tbuckley/cabot-search huggingface dataset:
Abstract LB-182: Combination of sulforaphane and 5-aza-2′-deoxycytidine slows the growth and upregulates the chemoattractant CCL5 in metastatic melanoma
Authors: Tung-Chin Chiang, Brian Koss, Aaron J. Storey, Jovanny Zabaleta, Samrat Roy Choudhury, Bradley D. Shields, Elizabeth C. Draper, L Joseph Su, Alan J. Tackett
Journal: Cancer Research (2020)

Abstract UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. We previously found that a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5 –aza –2 ′–deoxycytidine (DAC) slowed cell growth in melanoma at a greater rate than DAC alone. Here, we report a multi –omics analysis with combination and single drug treatment. We observed a significant increase in global protein abundance with an altered level of expression in the combination treatment as compared to individual treatment. Proteins associated with methylation patterns and with reactive oxidative species were found dysregulated in combination treatment. A comparison analysis of proteomic and transcriptomic data with Ingenuity Pathway Analysis showed common canonical pathways involved in phosphorylation (ERK/MAPK signaling) and immune response with combination treatment. The global DNA methylation pattern was analyzed to explore the impact of combination and single drug treatment on methylation status. Interestingly, we observed an increase in the levels of a critical immuno-regulator cytokine, C –C motif ligand 5 (CCL5), which functions as a chemoattractant for natural killer (NK) cells. Animal studies showed the level of CCL5in blood and tumor was increased with DAC and SFN combination treatment compared to that of control, which coincided with tumor reduction. Our data demonstrate the impact of SFN on the effectiveness of the FDA –approved drug DAC to reduce metastatic melanoma tumors. Citation Format: Tung-Chin Chiang, Brian Koss, Aaron J. Storey, Jovanny Zabaleta, Samrat Roy Choudhury, Bradley D. Shields, Elizabeth C. Draper, L Joseph Su, Alan J. Tackett. Combination of sulforaphane and 5-aza-2′-deoxycytidine slows the growth and upregulates the chemoattractant CCL5 in metastatic melanoma [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 LB-182.
Abstract 1036: Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)
Authors: Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang
Journal: Cancer Research (2020)

Abstract Embryonic ectoderm development (EED) is a key component of the polycomb repressive complex 1 (PRC1) and PRC2 and targeting EED by an allosteric mechanism represents a potentially attractive strategy for the treatment of human cancers. We report herein the discovery of a new class of highly potent and efficacious small-molecule EED inhibitors, as exemplified by UM-EEDi-5285. UM-EEDi-5285 binds to EED protein with a low nanomolar affinity and achieves IC50 values of &amp;lt; 1 nM in inhibition of cell growth in Pfeiffer and Karpas-422 lymphoma cell lines carrying an EZH2 mutation. UM-EEDi-5285 is capable of achieving complete and durable tumor regression in the KARPAS-422 xenograft model in mice at well-tolerated dose-schedules. The co-crystal structure of UM-EEDi-5285 in a complex with EED provides the structural basis for their high-affinity interaction. UM-EEDi-5285 is arguably the most potent and efficacious EED inhibitor reported to date. UM-EEDi-5285 is a promising lead compound for advanced preclinical development studies. Citation Format: Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED) [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 1036.
Abstract LB-234: Development of HER2 targeted HSP90 inhibitors delivery system
Authors: Kwangsuk Lim, Yudong Hong, Young-Wook Won
Journal: Cancer Research (2020)

Abstract Heat shock protein 90 (HSP90) plays a crucial role in the survival and growth of cancer cells by improvement of the stability and activity of many signaling proteins such as Akt, Raf-1 and HER2/neu. HSP90 inhibitors (HSP90i) such as geldamanycin (GM), AUY922 and STA-9090 have been developed for inhibition of multiple signaling pathways that are initiated by HSP90. Although geldanamycin derivatives (GM) which is the first class of HSP90 inhibitors were disappointing in the initial clinical trials, these studies have shown promise in patients with HER2 positive cancers. To improve anticancer efficacy of HSP90i, HER2 targeted HSP90i delivery system (HER2-HBD) was constructed because of difficulty in chemical modification of HSP90i. HER2-HBD consist of HER2 scFv and HSP90i binding domain, was expressed from 293 cells. This system could incorporate HSP90i into recombinant antibody fusion protein based on biological binding affinity. HER2-HBD and HSP90i was spontaneously formed HER2-HBD/HSP90i complex. HER2-HBD/HSP90i complex specifically delivered HSP90i into HER2 positive cancer cell and reduced cancer cell growth in vitro and in vivo test. HER2-HBD recombinant system based on biological affinity between HSP90i and HBD was not required chemical reaction to conjugate antibody and drug. This system might be useful targeted delivery systems for HSP90i without tailored conjugation method to develop antibody-drug conjugate (ADC) and also applied to develop targeted delivery systems for biological inhibitor drugs. Citation Format: Kwangsuk Lim, Yudong Hong, Young-Wook Won. Development of HER2 targeted HSP90 inhibitors delivery system [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 LB-234.
Abstract 1217A: Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells
Authors: Sadaaki Nishimura, Masakazu Yashiro, Tomohiro Sera, Yurie Yamamoto, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Kenji Kuroda, Tomohisa Okuno, Masaichi Ohira
Journal: Cancer Research (2020)

Abstract Background: Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. No driver gene responsible for the malignant potential of SGC has not been identified. Next-generation sequencing (NGS) technology has defined as the genomic landscape of various types of cancers, and has elucidated a number of novel driver mutations of gastric cancer. RHOA and CDH1 are characteristic mutations for SGC, but these mutations are not druggable. Novel molecular target therapy has been necessary for SGC based on its biological behavior. Objective: We sought to identify the characteristic driver gene which is responsible for SGC. Methods: DNA was isolated from six human SGC cell lines: OUCM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12, and OCUM-14. The mutational status of 90 cancer-associated genes was examined by next-generation sequencing. The expression level of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) in 708 gastric cancers was examined immunochemically, and the correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were analyzed. Results: The nonsynonymous mutations of STK11/LKB1 gene were found in three of the six SGC cell lines. Nonsense mutation of STK11/LKB1, which was associated with STK11/LKB1 loss (Y253*), was found in OCUM-12 cells, and missense mutation of STK11/LKB1 (F354L) was found in OCUM-2M cells and OCUM-14 cells. Rapamycin, an inhibitor of STK11/ AMP-activated protein kinase (AMPK)/mammalian target of rapamycin signaling (mTOR), showed inhibitory effects of SGC cells harboring STK11/LKB1 mutation. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth, and nodal involvement, in compared to the high STK11/LKB1 expression group. The 5-year survival rate of patients with low STK11/LKB1 expression was significantly poorer compared to those with high STK11/LKB1 expression (p&amp;lt;0.001). A conditional multivariate analysis showed that STK11/LKB1 expression status was an independent prognostic factor. Conclusion: SGC cells frequently showed the nonsynonymous mutations of STK11/LKB1. STK11/LKB1 mutation might be responsible for the malignant potential of SGC. STK11/AMPK/mTOR signaling might be one of the therapeutic targets for patients with SGC.1 Citation Format: Sadaaki Nishimura, Masakazu Yashiro, Tomohiro Sera, Yurie Yamamoto, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Kenji Kuroda, Tomohisa Okuno, Masaichi Ohira. Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells [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 1217A.
Abstract 4563: Immunoprevention of triple negative breast cancer by a multi-antigen, multi-peptide vaccine
Authors: Yian Wang
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is the most aggressive sub-type of breast cancer, comprising approximately 20% of all breast cancers, and has a poor prognosis due to its aggressive behavior and lack of effective targeted therapies. In the present study, we employed transcriptome and protein analyses to select genes that are uniquely overexpressed in human triple-negative breast cancer. Overexpression of selected genes, Cyclin A2, CDK1, Cyclin E2, PRC1, Kif15, TPX2, Ki67, Top2A, were confirmed on human breast cancer tissue microarrays and in TNBC derived cell lines from C3(1)/TAg mice. Antigen-specific MHC class II epitopes with promiscuous high-binding affinity were identified using the “combined scoring system”, based on their potential to elicit a selective Th1 immunity. Furthermore, all peptides were selected to have over 85% amino acid sequence homology between human and mice for potential clinical translation. Strong immunogenic peptides from five antigens were selected by immunogenicity testing in tumor naïve mice based on high IFN-γ and low IL-10 ELISpot response data. The selected peptides, Cyclin A2 (#335), CDK1 (#113), Cyclin E2 (#93, 298, 334), KIF15 (#129), and Top2A (#236, 410, 606), were combined to form a multi-antigen, multi-peptide vaccine (MAMPV). The tumor preventive efficacy of the MAMPV was evaluated in syngraft study using a TNBC model: C3(1)/TAg-REAR mice and a TNBC cell line derived from C3(1)/TAg (M6). MAMPV-vaccinated animals demonstrated a significant reduction in tumor volume, and significantly higher tumor infiltration of CD4+ T cells compared to the control animals. Pathological examination of major organs did not reveal any toxicity associated with the vaccine. Similar tumor preventive efficacy was demonstrated in genetically engineered mouse model (GEMM) using C3(1)/TAg mice. Taken together, our data indicate that formulation of the multi-antigen multi-peptide vaccine is highly immunogenic and has the potential to be safe and efficacious in the immunoprevention of TNBC. Citation Format: Yian Wang. Immunoprevention of triple negative breast cancer by a multi-antigen, multi-peptide vaccine [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 4563.
Abstract 2813: Tumor models driven by EGFR: Optimizing the preclinical profiling of EGFR-targeting agents
Authors: Markus Posch, Hagen Klett, Anne-Lise Peille, Gerhard Kelter, Armin Maier, Julia Schüler, Thomas M. Metz
Journal: Cancer Research (2020)

Abstract The epidermal growth factor receptor (EGFR, HER1, ERBB1) is a driver of many human cancers. Standard of care treatment for colon, head and neck and non-small cell lung cancer includes drugs targeting EGFR. Numerous molecular alterations activating the oncogenic potential of the EGFR gene have been described including activating point mutations, point mutations causing resistance against EGFR-targeting drugs, activating deletions and truncations as well as overexpression of EGFR and its ligands, occasionally induced by gene amplification. In other situations, EGFR has been identified as a driver in the absence of any obvious molecular alterations of the EGFR gene. The discovery and development of EGFR-targeting agents depends on the availability of relevant tumor models. We provide an overview of our collection of EGFR-driven tumor models, including PDXs along with PDX-derived cell lines and human tumor cell lines. We compare sensitivity profiles of tumor models for EGFR-targeting agents obtained in vivo and in vitro and demonstrate that for EGFR-targeting agents, data obtained in 2D and 3D assays are predictive for the in vivo situation. We propose an optimized strategy for the preclinical profiling of EGFR-targeting anti-cancer agents. Citation Format: Markus Posch, Hagen Klett, Anne-Lise Peille, Gerhard Kelter, Armin Maier, Julia Schüler, Thomas M. Metz. Tumor models driven by EGFR: Optimizing the preclinical profiling of EGFR-targeting agents [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 2813.
CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
Authors: Guangchuan Wang, Ryan D. Chow, Lvyun Zhu, Zhigang Bai, Lupeng Ye, Feifei Zhang, Paul A. Renauer, Matthew B. Dong, Xiaoyun Dai, Xiaoya Zhang, Yaying Du, Yujing Cheng, Leilei Niu, Zhiyuan Chu, Kristin Kim, Cun Liao, Paul Clark, Youssef Errami, Sidi Chen
Journal: Cancer Discovery (2020)

Abstract Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. KMT2D encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, Kmt2d-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that Kmt2d deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, and also highlight the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment. Significance: ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making. This article is highlighted in the In This Issue feature, p. 1775
Abstract 93: AMPK alpha1 and AMPK alpha 2 control TNBC proliferation through cell cycle regulation
Authors: Jeremy Johnson, Piotr Richahou, B. Mark Evers
Journal: Cancer Research (2020)

Abstract Introduction. Triple negative breast cancer (TNBC) is very aggressive, has a higher metastatic rate than other breast cancer subtypes, and lacks traditional targetable factors. AMPK-activated protein kinase (AMPK) is an important energy regulator within the cell that also impacts cancer progression. AMPK's catalytic subunit is composed of α1 and α2 isoforms, but little is known about their individual roles in TNBC. The purpose of this study was to establish the specific function of each isoform in TNBC with respect to expression, cell proliferation, cell cycle progression, and metabolism. Methods. (i) Immunohistochemistry, immunofluorescence, and immunoblotting were used to determine the expression and localization of AMPKα1 and AMPKα2 in TNBC PDX samples or cell lines. (ii) To study the role of each isoform individually, TNBC cells were transfected with siRNA to NTC, AMPKα1, or AMPKα2 (50 nM) and were either harvested for immunoblotting or subseeded for cell cycle analysis, proliferation assays, or Seahorse analysis. Results. (i) AMPKα1 expression was localized in the cytoplasm of all 9 TNBC PDX cell lines, whereas AMPKα2 was expressed predominantly in the nucleus in 6 of the 9 of TNBC samples. IF analysis of MDA-MB-231 cells confirmed expression findings in the PDX cell lines with AMPKα1 expression noted in the cytoplasm and AMPKα2 expression in both the cytoplasm and nucleus. (ii) siRNA knockdown of AMPKα1 or AMPKα2 induced G1 cell cycle arrest and decreased proliferation of MDA-MB-231 cells. Moreover, knockdown of AMPKα1 decreased levels of cyclin D1 in MDA-MB-231, MDA-MB-468, and BT-20 cells. siRNA knockdown of AMPKα1, but not AMPKα2, led to decreased basal and compensatory glycolysis in MDA-MB-231 cells. Conclusions. Our findings indicate that both AMPKα1 and AMPKα2 can impact cell cycle progression and proliferation in TNBC; both isoforms promote progression through the cell cycle, thus supporting the proliferative capacity of TNBC. Importantly, AMPKα1 may also affect TNBC proliferation by increasing energy availability through glycolysis. Citation Format: Jeremy Johnson, Piotr Richahou, B. Mark Evers. AMPK alpha1 and AMPK alpha 2 control TNBC proliferation through cell cycle regulation [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 93.
Abstract 3822: Genome-wide CRISPR library screen to identify synthetic lethal targets of a WEE1 degrader
Authors: Yangbo Yue, Hexiu Su
Journal: Cancer Research (2020)

Abstract Background: WEE1 kinase is a G2/M cell cycle checkpoint protein, activated to allow DNA repair prior to cell entry to mitosis. WEE1 kinase inhibitors have witnessed encouraging early clinical results in combination with chemotherapy and radiotherapy. We previously identified a small molecule WEE1 degrader and showed selective growth inhibition in pancreatic cancer cell lines. To further study the functional mechanism of this compound and to investigate the combinational inhibition of WEE1 degradation, we performed genome-wide CRISPR library screening in pancreatic cancer cell lines harboring either wildtype K-RAS or mutant K-RAS. The identified synthetic lethal targets may lead to tractable therapeutic opportunities in combination with this compound. Method: We conducted CRISPR screening in MIA-PaCa2 and PANC1 cell lines, harboring mutant and wild type K-RAS, respectively, with genome-wide Brunello library (2 vector system) in the presence or absence of the WEE1 degrader for 2 weeks. After harvesting the cells for deep sequencing, we analyzed the top hits whose inhibition showed synergetic cytotoxic effect with the compound. Results: According to the sequencing result, the deletion of several candidate genes increased the sensitivity to the compound, indicating combinational potential with this WEE1 degrader. Further validation studies are in progress. We will discuss possible mechanisms underlying the synthetic lethality. The pipeline we have established, from experimental design to bioinformatics analysis, can be applied to investigate functional mechanism and combination strategy of any target therapeutic agents. Citation Format: Yangbo Yue, Hexiu Su. Genome-wide CRISPR library screen to identify synthetic lethal targets of a WEE1 degrader [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 3822.
Abstract 620: The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock
Authors: Laura Lucia Trebucq, Goergina A. Cardama, Pablo Lorenzano Menna, Diego A. Golombek, Juan J. Chiesa, Luciano Marpegan
Journal: Cancer Research (2020)

Abstract Glioblastomas (GBM) account for almost half of the malignant central nervous system tumors and have the highest mortality rates with only about 5% of the adult patients surviving 5 years after diagnosis. Current therapy for GBM is generally very aggressive, combining chemotherapy, radiotherapy, and surgical removal and increased the life expectancy only from 11 to 14 months, but, almost no significant advances were made in the last decades. Taking this into account, more effective compounds and new strategies, such as chronotherapeutic ones, need to be developed. The novel drug 1A-116 specifically blocks the interaction of the Rho GTPase Rac1 with some of its activators (GEFs proteins, such as Tiam1) inhibiting cell motility and proliferation of GBM. To optimize the effectiveness of 1A-116 a chronotherapeutic approach was implemented in vitro by applying the drug at different circadian times to synchronized LN-229 human GBM cells. Cell cultures displayed a functional circadian clock measured by Bmal1-luc activity and BMAL1 protein expression. Expression of Tiam1 was also assessed, finding circadian expression rhythms. The effects of 1A-116 on either cell proliferation, motility and toxicity, were dependent on the circadian cellular clock. The preliminary in vivo studies consisted on treating nude mice with 1A or control at ZT3 or 12. We found that the median survival of the mice treated at ZT3 was 82 days and at ZT12 was 78 days. These results suggest that a chronopharmacological approach based on the drug 1A-116 is a feasible strategy to improve GBM treatment outcomes. Citation Format: Laura Lucia Trebucq, Goergina A. Cardama, Pablo Lorenzano Menna, Diego A. Golombek, Juan J. Chiesa, Luciano Marpegan. The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock [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 620.
RAPID RECOMMENDATIONS Low intensity pulsed ultrasound (LIPUS) for bone healing: a clinical practice guideline
Authors: R.W. Poolman, T. Agoritsas, R.A.C. Siemieniuk, I.A. Harris, I.B. Schipper, B. Mollon, M. Smith, A. Albin, S. Nador, W. Sasges, S. Schandelmaier, L. Lytvyn, T. Kuijpers, L.W.A.H. van Beers, M.H.J. Verhofstad, P.O. Vandvik
Journal: BMJ (2017)