bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A03: Isolation, characterization, and expansion of circulating tumor cells in head and neck cancers
Authors: Kulasinghe Arutha , Kapeleris Joanna , Kenny Liz , Warkiani Majid , Vela Ian , Thiery Jean Paul , O’Byrne Ken , Punyadeera Chamindie 
Published: September 2020

Abstract
Metastasis in head and neck cancer (HNC) patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in HNC. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. n=300 head and neck cancer patients were recruited to investigate the prognostic role of CTCs. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, inertial microfluidics) using matched patient samples, which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification). The presence of CTC clusters was associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression-free survival (PFS) (Hazard ratio [HR]: 4.946; 95% confidence interval [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof-of-principle study, we were able to demonstrate for the first time short-term patient-derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Recently, we have preliminary data that suggest that PD-L1 is frequently expressed on CTCs in HNC and an immunoscore may be able to identify patients likely to benefit from immunotherapy—a current unmet clinical need. Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression, and testing of therapies.
Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Majid Warkiani, Ian Vela, Jean Paul Thiery, Ken O’Byrne, Chamindie Punyadeera. Isolation, characterization, and expansion of circulating tumor cells in head and neck cancers [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 A03.
Abstract A20: Dysgeusia may play a role in negatively affecting mood and anxiety in post-radiation head and neck patients
Authors: Arnell Thomas , Self Quinn , Li Sharon , Nelson Carl 
Published: September 2020

Abstract
Introduction: Anxiety and depression are well-documented comorbid conditions that many patients with head and neck cancer experience. Furthermore, radiation therapy for many head and neck cancers is associated with significant morbidity. Dysgeusia, in particular, is almost universally experienced with total taste loss occurring in up to 73% of individuals radiated for head and neck cancers. Prior studies have demonstrated a significant correlation between decreased quality of life and dysgeusia. In this retrospective study, we wish to further characterize the association between taste disturbance and patient-reported anxiety and mood. With better understanding of this relationship, we may be able to effectively intervene in improving the quality of life for head and neck patients.
Methods: Forty-nine patients at The University of Vermont Medical Center who completed radiation therapy for head and neck cancer completed the University of Washington Quality of Life (QOL) Questionnaire at scheduled follow-up visits. Surveys were reviewed retrospectively for QOL measures, specifically patient-reported anxiety, mood, and taste.
Results: Taste scores were the lowest at follow-up weeks 0-3 and more than tripled by the last follow-up, at 48 weeks (p&gt;0.0001). The trend in taste improvement was most rapid during the first few weeks after radiation, but leveled off after 12 weeks. Mood and anxiety similarly improved across weeks after radiation when compared against taste.
Conclusion: Our data suggest a correlation between taste disturbance, mood, and anxiety in patients after head and neck radiation. This suggests that targeting treatments to improve patients’ sense of taste post-radiation may improve their psychiatric well-being.
Citation Format: Thomas Arnell, Quinn Self, Sharon Li, Carl Nelson. Dysgeusia may play a role in negatively affecting mood and anxiety in post-radiation head and neck patients [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 A20.
Abstract B10: Manipulating translesion synthesis proteins MAGE-A4 and RAD18 in a murine model of oral cancer
Authors: Wagner Bethany L. , Guo Jason , Gao Yanzhe , Vaziri Cyrus , Williams Scott E. 
Published: September 2020

Abstract
Head and neck squamous cell carcinomas (HNSCCs) account for 6% of cancers worldwide. Because of their link to carcinogens such as alcohol and tobacco, HNSCCs are characterized by a high mutational burden and genome instability. Cancer recurrence due to chemoresistance, or a tolerance of chemotherapy-induced mutations, is the major cause of mortality in HNSCCs. DNA damage response pathways, such as translesion synthesis (TLS), are activated in response to genotoxic stress, including from conventional chemotherapy. The TLS pathway facilitates repair of certain types of mutations and thus is important for DNA damage tolerance. However, TLS polymerases are error-prone and therefore, paradoxically, may promote genome instability. In this way, elevated or “pathologic” TLS in the context of a cancer cell may be a “double-edged sword,” conferring damage tolerance but at the expense of introducing additional mutations that could fuel tumor growth. We have previously shown that melanoma antigen A4 (MAGE-A4) recruits the E3 ubiquitin ligase Rad18 to stalled replication forks where it monoubiquitinates PCNA to recruit TLS polymerases to bypass the lesion. In HNSCC, MAGE-A4 overexpression correlates with both increased mutational burden and worse prognosis. We hypothesize that aberrant high MAGE-A4 expression tolerizes cancer cells to excessive mutations, making them invulnerable to the DNA-damaging effects of traditional chemotherapies. In order to gain a better understanding of the consequences of MAGE-A4 overexpression and TLS activation in oral tumors in vivo, we created a genetically engineered mouse model that expresses MAGE-A4 under the control of an epithelial-specific Cre driver. When treated with the potent mutagen 4NQO in their drinking water, both transgenic and control mice developed oral tumors. The collected squamous cell carcinomas were analyzed using whole-exome sequencing and immunofluorescence to examine whether MAGE-A4+ tumors gained more mutations and were more invasive than MAGE-A4- or RAD18 KO tumors. Together, these data provide a greater understanding of MAGE-A4 and RAD18 biology and TLS in oral cancers.
Citation Format: Bethany L. Wagner, Jason Guo, Yanzhe Gao, Cyrus Vaziri, Scott E. Williams. Manipulating translesion synthesis proteins MAGE-A4 and RAD18 in a murine model of oral 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 B10.
Abstract IA12: Metabolic barriers to effective immunotherapy of cancer
Authors: Delgoffe Greg M. 
Published: September 2020

Abstract
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

Abstract
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

Abstract
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&lt;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

Abstract
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

Abstract
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

Abstract
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.