen. A serum protein biomarker signature for the detection of early stages of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B43.
Abstract IA10: Traditional and modern approaches for prevention and early detection
Authors: Levine Douglas A. 
Published: September 2020

Abstract
Conventionally, serum CA-125 measurements and ultrasonography have been used to try to detect ovarian carcinoma at early stage. These methods have not been proven to result in early-stage detection and seem to convey little survival benefit. It is now widely accepted that such methods are not justified for widespread use in cancer screening, and the US Preventative Services Task Force recommends against their use. CA-125 and human epididymis protein 4 (HE4) are involved in ovarian tumorigenesis, overexpressed by malignant epithelial cells, and found in patient serum. Increased levels of these proteins as well as others in patient ascites, and uterine fluid, as compared to serum, suggest that their detection may be enhanced by measurements taken from within the uterine cavity or other locations more proximal to the ovaries and fallopian tube where tumors most commonly originate. The knowledge that most high-grade serous carcinomas originate from the distal fallopian tube creates an opportunity for new screening and prevention approaches that were previously impractical when the site of origin was thought to be the ovarian surface epithelium. The fallopian tube can be accessed via a transvaginal/transuterine route, and the fallopian tubes are not necessary for normal biologic function once childbearing is complete. Based on the hypothesis that serous tubal intraepithelial carcinoma (STIC) is the precursor of most high-grade serous carcinomas (HGSCs), innovative studies aimed at providing a realistic clinical method for reducing the burden of ovarian cancer are under way. In this presentation we will discuss the latest knowledge regarding approaches for prevention and early detection of ovarian cancer. We will discuss the role of precursor lesions in the development and metastatic spread of invasive ovarian cancers. We will review ongoing and planned clinical trials of surgical prevention and discuss missed opportunities for chemoprevention. We will also discuss more innovative approaches to early detection through minimally invasive access to the distal fallopian tube and nanotechnology for highly sensitive protein detection. The approaches and others hold great promise to transform the paradigm of early ovarian cancer detection from one of traditional serum-based biomarkers to one that incorporates the current concepts of ovarian cancer origins, proximal measurements of tissue-based biomarkers, and novel circulating biomarkers.
Citation Format: Douglas A. Levine. Traditional and modern approaches for prevention and early detection [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA10.
Abstract PR01: Assessment of PARPi and cisplatin resistance in BRCA1 exon 11 mutant patient -derived xenografts
Authors: Krais John J , Clausen Emma , Khazak Vladimir , Astsaturov Igor , Scott Clare L , Johnson Neil 
Published: September 2020

Abstract
Introduction: The BRCA1 protein contributes to homologous recombination (HR) repair of DNA breaks. BRCA1 mutations often result in dysfunction or absence of BRCA1 proteins. Consequently, BRCA1 mutations induce PARP inhibitor (PARPi) and cisplatin sensitivity. BRCA1 exon 11 is the largest exon and harbors a plethora of germline mutations. BRCA1 exon 11 is subject to alternative splicing and can generate the BRCA1-Δ11q isoform. This isoform is a hypomorphic variant that removes germline exon 11 mutations allowing for translation through to the end of the protein. In this study we examined PARPi and cisplatin sensitivity and resistance in a panel of BRCA1 exon 11 mutant PDX tumors.
Experimental Procedures: Wild-type BRCA1 PDX036, exon 13 truncating BRCA1 mutant PDX1126, and BRCA1 exon 11 mutants PDX017, PDX056, and PDX124 were utilized. Using these models, we developed several isogenic sets of cisplatin and PARPi sensitive/resistant PDX using serial passaging and treatments. Additionally, we developed a method for lentiviral manipulation of PDX models to study resistance mechanisms. We assessed tumors for cisplatin and PARPi sensitivity and examined BRCA1 and 53BP1 expression by Western blotting and immunohistochemistry.
Results: We observed variable responses to cisplatin and PARPi treatments among PDX models despite the presence of BRCA1 mutations that abrogated expression of full-length BRCA1. PDX196 expressed an abundance of BRCA1-Δ11q and exhibited resistance to both PARPi and cisplatin treatments. Interestingly, exon 11 mutant PDX017, 056, and 124 initially responded to both cisplatin and PARPi treatments. Serial passaging and treatments ultimately elicited resistance in each of these models and in some tumors coincided with an increase in BRCA1-Δ11q expression. Additionally, PARPi and cisplatin-resistant PDX017 tumors exhibited a simultaneous reduction of 53BP1 and increased BRCA1-Δ11q expression. In contrast to the BRCA1 exon 11 mutant PDX models, exon 13 mutant PDX1126 failed to develop resistance after multiple rounds of serial passaging with either cisplatin or PARPi treatments. However, when PDX1126 cells were transduced with lentivirus containing BRCA1-Δ11q cDNA, a rapid acquisition of cisplatin resistance occurred.
Conclusions: Our data indicate BRCA1-Δ11q expression is variable in BRCA1 exon 11 mutant tumors, but nevertheless, when abundantly expressed, supports resistance to cisplatin and PARPi.
This abstract is also being presented as Poster A46.
Citation Format: John J Krais, Emma Clausen, Vladimir Khazak, Igor Astsaturov, Clare L Scott, Neil Johnson. Assessment of PARPi and cisplatin resistance in BRCA1 exon 11 mutant patient -derived xenografts [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR01.
Abstract PR07: Reprogramming the tumor microenvironment with losartan to enhance immunotherapy of ovarian cancer
Authors: Sun Yao , Zhao Wenjianlong , Spriggs David R. , Jain Rakesh K. , Xu Lei 
Published: September 2020

Abstract
Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T cells—which have revolutionized the treatment of multiple malignancies—have had limited efficacy in OvCa patients. This lack of efficacy is partly due to abnormal extracellular matrix (ECM) deposition leading to a buildup of compressive forces that induce vessel collapse, hypoperfusion, poor delivery of nutrients and drugs, and compromised trafficking of cytotoxic T cells to these tumors. The resulting tumor microenvironment (TME) is also hypoxic, acidic, and immunosuppressive. Our overarching hypothesis is that losartan, an FDA-approved antihypertensive drug that blocks angiotensin signaling, can overcome these challenges by normalizing the TME to enhance the delivery and efficacy of therapies in OvCa. Retrospective study showed that treatment with angiotensin blockers is associated with a 30-month overall survival benefit in OvCa patients. In our OvCa models, losartan reduced matrix content and reopened compressed vessels. As a result, blood perfusion increased, leading to enhanced drug delivery and improved chemotherapy efficacy. Losartan also relieved lymphatic vessel collapse in the diaphragm, which increased the drainage of peritoneal fluid and reduced ascites. Using unbiased RNASeq analysis, we found that in addition to normalizing the tumor matrix and vasculature, losartan treatment also activates immune response pathways. Furthermore, losartan increases the infiltration and function of immune effector cells and improves the outcome of immunotherapy using ICBs. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and immunotherapy in ovarian cancer patients.
This abstract is also being presented as Poster B75.
Citation Format: Yao Sun, Wenjianlong Zhao, David R. Spriggs, Rakesh K. Jain, Lei Xu. Reprogramming the tumor microenvironment with losartan to enhance immunotherapy of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR07.