tbuckley/cabot-search huggingface dataset:
Abstract A67: Understanding HIF1A-mediated therapy in clear cell ovarian cancer
Authors: Colles Price, Stanley Gill, Zandra V. Ho, Shawn M. Davidson, Erin Merkel, James M. McFarland, Lisa Leung, Andrew Tang, Maria Kost-Alimova, Aviad Tsherniak, Oliver Jonas, Francisca Vazquez, William C. Hahn
Journal: Clinical Cancer Research (2020)

Abstract Previously, we have used an integrated approach to use genome-scale screening in RNAi and CRISPR-Cas9 to identify several putative cancer dependencies. From these putative dependencies, we discovered EGLN1 was a significant and selective dependency in ovarian cancer and EGLN1 dependency was further enriched in clear-cell ovarian cancers. Genetic knockout and small-molecule inhibition of EGLN1 reduced cell proliferation and increased apoptosis in vitro and in vivo. We found the function of EGLN1 as a cancer dependency is through its canonical role as a negative HIF1A regulator and knockout of HIF1A, but not HIF2A, rescues genetic knockout and small-molecule inhibition of EGLN1. Genetic and small-molecule suppression of VHL, downstream of EGLN1 in the degradation of HIF1A, similarly reduces proliferation and increases apoptosis, and is rescued by HIF1A knockout. Further, we found that forced expression of a mutated HIF1A that blocks EGLN1-dependent hydroxylation reduces proliferation and promotes apoptosis. Using RNA-sequencing, we identified several putative downstream targets of HIF1A and confirmed that HIF1A directly binds and drives transcription of negative MYC regulator MXI1. Further, we found that knockout of MXI1 reduced the effects of EGLN1-mediated suppression, indicating HIF1A-driven MYC suppression as one mechanism underlying EGLN1 dependency. Further understanding of HIF1A-mediated suppression of ovarian cancer progression will be critical to potential small-molecule therapy. Citation Format: Colles Price, Stanley Gill, Zandra V. Ho, Shawn M. Davidson, Erin Merkel, James M. McFarland, Lisa Leung, Andrew Tang, Maria Kost-Alimova, Aviad Tsherniak, Oliver Jonas, Francisca Vazquez, William C. Hahn. Understanding HIF1A-mediated therapy in clear cell 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 A67.
Abstract 4808: ONC201 decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, intregrated stress response and tumor cell death
Authors: Lanlan Zhou, Howard P. Safran, Michael J. Glantz, Wafik S. El-Deiry
Journal: Cancer Research (2020)

Abstract Brain tumors are one of the most lethal cancers in children and young adults. We previously reported that first-in-class small-molecule imipridone ONC201 can antagonize dopamine receptor D2 (DRD2), inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce growth arrest or cell death in tumor cells. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant glioma patients. We hypothesized that ONC201 may synergize with radiotherapy and temozolomide in brain tumors. Glioblastoma (GBM: SNB19, T98G and U251), diffuse intrinsic pontine glioma (DIPG: SU-DIPG-IV and SU-DIPG-36) and atypical teratoid rhabdoid tumor (ATRT: BT-12, BT-16) cell lines were tested using cell viability or colony formation assays with ONC201 up to 20 μM alone or in combination with radiotherapy up to 8 Gy and temozolomide up to 100 μM. We observed synergy between ONC201 and radiation and temozolomide by multiple assays with the best combination index of 0.31 under the treatment of 0.625 μM ONC201, 25 μM TMZ and 4 Gy irradiation in cell viability assay. We observed induction of PKA substrate phosphorylation as a marker of DRD2 antagonism, induction of ATF4 as a marker of ISR activation, and multiple markers of cell death in treated brain tumor cells. Mitochondrial dysfunction induced by ONC201 was greatly reflected in reduction of maximal cell respiration in brain tumor cell lines. ClpXP is a proteolytic machine in mitochondria comprising of the protein chaperone ClpX and protease ClpP, a recently described binding target of ONC201. We have observed that ONC201 induced cytotoxicity depends on ClpP and knockdown of ClpP strongly protects multiple human cancer cell lines from ONC201-mediated (but not other drugs, e.g. temozolomide) cytotoxicity. The ClpX protein level decreased dramatically upon ONC201 treatment. We are exploring the potential interplay between ClpP, dopamine receptors, the ISR and TRAIL signaling pathways after single agent or combinatorial treatments. Our data suggests that ONC201 may be combined synergistically with temozolomide or radiation to address gliomas, along with potential pharmacodynamic biomarkers. The results implicate ClpX and ClpP in downstream cell death induction following ONC201 treatment of brain tumor cells. Citation Format: Lanlan Zhou, Howard P. Safran, Michael J. Glantz, Wafik S. El-Deiry. ONC201 decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, intregrated stress response and tumor cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4808.
Severe Acute Kidney Injury in Patients with COVID-19 and Acute Respiratory Distress Syndrome
Authors: Khalil Chaibi, Myriam Dao, Tài Pham, Victor D. Gumucio-Sanguino, Fabio A. Di Paolo, Arthur Pavot, Yves Cohen, Didier Dreyfuss, Xosé Pérez-Fernandez, Stéphane Gaudry
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Celebrating the ERS HERMES Self-Assessment Course
Authors: Robert Primhak, Zuzana Tumova, Amy Auer, Daiana Stolz
Journal: European Respiratory Journal (2020)

<b>The ERS HERMES self-assessment course has developed over the past 2 years into a well-established course giving the opportunity to access European standard formative assessments</b>https://bit.ly/3i1fEHL
Abstract 4872: Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53
Authors: Pradip K. De, Jennifer C. Aske, Joseph P. Costello, Ethan Thompson, Nandini Dey
Journal: Cancer Research (2020)

Abstract Background: Apoptosis is the therapeutic goal following the administration of anti-cancer drugs. BCL2 and p53 are two important nodes in the apoptosis signaling pathway. Previous reports have shown that the anti-apoptotic protein BCL2 and p53 degrader MDM2 are overexpressed in many solid neoplasms, including ovarian cancers, and associated with poor clinical outcome. Purpose: Since monotherapy in cancer is generally not providing long-lasting clinical responses, here, we hypothesize that concomitant p53 activation (by an inhibitor of MDM2-p53 interaction, e.g. AMG232) and BCL2 inhibition (by venetoclax) induce maximum apoptosis and markedly reduce tumor cell proliferation in ovarian clear cell and endometrioid carcinomas with wild type (WT) TP53. Methods: We tested the anti-proliferative and apoptotic activity of venetoclax (V) alone, AMG 232 alone (A), and a combination of V plus A in ovarian clear cell carcinoma (OVISE cells) and ovarian endometrioid carcinoma cell lines (A2780 &amp; isogenic Cisplatin resistant A2780CisR). Results: 1) A binds the MDM2 protein, blocks MDM2-p53 interaction, and induces p53 expression and activity, 2) p53 effector molecule p21 is robustly induced following the treatment of A, 3) the anti-proliferative activity of V or A was observed by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom, 4) all three cell lines exhibited an increase in annexin V positivity (initiation of apoptotic activity) following V or A treatment, 5) importantly, a combination of V plus A robustly induced the apoptotic markers e.g. cleaved-CASPASE3/7, cleaved PARP1 and BIM protein expression in all cell lines, 6) high mitochondrial depolarization was also observed following the combination of treatment, 7) similar to protein expression data, mRNA data also showed that pro-apoptotic/cell cycle inhibitor transcripts such as p21 and PUMA mRNA expression were significantly increased and 8) normoxic HIF1α degradation is not rescued following the treatment of MDM2-p53 interacting inhibitor A however A-induced p53 activation inhibits hypoxic HIF1α accumulation. Conclusion: These data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy for ovarian clear cell and endometrioid carcinomas patients that retain WT-TP53. Citation Format: Pradip K. De, Jennifer C. Aske, Joseph P. Costello, Ethan Thompson, Nandini Dey. Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4872.
Abstract 5142: Proteome-wide analysis identifies three subgroups of diffuse-type gastric cancer
Authors: Wenwen Huang, Xia Xia, Dongdong Zhan, Lin Shen, Jun Qin
Journal: Cancer Research (2020)

Abstract Background: Gastric cancer (GC) is highly heterogeneous and the leading cause of cancer death. Diffuse-type gastric cancer (DGC) is one of poor-prognosis GC subtypes with few treatment options. Genomic subtyping classifies overall gastric cancers into different subgroups that associate with prognosis and therapeutic targets, but it has not translated into clinical benefit. Proteomic subtyping with DGC may offer the potential for personalized risk stratification and treatment recommendation. Methods: We developed a workflow using fast mass spectrometry and ConsensusClusterPlus (CCP) consensus clustering for proteomic subtyping and applied it to 99 DGC formalin-fixed, paraffin-embedded (FFPE) samples. Results: In this study, 99 FFPE tumor samples were analyzed and classified into three proteomic subtypes (DGCP1-3) based on proteome-wide data, which were significantly associated with prognosis and response to chemotherapy. DGCP1 is with the best survival and DGCP3 is with the worst survival. DGCP2 derives benefit from chemotherapy. The rest of the subtypes do not receive benefit from chemotherapy. Specific signaling pathways are enriched in the subtypes: DGCP1/innate immune system; DGCP2/metabolism of RNA plus cell cycle; DGCP3/Extracellular Matrix (ECM). The classification with subtype-specific proteins provides a roadmap for stratifying patients into subgroups in trials of chemotherapy, targeted, and immune therapies. Conclusions: Proteomic subtyping of DGC identified three subgroups that have significant associations with distinct clinical characteristics. The DGCP subtyping can be further verified in more clinical cohorts and used to predict prognosis and recommend clinical actions in DGC treatment. Citation Format: Wenwen Huang, Xia Xia, Dongdong Zhan, Lin Shen, Jun Qin. Proteome-wide analysis identifies three subgroups of diffuse-type gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5142.
Abstract 130: CpG binding protein promotes cell proliferation through H3K4 methylation in ovarian cancer
Authors: Liu-qing Yang, Han-yin Hu, Yao Han, Heng-Yan Zhu, Xiao-min Wang, Lei Ao, Ying Xu, Xuan Huang, Xuan Che, Li-Zhong Wang, Ya-Bo Jiang, Chun-wei Xu, Shu-Qun Cheng, Michal Heger, Wei-wei Pan
Journal: Cancer Research (2020)

Abstract E3 ubiquitin ligase CRL4 complex activation requires cullin neddylation. MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, reportedly blocked cullin neddylation and inactivated cullin (CUL)-RING E3 ligases (CRLs). Studies have shown that MLN4924 inhibits cell proliferation and survival. We examined the oncostatic and cytotoxic properties of MLN4924 in ovarian cancer. MLN4924 blocked human cancer cell proliferation in nude mice by inhibiting CpG binding protein CFP1 expression. Loss of CFP1 reduced cell growth, promoted apoptosis, and increased senescence. CFP1-dependent H3K4 trimethylation is necessary to maintain the expression of target genes in ovarian cancer cells. We identified bone marrow stromal cell antigen 2 (BST2) and noggin (NOG) as direct targets of CFP1. Their expression was selectively induced by CFP1 deletion. Furthermore, deletion of NOG and overexpression of BST2 prevented the growth-inhibitory effect of CFP1 loss. Our study further demonstrated that CRL4 inactivation reduced CFP1 transcription and trimethylation on lysine 4 of histone H3, which in turn inhibited cell proliferation and induced apoptosis. Therefore, CRL4 constitutes a druggable target in ovarian cancer. Citation Format: Liu-qing Yang, Han-yin Hu, Yao Han, Heng-Yan Zhu, Xiao-min Wang, Lei Ao, Ying Xu, Xuan Huang, Xuan Che, Li-Zhong Wang, Ya-Bo Jiang, Chun-wei Xu, Shu-Qun Cheng, Michal Heger, Wei-wei Pan. CpG binding protein promotes cell proliferation through H3K4 methylation in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 130.
Abstract 3658: Brd4-bound enhancers drive critical sex differences in glioblastoma
Authors: Najla Kfoury-Beaumont, Zongtai Qi, Michael Wilkinson, Lauren Broestl, Kristopher Berrett, Arnav Moudgil, Sumithra Sankararaman, Xuhua Chen, Jay Gertz, Robi Mitra, Joshua B. Rubin
Journal: Cancer Research (2020)

Abstract Sex can be an important determinant of cancer phenotype and exploring sex-specific tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established model of glioblastoma, we discovered transcriptome-wide sexual dimorphism in gene-expression that was concordant with sex differences in H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 co-localization with Myc and p53. The sex-specific enhancer usage drove sex differences in stem cell function and tumorigenicity. Moreover, male and female GBM cells exhibited opposing responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis, while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Thus, for the first time, Brd4 activity is revealed to drive a sexually dimorphic stem cell and tumorigenic phenotype, resulting in diametrically opposite responses to BET inhibition in male and female glioblastoma cells. This has critical implications for the clinical evaluation and use of BET inhibitors. Citation Format: Najla Kfoury-Beaumont, Zongtai Qi, Michael Wilkinson, Lauren Broestl, Kristopher Berrett, Arnav Moudgil, Sumithra Sankararaman, Xuhua Chen, Jay Gertz, Robi Mitra, Joshua B. Rubin. Brd4-bound enhancers drive critical sex differences in glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3658.
Abstract 1394: Gene expression profile in BCBL-1 cell line following activation of KSHV
Authors: Samantha L. Haines, Sabrina R. Bishop, Viktorija Podlutskaya, Andrej Podlutsky
Journal: Cancer Research (2020)

Abstract Patients with HIV/AIDS are at a 3,400 times higher risk of developing Kaposi's sarcoma when compared to healthy populations. Our hypothesis is that the upregulation of viral associated proteins is causing an increase in DNA damage, allowing for the higher incidence rate of Kaposi's sarcoma in infected populations. The direct mechanisms leading to this increased risk is unknown, but the viral infection with Kaposi's sarcoma-associated herpesvirus (KSHV) is an apparent cause of this risk. The cell is under attack of endogenous threats including oxidative stress, causing DNA damage and leading to mutations, but the viral proteins may interfere with the repair mechanisms. In previous experiments we looked at DNA repair dynamics following X-ray exposure in the two different stages and determined there is an inefficiency in the DNA repair process in the cells during active production of viral particles. This project aimed to compare the transcriptomes of the BCBL-1 cell line during latent and acute phases of KSHV production. Our results are showing that genes involved in genome stability are differently expressed during the lytic stage. Comparison of these two transcriptomes allows for identification of which proteins are being upregulated during active viral production. This may be of importance for the HIV/AIDS cancer patients because it shows the mechanisms behind genome stability in KSHV-infected cells. 1) Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Numbers UL1GM118991, TL4GM118992, or RL5GM118990. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 2) NASA EPSCoR, NNH15ZHA003C Citation Format: Samantha L. Haines, Sabrina R. Bishop, Viktorija Podlutskaya, Andrej Podlutsky. Gene expression profile in BCBL-1 cell line following activation of KSHV [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1394.
Abstract A11: Copy-number analysis of understudied black women ovarian cancers
Authors: Joe R. Delaney
Journal: Clinical Cancer Research (2020)

Abstract Cancer disparities research has a sample number problem, especially in serous ovarian cancer (SOC). Driver genes for SOC are mutated in &amp;lt;10% of patients, with the sole exception of p53. Even with hundreds of patients, this limits the ability to perform gene-oriented statistics between racial groups, even in the relatively diverse population in the United States. Yet research is needed; the CONCORD-2 study and researchers at the Hollings Cancer Center have consistently found worse prognosis for black patients with SOC, despite correcting for socioeconomic factors. Biologic tumor-intrinsic factors may explain some aspects of the worse prognosis. The Cancer Genome Atlas (TCGA) well mapped the US population for Caucasians and African Americans (77% white, 12% black), but with only 12% of samples within the second most prevalent racial group, driver genes are missed. For example, while BRCA1 mutation was found in tumors from white patients, it was not found in tumors from black patients. However, research need not be limited to amino-acid level mutations and indels; copy-number alterations (CNAs) likely drive the biology of SOC, with the average number of genes affected per TCGA tumor around 16,000. Pathway-level analyses of these widely disrupted genes can find significant differences between racial/ethnic groups. Here, we present evidence that significant differences are present in somatic CNA data for the pathways: xenobiotic metabolism, cAMP kinase signaling, and adaptive immune response. An expansion of research into somatic CNAs is warranted in underrepresented minority groups to better understand how treatment options and prognostic markers may differ. Citation Format: Joe R. Delaney. Copy-number analysis of understudied black women ovarian cancers [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 A11.
Abstract 5859: Genomic correlates of response to immune checkpoint inhibitors in advanced head and neck squamous cell carcinoma
Authors: Nisarg A. Patel, Natalie I. Vokes, Haitham Elmarakeby, Glenn J. Hanna, Eliezer M. Van Allen
Journal: Cancer Research (2020)

Abstract Background: Objective response rates for patients with advanced head and neck squamous cell carcinoma (HNSCC) receiving PD-1/L1 immune checkpoint inhibitors (ICI) without chemotherapy remain under 25%. Some studies suggest that HNSCC patients with human papillomavirus (HPV)-associated disease and high tumor mutational burden (TMB) derive greater benefit, although these findings do not yet guide patient selection. We hypothesized that uniform genomic analysis of a larger cohort may help place the predictive value of TMB in a broader biological context and identify more robust predictors of response. Methods: 274 patients with biopsy-proven HNSCC treated with ICI at our institution from June 2014 to September 2018 were identified. Following targeted massively parallel sequencing, single nucleotide variant calling, and quality control measures, 127 samples were available for analysis. Clinical records were reviewed to determine radiographic response and overall survival. Responders included complete or partial responders by RECIST v1.1. Nonresponders included those with progressive or stable disease. We evaluated associations between genomic features and response using standard statistical methods. Results: TMB for the entire cohort was significantly higher among responders (p = 0.01, Fisher's); however, it had poor predictive power (AUROC = 0.68). Among the entire cohort, somatic mutations in NOTCH1 were enriched in responders (12/26 R, 17/101 NR, p = 0.003). After correcting for TMB, NOTCH1 remained associated with complete or partial response (p &amp;lt; 0.05, logistic regression). After adjusting for mutations in NOTCH1, no significant difference in TMB was observed between responders and nonresponders (p &amp;gt; 0.05, logistic regression). Among HPV-negative responders, somatic mutations in CDK12, a transcription-associated kinase whose loss is associated with genomic instability, neoantigen burden, and T cell infiltration, were enriched (3/26 R, 0/101 NR, p = 0.008, Fisher's). Conclusion: Through uniform genomic analysis of the largest ICI-treated HNSCC cohort to-date, we validated prior findings regarding the significance of TMB and NOTCH1 as correlates of response for ICI in HNSCC. We also show that TMB alone is insufficient as a predictor of response. We identify CDK12 as a variant with a mechanistic relationship to tumor immunology as a possible correlate of response in HPV-negative patients, which warrants further investigation. Citation Format: Nisarg A. Patel, Natalie I. Vokes, Haitham Elmarakeby, Glenn J. Hanna, Eliezer M. Van Allen. Genomic correlates of response to immune checkpoint inhibitors in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5859.