bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA12: Metabolic barriers to effective immunotherapy of cancer
Authors: Delgoffe Greg M.
Published: September 2020

The tumor microenvironment presents a number of barriers to antitumor immunity, both immunologic and nonimmunologic in nature. It is now appreciated that, driven by the deregulated energetics of the cancer cells, the tumor microenvironment possesses a distinct metabolic landscape that may be detrimental to immune function, thus acting as a resistance mechanism to immunotherapy. I will discuss the metabolic defects present in tumor-infiltrating T cells and highlight the mechanistic underpinnings that drive these deficiencies. Further, I will discuss how genetic engineering, pharmacologic intervention, and costimulatory immunotherapy can be employed to modulate the metabolism of infiltrating T cells. Finally, I will describe how profiling the metabolism of patient tumor cells can yield insight into the regulation of immunity and the response to immunotherapy.

Citation Format: Greg M. Delgoffe. Metabolic barriers to effective immunotherapy of cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA12.
Abstract IA21: Integrating head and neck cancer immunotherapy into locally advanced treatment
Authors: Ferris Robert
Published: September 2020

Recognition that the immune system plays an important role in the development and progression of cancer has permitted a renaissance in the testing of agents designed to stimulate antitumor immunity. Recent FDA approvals have validated that cancer immunotherapy is now established as a standard-of-care agent in many tumor types, primarily in the recurrent/metastatic (R/M) setting. For those with previously untreated, locally advanced disease, the future portends an exciting and rational approach to integrating this new type of therapy into conventional cancer treatment. We will present recent trials and biomarkers of targeted immunotherapy and correlation with response. Human papillomavirus associated (HPV+) oropharyngeal cancer (OPC) is an emerging entity with improved prognosis and distinct staging system from traditional HPV-negative HNSCC. The lecture will address how PD-1-based immunotherapy may represent deintensification without decreased survival for stage I patients at low or intermediate risk, or as an “add-on” strategy for intensification in conjunction with postoperative adjuvant radiation (RT) or chemoradiation (CRT). In addition, neoadjuvant approaches provide dynamic insight into immunosuppression and responses, and guide rational immunotherapeutic combinations for targeting immune checkpoint receptors and inflammatory agonists, including the development of predictive biomarkers to facilitate efficient patient selection. Indeed, a major deficiency of targeted immunotherapies is the lack of dynamic biomarkers to monitor alterations in the tumor microenvironment. Neoadjuvant “window of opportunity” trials present a useful method to obtain predictive biomarkers for patients receiving novel immunotherapeutic agents modulating tumor-infiltrating lymphocytes.

Citation Format: Robert Ferris. Integrating head and neck cancer immunotherapy into locally advanced treatment [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA21.
Abstract A15: Noncanonical NF-kappaB signaling is associated with poor ovarian cancer prognosis
Authors: Hufnagel Demetra , Wilson Andrew J. , Saxon Jamie , Khabele Dineo , Blackwell Timothy , Crispens Marta A. , Yull Fiona , Beeghly-Fadiel Alicia
Published: September 2020

Objective: Mediated by a family of transcription factors, the canonical and noncanonical nuclear factor-kappaB (NF-kB) signaling pathways have key roles in inflammation, innate immunity, and cancer development and progression. As prior ovarian cancer studies have evaluated only canonical NF-kB transcription factors in relation to survival, this study was undertaken to evaluate both canonical and noncanonical NF-kB pathway components in tumor samples from epithelial ovarian cancer cases from the Vanderbilt Tissue Repository for Ovarian Cancer (TROC).

Methods: We abstracted clinical data from electronic medical records and assayed p65 (representing the canonical NF-kB pathway) and p52 (representing the noncanonical NF-kB pathway) by immunohistochemistry for 197 TROC samples. Nuclear and cytoplasmic staining in tumor cells was semiquantified by H-scores and dichotomized at median values. Associations with progression-free survival (PFS) and overall survival (OS) were quantified by hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional-hazards regression.

Results: Median cytoplasmic and nuclear p65 and p52 H-scores were significantly higher among high-grade and serous cases; median p52 H-scores were also significantly higher among late-stage cases and patients treated with chemotherapy (all Wilcoxon rank sum p<0.05). In unadjusted regression models, higher nuclear p65 and higher nuclear p52 were associated with approximately 40% and 70% shorter PFS and OS, respectively, but these associations were attenuated by adjustment for age, stage, tumor type, race, chemotherapy, and residual disease. In multivariable adjusted models, higher cytoplasmic p52 was associated with more than 50% shorter PFS (HR 1.68, 95% CI 1.18-2.39) and OS (HR 1.53, 95% CI 1.06-2.21). Furthermore, when cytoplasmic and nuclear staining were combined, and mutually adjusted models included both p52 and p65, only p52 remained associated with worse PFS (HR 1.57, 95% CI 1.10-2.37) and OS (HR 1.51, 95% CI 1.05-2.15).

Conclusions: This is the first study to demonstrate that p52, representing noncanonical NF-kB signaling, may be an independent prognostic factor for epithelial ovarian cancer. Approaches to inhibit noncanonical NF-kB signaling should be explored as novel therapies for ovarian cancer are needed.

Citation Format: Demetra Hufnagel, Andrew J. Wilson, Jamie Saxon, Dineo Khabele, Timothy Blackwell, Marta A. Crispens, Fiona Yull, Alicia Beeghly-Fadiel. Noncanonical NF-kappaB signaling is associated with poor ovarian cancer prognosis [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 A15.
Abstract A38: ATM inhibitor synergizes with glycolysis inhibition in ovarian cancer cells
Authors: Chen Chi-Wei , Dahl Erika S. , Leon Kelly E. , Buj Raquel , Aird Katherine M.
Published: September 2020

Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy in the USA. While therapies such as inhibitors against poly (ADP-Ribose) polymerase (PARP) are emerging as the standard treatment for EOC patients, this strategy is limited to the subset of patients harboring particular genetic alterations in the DNA damage response pathway, making them homologous recombination (HR) deficient. Approximately 50% of EOC patients are HR proficient, which corresponds to PARP inhibitor resistance and worse patient survival. Therefore, novel therapies for this subset of patients are urgently needed. We found that the DDR gene ATM is upregulated in a subset of EOC patients, which is associated with worse progression-free survival. This suggests that targeting ATM may be beneficial for these EOC patients. Our previous publication demonstrated that inhibition of ATM alters cellular metabolism. Therefore, we aimed to explore ATM inhibitor-mediated metabolic vulnerabilities in EOC to develop them as novel therapeutic strategies. We found that inhibition of ATM increases glucose uptake but not lactate of multiple EOC cells using YSI Bioanalyzer and the fluorescent glucose analog 2NBDG by flow cytometry. Seahorse analysis further indicates that glucose is not being used for Warburg effect. Using an shRNA screen, we identified SLC2A11 and SLC2A12 as the transporters that mediate glucose uptake upon ATM inhibition. To determine whether the observed changes can be exploited for therapeutic benefit, we combined ATM inhibition with the known inhibitor of glycolysis, fenofibrate. We found that while neither ATM inhibition or fenofibrate alone had a robust effect on cell proliferation, the combination was synergistic. Mechanistically, we determined that the combination resulted in cellular senescence using SA-B-Gal assay and detected PML body by immunofluorescence. Using 53PB1 and gH2AX as DDR markers, we concluded that the combination causing synthetic lethal is DDR independent manner. In this study, we found that ATM-SLC2A11/12 axis mediating glucose uptake in EOC cells. Mechanistically understand the role of ATM beyond DDR. Together, our results suggest that metabolic changes induced by ATM inhibitors in EOC are a potential target for the treatment for EOC.

Citation Format: Chi-Wei Chen, Erika S. Dahl, Kelly E. Leon, Raquel Buj, Katherine M. Aird. ATM inhibitor synergizes with glycolysis inhibition 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 A38.
Abstract A51: The role of ATF6-mediate AP-1 signaling in promoting PARP inhibitor-resistant ovarian cancer
Authors: McMellen Alexandra N. , Bitler Benjamin G.
Published: September 2020

The purpose of this study is to define the role of AP-1 mediated DNA repair in PARP inhibitor (PARPi)-resistant high-grade serous ovarian cancer (HGSOC). AP-1 is a dimeric transcription factor comprising Jun, Fos, and/or ATF proteins and its signaling is known to regulate multiple DNA repair genes, including PARP1. Wnt activation can promote AP-1 signaling and upregulates expression of AP-1 subunits. We previously published that hyperactive Wnt signaling in PARPi-resistant HGSOC cells promotes DNA repair and attenuates PARPi response. We therefore hypothesized that Wnt signaling drives PARPi resistance thorough increased AP1-signaling and subsequent enhanced DNA repair. We performed transcription factor analysis of RNA sequencing data from TP53/BRCA2-mutated olaparib-sensitive (PEO1) and -resistant (PEO1-OR) HGSOC cells. We observed increased AP-1 target genes in resistant cells and confirmed elevated AP-1 activity with a reporter assay. Quantitative PCR (qPCR) demonstrated that a majority of AP-1 subunits were upregulated in olaparib-resistant cells, namely JUN, ATF5, and ATF6. An shRNA screen was performed to determine which AP-1 subunits are necessary to convey olaparib resistance. Four out of five shRNAs targeting ATF6 effectively resensitized PARPi-resistant cells to olaparib. We confirmed that ATF6 protein was elevated in PEO1-OR cells. To further explore the role of ATF6 in AP-1 mediated PARPi resistance, ATF6 was stably knocked down in PEO1-OR cells. Colony formation assays confirmed that loss of ATF6 resensitized cells to olaparib. Knockdown of ATF6 also resulted in decreased transcription of PARP1, as measured by qPCR, and higher baseline levels of DNA damage, as measured by phosphorylated histone gamma-H2AX. Future studies will evaluate ATF6-dependent DNA repair in in vitro and in vivo models of PARPi-resistant HGSOC. In summary, these data indicate activation of AP-1 signaling through increased expression of ATF6 is promoting enhanced DNA repair capacity, which could be contributing to PARPi resistance. Thus, pharmacologic inhibition of AP-1 or ATF6 could provide a targetable approach to overcome resistance and improve patient outcomes.

Citation Format: Alexandra N. McMellen, Benjamin G. Bitler. The role of ATF6-mediate AP-1 signaling in promoting PARP inhibitor-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 A51.
Abstract A54: Targeting new links in the proteostasis network as novel therapies in high-grade serous ovarian cancer
Authors: Lighty Kinzie , Shin Yonghyun , Mesmer Fahmi , Nakshatri Harikrishna , Iwanicki Marcin , Mitra Sumegha
Published: September 2020

High-grade serous ovarian cancer (HGSOC) is the most lethal subtype of ovarian cancer with high case-to-fatality ratio. However, not much advancement has been seen in the field in terms of novel adjuvant therapies. Somatic or germline mutations in HGSOC along with copy number variations results in intratumoral genetic heterogeneity, which leads to tumor growth and development of chemoresistant clones and treatment resistance. Moreover, molecular heterogeneity also leads to the accumulation of aberrant peptides and protein complexes with altered stoichiometry, causing extensive proteotoxic stress in cancer cells and adding to the known misfolded proteins stress in cancer cells due to enhanced protein synthesis, thus making these cancer cells more dependent on the protein clearance mechanisms. Not much is known about the molecular targets from the proteostasis network and their therapeutic potential in HGSOC. Here we explore the regulation and role of different components of ubiquitin proteasome system (UPS) in HGSOC and investigate the therapeutic effect of small-molecule inhibitors of UPS. We identified overexpression of deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in HGSOC, and high UCHL1 levels were correlated with the disease stage, tumor grade, and poor clinical outcome. UCHL1 overexpression in HGSOC was driven by mutant p53-mediated H3K4 trimethylation at the UCHL1 regulatory region. Mutant p53-UCHL1 axis transcriptionally promoted the expression of proteasomal subunit alpha 7 (PSMA7) and acylaminoacyl-peptide hydrolase (APEH), resulting in increased proteasome activity in HGSOC. Silencing UCHL1 or inhibiting proteasome activity in vitro and in vivo remarkably reduced HGSOC growth. Together, these results highlight the novel mechanisms of regulation of proteostasis in HGSOC and potential therapies targeting regulators of proteasome pathway.

Citation Format: Kinzie Lighty, Yonghyun Shin, Fahmi Mesmer, Harikrishna Nakshatri, Marcin Iwanicki, Sumegha Mitra. Targeting new links in the proteostasis network as novel therapies in high-grade serous 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 A54.
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

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

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

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

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 <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

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 < 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

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

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

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.
Abstract PR10: High-throughput functional and multi-omic single-cell characterization to elucidate ovarian intratumor and microenvironmental heterogeneity
Authors: Beaumont Kristin G. , Hake Austin , Wang Ying-Chih , Shah Hardik , Allette Kimaada , Hamou Wissam , Dave Arpit , Andreou Christina , Strahl Maya , Arib Hanane , Antoine Alesia , Ellis Ethan , Smith Melissa , Dottino Peter , Martignetti John , Schadt Eric E. , Sebra Robert P.
Published: September 2020

The genetic and functional complexity of bulk tumor tissue and its associated microenvironment, comprising heterogeneous cellular clones, has become more evident due to rapid advances in single-cell and deep-sequencing technologies. In this research, we present methods to better characterize clonal diversity from patient-derived cell lines and tumor biopsies at the single-cell level. We will profile intratumor and microenvironmental heterogeneity through single-cell selection, single-cell DNA and RNA sequencing, and real-time functional data. In addition to genetic data, single-cell real-time growth dynamics alongside CA125 secretion will be discussed as real-time functional assays. This approach uses bulk or discriminate selection of cells based on phenotype across a broad range of cellular inputs. Targeted cells from the tumor and its microenvironment were manipulated using light-induced dielectrophoresis into holding areas on the BLI Beacon platform for single-cell isolation and/or culture for monitoring growth kinetics and conducting functional screening. Hundreds to thousands of independent cells or batches were selected from resected tumor and adjacent tissue; genomic DNA was amplified and characterized using Ion Torrent AmpliSeq targeted panels and/or MissionBio Tapestri scDNA-Seq. Collectively this genomic data were used to identify cellular clonality and better address the degree of clonal heterogeneity across these tumors when compared to bulk sequencing. Specifically, growth kinetics, differential expression, and TP53 mutation profiling will be discussed in the context of several pilot primary tumor-derived samples. Orthogonal RNA-Seq data obtained using 1,500-5,000 cells per sample for 3’ mRNA scRNA-Seq on the 10X Genomics Chromium platform will also be discussed. Through the integration of these technologies, we hope to showcase an efficient and comprehensive method for assessing intratumor and microenvironmental heterogeneity.

This abstract is also being presented as Poster B53.

Citation Format: Kristin G. Beaumont, Austin Hake, Ying-Chih Wang, Hardik Shah, Kimaada Allette, Wissam Hamou, Arpit Dave, Christina Andreou, Maya Strahl, Hanane Arib, Alesia Antoine, Ethan Ellis, Melissa Smith, Peter Dottino, John Martignetti, Eric E. Schadt, Robert P. Sebra. High-throughput functional and multi-omic single-cell characterization to elucidate ovarian intratumor and microenvironmental heterogeneity [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 PR10.
Epigenetic Awakening of Viral Mimicry in Cancer
Authors: Janin Maxime , Esteller Manel
Published: September 2020

In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation.

See related article by Deblois et al., p. 1312.
Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity
Authors: Kotanides Helen , Li Yiwen , Malabunga Maria , Carpenito Carmine , Eastman Scott W. , Shen Yang , Wang George , Inigo Ivan , Surguladze David , Pennello Anthony L. , Persaud Krishnadatt , Hindi Sagit , Topper Michael , Chen Xinlei , Zhang Yiwei , Bulaon Danielle K. , Bailey Tim , Lao Yanbin , Han Bing , Torgerson Stacy , Chin Darin , Sonyi Andreas , Haidar Jaafar N. , Novosiadly Ruslan D. , Moxham Christopher M. , Plowman Gregory D. , Ludwig Dale L. , Kalos Michael
Published: September 2020

The programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) coinhibitory pathway suppresses T-cell–mediated immunity. We hypothesized that cotargeting of PD-1 and PD-L1 with a bispecific antibody molecule could provide an alternative therapeutic approach, with enhanced antitumor activity, compared with monospecific PD-1 and PD-L1 antibodies. Here, we describe LY3434172, a bispecific IgG1 mAb with ablated Fc immune effector function that targets both human PD-1 and PD-L1. LY3434172 fully inhibited the major inhibitory receptor–ligand interactions in the PD-1 pathway. LY3434172 enhanced functional activation of T cells in vitro compared with the parent anti–PD-1 and anti–PD-L1 antibody combination or respective monotherapies. In mouse tumor models reconstituted with human immune cells, LY3434172 therapy induced dramatic and potent antitumor activity compared with each parent antibody or their combination. Collectively, these results demonstrated the enhanced immunomodulatory (immune blockade) properties of LY3434172, which improved antitumor immune response in preclinical studies, thus supporting its evaluation as a novel bispecific cancer immunotherapy.
Controvérsias em museus de ciências: reflexões e propostas para educadores
Authors:   Universidade de São Paulo. Faculdade de Educação, Marandino Martha , Contier Djana ,   Universidade de São Paulo. Faculdade de Educação, Navas Ana Maria ,   Universidade de São Paulo. Faculdade de Educação, Bizerra Alessandra ,   Universidade de São Paulo. Faculdade de Educação, Neves Ana Luiza Cerqueira das ,   Universidade de São Paulo. Faculdade de Educação
Published: September 2020

Fruto de um trabalho colaborativo, o livro é mais uma produção elaborada pelo Grupo de Estudo e Pesquisa em Educação Não Formal e Divulgação da Ciência (GEENF) da Faculdade de Educação da Universidade de São Paulo (USP) e outras instituições não menos importantes citadas na obra, que traz textos de referência e revisões de literatura sobre o foco central: as controvérsias, a educação e os museus de ciência, mas também resultados de pesquisas e ações realizadas pelos autores. Em particular, compartilha conteúdos do curso de formação de educadores de museus, intitulado "Museus de Ciências e Temas Controversos", voltado para lidar com controvérsias científicas nas visitas guiadas. Nesse sentido, e a partir da constatação da pouquíssima presença de referências sobre o tema em português, esta publicação promove o acesso a alguns dos principais trabalhos existentes, com intuito de aproximar a pesquisa da prática pedagógica museal.
O arquivo pessoal de José Petronilo de Santa Cruz
Authors: Quinta Hugo , Silva Wilton Carlos Lima da
Published: September 2020

Este artigo investiga o arquivo pessoal de José Petronilo de Santa Cruz e abarca aspectos (auto)biográficos e da cultura escrita relacionada à Livraria Duas Cidades, fundada e dirigida por Santa Cruz na cidade de São Paulo. As cartas, fotografias e outros documentos abordam os anos em que ele editou obras religiosas, universitárias, poéticas, e edificou uma rede de sociabilidade em torno da livraria.
The Origins of Sovereign Risk Ratings
Authors: Pinheiro Diogo L.
Published: September 2020

Sovereign Risk Ratings are controversial measures used to determine a country’s creditworthiness. They are supposed to measure not only a country’s ability, but willingness to repay its debts. Much has been said about what it is that is actually measured by these ratings. But relatively little attention has been paid to who gets rated. That is, there is substantially less research on the issue of the when and the why a nation gets rated by one of the leading Credit Rating Agencies. The objective of this article is to try to understand that, and to sort through different theories for the emergence and spread of sovereign risk ratings. We find that institutional and political aspects matter just as much as economic ones, and that therefore sovereign risk ratings may play a role in political and social issues.
Pedagogies of Solidarity
Authors: Heidemann Kai A.
Published: September 2020

Sociological scholarship on social movements has shed important light on the role of knowledge production for processes of collective action and mobilization. However, much of this research overlooks the question of how movement-based knowledge emerges from within institutionalized settings of formal education. Drawing on a qualitative case study, this article examines the repertoire of knowledge-building practices mobilized from within a state-based system of adult education in francophone Belgium. Building on social movement theory, it is shown how formalized sites of adult education can empower the presence of social movements in society when they adopt counter-hegemonic principles of popular education that allow them to act as free spaces which facilitate the construction of strategic capacities and collective identities.
Language Vitality and Langauge Attitude of the Karen Ethnic Group in the Western Region of Thailand: A Preliminary Report
Authors: Burusphat Somsonge , Suraratdecha Sumittra , Patpong Patama , Saengmanee Amon
Published: September 2020

This paper presents preliminary findings of the research project entitled “Ethnicity, Language, Culture and Ethnic Tourism Development.” It has three goals. First, it aims to identify the Karen language spoken in six provinces in the western region of Thailand, namely, Kanchanaburi, Ratchaburi, Phetchaburi, Prachuap Khiri Khan, Suphan Buri, and Nakhon Pathom. The next goal is to explore Karen language use and attitudes towards languages of the wider community. The final goal is to evaluate the development of sustainable ethnic tourism in the region. A preliminary survey of language use and attitude of Karen people towards the Karen language and Ethnic Tourism Development (ETD) in these six provinces was carried out using a qualitative approach. Thirty subjects made up of local administrators and community leaders were interviewed using two kinds of guided questionnaires, community and personal questionnaires.
The first Afrotropical species of Porophila Dybas (Coleoptera, Ptiliidae)
Authors: JAŁOSZYŃSKI PAWEŁ
Published: September 2020

Porophila Dybas was so far represented by four nominal species distributed in USA (Oregon) and the Russian Far East (Primorsky Krai). The first Afrotropical species, P. chakalaka sp. n. is described, based on specimens collected in the western region of Republic of South Africa. The new species is associated with fruiting bodies of the Polyporaceae fungus Lenzites elegans (Spreng.) Pat. (= Trametes elegans (Spreng.) Fr.). Morphological structures of P. chakalaka are illustrated in detail, and host fungus associations of Porophila species are summarized.