bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA10: Targeting glutamine metabolism as a means of enhancing immunotherapy for cancer
Authors: Powell Jonathan , Leone Robert , Oh Min-Hee , Rais Rana , Majer Pavel , Slusher Barbara 
Published: September 2020

Abstract
Tumors possess specialized metabolic programming that facilitates their rapid growth. We have developed a novel glutamine antagonist that not only demonstrates single-agent efficacy in a variety of mouse tumor models but also synergizes with anti-PD-1, adoptive cellular therapy (ACT), and A2aR antagonism to overcome resistance to immunotherapy and promote durable cures. Our data demonstrate that targeting tumor glutamine metabolism alters the tumor microenvironment by making it less acidic, less hypoxic, and more nutrient replete. These alterations lead to enhanced endogenous antitumor responses (in the absence of additional immunotherapy). Further analysis of tumor-infiltrating lymphocyte (TIL) reveals markedly increased infiltration of CD8+ T cells with increased proliferative index (Ki67) and the generation of robust memory phenotypes in the treated mice. Further, RNA sequencing data revealed that CD8+ TIL from vehicle-treated mice showed significantly enhanced expression of apoptotic transcriptional programs compared with TIL from treated mice. Additionally, targeting glutamine metabolism leads to decreased MDSC with an increase in inflammatory TAMs. Furthermore, we observe a downregulation of IDO and a marked decrease in kynurenine in the tumors of treated mice. These changes in macrophage subsets also correlated with decreased metastasis. Overall our findings suggest a novel “metabolic” approach to enhancing immunotherapy for cancer.
Citation Format: Jonathan Powell, Robert Leone, Min-Hee Oh, Rana Rais, Pavel Majer, Barbara Slusher. Targeting glutamine metabolism as a means of enhancing immunotherapy for 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 IA10.
Abstract PR02: Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status
Authors: Ghasemi Farhad , Prokopec Stephenie D. , MacNeil Danielle , Mundi Neil , Howlett Christopher , Stecho William , Fung Kevin , Yoo John , Winquist Eric , Gameiro Steven , Sahovaler Axel , Plantinga Paul , Mymryk Joe S. , Barrett John W. , Boutros Paul C. , Nichols Anthony C. 
Published: September 2020

Abstract
Smoking has historically been recognized as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). This study aimed to assess the mutational differences between heavy smokers (&gt;20 pack-years) and never smokers among the HNSCC patients within The Cancer Genome Atlas (TCGA). Single nucleotide variation (SNV) and copy number aberration (CNA) differences between heavy smokers and never smokers were compared within HPV-positive (n=67) and negative (n=431) TCGA HNSCC cohorts, and the impact of these mutations on survival was assessed. No genes were differentially mutated between smoking and never smoking patients with HPV-positive tumors. By contrast, in HPV-negative tumors, NSD1 and COL1A11 were found to be more frequently mutated in heavy smokers, while CASP8 was more frequently altered in never smokers. HPV-negative patients with NSD1 mutations experienced significantly improved overall survival compared with NSD1 wild-type patients. This improved prognosis was validated in an independent cohort of 77 oral cavity cancers and a meta-analysis that included two additional datasets (688 total patients, hazard ratio for death 0.44, 95% CI 0.30-0.65). NSD1 mutations are more common in HPV-negative heavy smokers and define a cohort with favorable prognosis, and may represent a clinically useful biomarker to guide treatment deintensification for HPV-negative patients.
Citation Format: Farhad Ghasemi, Stephenie D. Prokopec, Danielle MacNeil, Neil Mundi, Christopher Howlett, William Stecho, Kevin Fung, John Yoo, Eric Winquist, Steven Gameiro, Axel Sahovaler, Paul Plantinga, Joe S. Mymryk, John W. Barrett, Paul C. Boutros, Anthony C. Nichols. Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status [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 PR02.
Abstract PR07: WEE1 inhibition triggers premature mitotic entry in HPV16-E6-expressing cells independent of p53 inactivation
Authors: Diab Ahmed , Swanger Jherek , Gem Hakan , Galloway Denise , Mendez Eduardo , Sidorova Julia , Clurman Bruce 
Published: September 2020

Abstract
Inhibition of the protein kinase WEE1 induces cancer cell death by forcing cells arrested in S-phase directly into mitosis. However, in the absence of S-phase perturbations, WEE1 inhibition is typically insufficient to trigger premature mitosis. Here, we show that WEE1 inhibition alone drives premature mitotic entry in HPV+ head and neck cancer cells. We also observed unscheduled mitotic entry in E6- and E6E7-expressing HPV-negative UMSCC74a cells upon WEE1 inhibition, but not in empty vector controls. Unlike E6 expression, p53 depletion alone was not sufficient to cooperate with WEE1 inhibition to effect forced mitotic entry. In vitro kinase assays showed elevated CDK1 activity in E6 and E6E7 cells compared to empty vector controls, particularly after WEE1 inhibition. We find that addiction of E6E7 cells to cell cycle inhibitor p21 causes the AZD1775-mediated CDK hyperactivation, therefore intensifying genotoxic replication stress. WEE1 inhibition therefore exacerbates E6E7-associated replication stress leading to slowing of replication forks, excess single-stranded DNA, and elevated RPA loading. RPA depletion further sensitized E6E7 cells to WEE1 inhibition-induced ssDNA accumulation, DNA damage, and cell death, implying a role for RPA in limiting WEE1i-induced replication stress in E6E7-expressing cells. Hallmarks of replication stress and DNA damage persisted in E6E7-expressing cells after recovery from WEE1 inhibition. These observations collectively explain the unique hypersensitivity of HPV+ head and neck tumors to WEE1i.
Citation Format: Ahmed Diab, Jherek Swanger, Hakan Gem, Denise Galloway, Eduardo Mendez, Julia Sidorova, Bruce Clurman. WEE1 inhibition triggers premature mitotic entry in HPV16-E6-expressing cells independent of p53 inactivation [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 PR07.
Abstract A18: Evaluating the potential to repurpose statins for ovarian cancer therapy
Authors: Kroeger Paul T. , Drapkin Ronny 
Published: September 2020

Abstract
The recent success of PARP inhibitors in patients with BRCA1/2 mutant ovarian tumors highlights the importance of identifying druggable vulnerabilities in this disease. The fact that not all ovarian cancer patients will benefit from PARP inhibitors or experience durable responses places great emphasis on the need to identify additional therapies. Repurposing existing FDA-approved drugs offers an opportunity to accelerate the progress of drug development. Statins are drugs primarily prescribed for hypercholesterolemia and have been scrutinized for decades. Some studies demonstrated, through epidemiologic approaches and experimental studies, that statins have anticancer properties. We hypothesized that statins can be repositioned as part of a therapeutic regimen for HGSOC. Here, we demonstrate that certain ovarian cancer cell lines are exquisitely sensitive to treatment with statins. In addition, we show that the sensitivity to statins is an on-target effect by rescuing with downstream members of the mevalonate pathway. Our ongoing studies reveal that HGSOC cells that are sensitive to stain treatment manifest an amplification of chromosome 1q21. Within this genomic region are the S100 proteins, previously identified as potential biomarkers in several cancers, as well as the antiapoptotic protein MCL1. Using reverse phase protein arrays (RPPA) we found that MCL1 levels were altered in statin-sensitive cell lines, while there was no such change in non-sensitive lines. After identifying MCL1 as a potential marker of response, Western blot analysis demonstrated a dose-dependent decrease in the protein level of MCL1 with increasing statin concentration. Additionally, a short, proapoptotic splice variant of MCL1 was produced upon statin treatment, but only in the sensitive lines. Mechanistically, we find that phospho-YAP (inactive) is upregulated after statin treatment. Using a syngeneic cell line system, we were able to demonstrate that overexpression of YAP increases sensitivity to statins. Interestingly, a constitutively active form of YAP (nonphosphorylatable) remains insensitive, suggesting the importance of the phosphorylation event itself. This data corroborated previous research that suggested that multiple different statins decrease nuclear YAP and suggest a mechanism for statin sensitivity. Given its role as an oncogene, the apparent ability of statins to deactivate YAP and downregulate MCL1 steers statins in a promising direction for their repositioning for future therapeutic use.
Citation Format: Paul T. Kroeger, Jr., Ronny Drapkin. Evaluating the potential to repurpose statins for ovarian cancer therapy [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 A18.
Abstract A25: Withaferin A ameliorates ovarian cancer-induced cachexia through regulation of NF-kB/NLRP3 signaling
Authors: Straughn Alex R. , Ratajczak Mariusz Z. , Kakar Sham S. 
Published: September 2020

Abstract
A majority of ovarian cancer patients exhibit clinical symptoms of cachexia, which accounts for up to 30% of cancer deaths depending on the oncologic setting. Withaferin A is a steroidal lactone with anti-inflammatory properties and is known to inhibit the growth of ovarian cancer and reduce metastasis through targeting cancer cells and cancer stem cells. The purpose of this study was to investigate whether Withaferin A could ameliorate the cachectic phenotype induced by ovarian cancer. We believe that treatment with Withaferin A could rescue body composition and muscle strength changes. The ovarian cancer cell line A2780 was xenografted into severely immunodeficient NSG mice via an intraperitoneal (i.p.) injection. Control mice received an i.p. injection of sterile saline. Following an engraftment period, mice were treated with vehicle or Withaferin A via i.p. injection every 3 days until the end of the study. Body weight and grip strength were assessed on a weekly basis. DEXA scan was performed post mortem, followed by collection/sectioning/staining of tumor samples and various skeletal muscle tissue. Withaferin A treatment significantly reduced the mortality rate associated with ovarian cancer. Treatment with Withaferin A inhibited an accumulation of adipose tissue within the thoracoabdominal region, associated with ovarian cancer progression. Low doses of Withaferin A were protective for forelimb and total limb grip strength, whereas higher doses were initially protective but resulted in a significant reduction. Further, Withaferin A ameliorated the reduction in myofibrillar cross-sectional area induced by ovarian cancer. Additionally, treatment with Withaferin A completely inhibited the slow-to-fast myofiber-type conversion seen in the settings of cancer cachexia. Lastly, using immunohistochemical staining and qPCR, we demonstrate that Withaferin A causes a downregulation of NF-kB-dependent proinflammatory cytokines and inhibits activation of the NLRP3 inflammasome, which are known to mediate cachectic signaling. Collectively, we provide preliminary data indicating that in ovarian cancer-induced cachexia, body composition changes and weakening of the skeletal muscle can be ameliorated through a downregulation of NF-kB-NLRP3 signaling.
Citation Format: Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar. Withaferin A ameliorates ovarian cancer-induced cachexia through regulation of NF-kB/NLRP3 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 A25.
Abstract A26: Molecular analysis of short- vs. long-term ovarian cancer survivors
Authors: Stur Elaine , Dal Molin Graziela Zibetti , Wu Sherry , Baggerly Keith , Tworoger Shelley , Levine Douglas , Karlan Beth , Moore Kathleen , Lutgendorf Susan , Sood Anil 
Published: September 2020

Abstract
Background: High-grade serous ovarian carcinomas (HGSOC) comprise the majority of ovarian cancer cases and usually present at diagnosis with late stages of disease. Despite having similar histology, patients with HGSOC often experience highly variable outcomes. The underlying determinants for long-term (LT- ≥10 years) versus short-term (ST- &lt;3 years) survival are largely unknown. The present study sought to identify molecular predictors of LT survival for women with HGSOC. To achieve this, we used deep molecular analysis of tumors from LT and ST survival patients of HGSOC.
Methods: For the discovery tumor cohort, RNA sequencing was conducted on twenty-four (24) frozen samples HGSOC tumors (12 from LT and 12 from ST survivors). A validation cohort included 29 samples (15 from LT and 14 from ST survivors). In vitro studies were carried out using OVCAR8 and SKOV3 cell lines.
Results: From RNAseq analysis, a total of 11 genes were differentially expressed between ST and LT survivors (fold change &gt;2, p &lt; 1 × 10-5, FDR &lt;0.01). A secondary screen was used to eliminate genes that were expressed below threshold levels (fold change &gt;2). Three genes were overexpressed in LT survivors; one had sufficient expression for future therapeutic benefit—TMEM62. In the subsequent validation cohort, TMEM62 had the most significant result of the initial genes of interest, with qRT-PCR data demonstrating an average 3.0-fold higher expression of TMEM62 mRNA in LT versus ST survivors. Next, OVCAR8 and SKOV3 ovarian cancer cells were transfected with TMEM62 using a bacterial plasmid; increased expression of TMEM62 led to decreased proliferation (OVCAR8 73%; SKOV3: 33%), invasion (OVCAR8: 73%; SKOV3: 33%), and a slight decrease in migration (about 2%) in both cell lines. Using a protein array, a decrease in chemokines in SKOV3 cells (MIF, Serpin E1, IL6, CXCL7, IL8, Midkine, and CXCL1) was observed, suggesting that increased TMEM62 expression may lead to reduced tumor inflammatory markers.
Conclusion: Our results demonstrate that TMEM62 may be a novel treatment target for HGSOC given its much higher expression in those patients who achieve long-term survival. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes.
Citation Format: Elaine Stur, Graziela Zibetti Dal Molin, Sherry Wu, Keith Baggerly, Shelley Tworoger, Douglas Levine, Beth Karlan, Kathleen Moore, Susan Lutgendorf, Anil Sood. Molecular analysis of short- vs. long-term ovarian cancer survivors [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 A26.
Abstract A37: PAX8 drives ovarian cancer angiogenesis through interaction with SOX17
Authors: Chaves-Moreira Daniele , Mitchell Marilyn A. , Rendi Jessica , Nameki Robbin , Brady Donita C. , Sidoli Simone , Garcia Benjamin , Morin Patrice J. , Lawrenson Kate , Drapkin Ronny 
Published: September 2020

Abstract
A major problem in the treatment of ovarian cancer is the heterogeneity among ovarian tumors. DNA and RNA sequencing studies have demonstrated both intertumoral and intratumoral genetic variation. Despite efforts to elucidate common signaling pathways among various ovarian cancer subtypes, few have led to meaningful patient stratification or individualized targeted molecular therapies. A theoretical new approach to the treatment of ovarian cancer would be to target the signaling pathways that are essential to the development of the HGSOC progenitor cells, the secretory epithelium of the fallopian tube (FT). PAX8, a transcription factor that identifies and sustains high-grade serous ovarian carcinomas (HGSOC), is also the main regulator of FT development. We investigated whether blocking the ability of PAX8 to influence its gene targets, either by interrupting PAX8 protein-protein interactions or by inhibiting the products of PAX8-driven signaling, has the potential to eliminate the primary growth stimulus for high-grade serous tumors. Herein, we have identified SOX17 as a bona fide PAX8-interacting partner and elucidated their collaborative impact on HGSOC. We observed that PAX8 and SOX17 are master regulators of HGSOC identity, as both were found binding in super-enhancer regions regulating most of the same set of genes. Ontology analysis after PAX8 or SOX17 loss showed alteration in three main pathways: cell cycle, apoptosis, and angiogenesis. Most remarkably, we discovered that PAX8 and SOX17 regulate angiogenesis in vitro and in vivo by suppressing SERPINE1, which enables VEGFR2 signaling pathway. These results broaden our understanding of the roles of PAX8 and SOX17 in the regulation of angiogenesis and suggest novel therapeutic strategies that could overcome ovarian cancer heterogeneity and resistance.
Citation Format: Daniele Chaves-Moreira, Marilyn A. Mitchell, Jessica Rendi, Robbin Nameki, Donita C. Brady, Simone Sidoli, Benjamin Garcia, Patrice J. Morin, Kate Lawrenson, Ronny Drapkin. PAX8 drives ovarian cancer angiogenesis through interaction with SOX17 [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 A37.
Abstract A42: Potassium channel activity unveils ovarian cancer vulnerability: From signaling to precision medicine
Authors: Lopes Daniela Fukushiro , Hegel Alexandra , Senyuk Vitaly , Russo Angela , Liotta Margaret , Potkul Ronald , Beeson Craig , Brurgette Joanna , Gentile Saverio 
Published: September 2020

Abstract
Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiologic and pathologic conditions. Also, studies on ion channels have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that the Kir6.2/SUR2 potassium ion channel can be a prognostic factor in gynecologic cancers. Here we present data showing that the Kir6.2/SUR2 channel activity control biochemical pathways underlying proliferation and metabolism in gynecologic cancers, including endometrioid and high-grade serous ovarian cancer. Use of activators of the Kir6.2/SUR2 produced an arrest of the cell cycle, a significant mitochondrial dysfunction that is associated with alteration of the oxidative cellular state and DNA damage in cisplatin-resistant ovarian cancer. Also, our in vivo experiments show the antigrowth effects of pharmacologically targeting Kir6.2/SUR2 on ovarian cancer with FDA-approved molecules. This study offers the opportunity to consider the therapeutic benefits of repurposing drugs targeting the Kir6.2/SUR2 channel for a treatment of gynecologic cancers that is efficient and safe.
Citation Format: Daniela Fukushiro Lopes, Alexandra Hegel, Vitaly Senyuk, Angela Russo, Margaret Liotta, Ronald Potkul, Craig Beeson, Joanna Brurgette, Saverio Gentile. Potassium channel activity unveils ovarian cancer vulnerability: From signaling to 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 A42.
Abstract A47: Preclinical efficacy of CPI-1688, a novel EZH2 inhibitor, in epithelial ovarian cancer with alterations in the SWI/SNF chromatin remodeling complex
Authors: Magno Elizabeth , Karakashev Sergey , Mertz Jennifer , Trojer Patrick , Zhang Rugang 
Published: September 2020

Abstract
Epithelial ovarian cancer is a paradigm for exploring precision medicine in the context of genetic alteration in the SWI/SNF chromatin remodeling complex. For example, the ARID1A subunit of the SWI/SNF complex is mutated in more than 50% of clear cell ovarian carcinomas. In addition, CARM1 is amplified/overexpressed in ~20% of high-grade serous ovarian cancer. CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 regulates the SWI/SNF genome-wide distribution by post-transcriptionally methylating SWI/SNF core subunit BAF155. EZH2 is the catalytic subunit of the polycomb repressive complex that typically suppresses its gene expression through generating lysine 27 trimethylation on histone H3 (H3K27me3). Our previous studies established that inhibition of the methyltransferase activity of EZH2 is synthetically lethal with ARID1A mutation or CARM1 overexpression due to the antagonistic roles played by the SWI/SNF and EZH2/PRC2 complexes. Here we report the preclinical efficacy of CPI-1688, a highly selective second-generation EZH2 methyltransferase inhibitor, in ARID1A mutated clear-cell ovarian cancer cells and CARM1 overexpressed high-grade serous ovarian cancer cells. Notably, the antitumor effects conferred by CPI-1688 correlate with ARID1A mutation or CARM1 expression status. In addition, at the pharmacodynamic levels, the observed efficacy correlates with a reduction in H3K27me3 both in vitro and in vivo. This suggests that the observed antitumor effects are due to on-target inhibition of EZH2 methyltransferase activity. Finally, this observed selectivity correlates with reactivation of EZH2 target tumor suppressor genes. Together, these results indicate that CPI-1688 is a promising new therapeutic for ovarian cancer with ARID1A mutation or CARM1 overexpression.
Citation Format: Elizabeth Magno, Sergey Karakashev, Jennifer Mertz, Patrick Trojer, Rugang Zhang. Preclinical efficacy of CPI-1688, a novel EZH2 inhibitor, in epithelial ovarian cancer with alterations in the SWI/SNF chromatin remodeling complex [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 A47.