tbuckley/cabot-search huggingface dataset:
Abstract 4742: Targeting the RNA-binding protein LARP1 overcomes therapeutic resistance in ovarian cancer
Authors: Abdelrahman M. Elsayed, Paola Amero, Emine Bayraktar, Anil K. Sood, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo
Journal: Cancer Research (2024)

Abstract La-related protein 1 (LARP1) is an RNA-binding protein that plays a pivotal role in regulating mRNA on a post-transcriptional level. Overexpression of LARP1 has been detected in multiple cancers substantiating the critical role of LARP1 as a driver for cancer progression. This study aims to investigate the downstream target pathways regulated by LARP1 and to determine the impact of LARP1 targeting on the resistance to cisplatin and olaparib therapy in ovarian cancer (OC). Analysis of The Cancer Genome Atlas OC dataset, reverse phase protein array, in vitro functional and mechanistic experiments, and a xenograft OC mouse model using OVCAR8 cell line were executed. Our results revealed that overexpression of LARP1 is negatively correlated with progression-free survival in OC patients. Furthermore, LARP1 knockdown using two independent small interfering RNAs (siRNAs) suppressed cell growth, invasion, and migration, and ameliorated cisplatin resistance in vitro. Mechanistic analyses identified AXL as a target of LARP1 and this finding was further supported clinically in which co-overexpression of LARP1 and AXL is associated with poor prognosis in OC. Furthermore, LARP1 knockdown resulted in reduced phosphorylation of mTOR, AKT, and SRC with no significant effect on FAK. In vivo, administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoparticles loaded with LARP1-siRNA suppressed tumor growth and improved the response to cisplatin and olaparib in a xenograft OC mouse model. In conclusion, LARP1 acts as an oncogenic RNA-binding protein in OC, and targeting LARP1 may represent an innovative therapeutic approach for ameliorating resistance to chemotherapy and targeted therapy in OC. Keywords: RNA-binding proteins; cisplatin resistance; olaparib resistance; chemotherapy resistance; LARP1; ovarian cancer. Citation Format: Abdelrahman M. Elsayed, Paola Amero, Emine Bayraktar, Anil K. Sood, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo. Targeting the RNA-binding protein LARP1 overcomes therapeutic resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4742.
Abstract 3950: Dedifferentiation unveils origin of Ewing sarcoma
Authors: Utkarsh Kapoor, Christoph Hafemeister, Lisa Shaw, Karin Muelbacher, Julia Moldaschl, Dominik Egger, Stefan Toegel, Cornelia Kasper, Matthias Farlik, Florian Halbritter, Heinrich Kovar
Journal: Cancer Research (2024)

Abstract Ewing sarcoma (ES) is an aggressive pediatric bone tumor in adolescents primarily driven by the expression of the fusion oncogene EWS::FLI1. Although the etiology of ES remains controversial, human mesenchymal stem cells (hMSCs) are considered to be the likely cell of origin. This is not only due to their ability to tolerate ectopic EWS::FLI1 expression, but also because the transcriptome of EWS::FLI1 expressing hMSCs is highly similar to that of primary Ewing tumors. However, to date a cellular differentiation-based model of ES does not exist. With the intent to understand ES histogenesis, this study aims to establish the first comprehensive single-cell differentiation atlas (both transcriptome and epigenome) of juvenile bone marrow-derived hMSCs with and without EWS::FLI1 expression. We sought to study the consequences of inducing the EWS::FLI1 oncogene expression at various time points of hMSC differentiation into adipo-, chondro-, osteo- and neuro-genic lineages. Our workflow utilizes physiology-mimicking conditions including serum-free differentiation, hypoxia, and growth/differentiation as spheroids. We pooled bone marrow-derived hMSCs isolated from eleven healthy juvenile donors, engineered them to conditionally express EWS::FLI1, and carried out multi-lineage differentiation for 10 days where EWS::FLI1 was induced daily for 24h or 72h. This temporally resolved atlas of 105 samples representing normal and perturbed differentiation allowed us to map ES patient tumor data to multiple lineages and time-points across stages of lineage commitment. Single-cell RNA-seq analysis of ~271,000 transcriptomes revealed an apparent and dynamic dedifferentiation in the presence of EWS::FLI1 across all four lineages. Preliminary analysis of genes detected in the EWS::FLI1 high cluster uncovers a specific lineage preference and time window that shares the transcriptomic signature with tumor cells, indicating the potential cell/stage of tumor-origin. Our results provide new insight into the enigmatic cell of origin of Ewing sarcoma, laying the foundation for the development of much-needed pre-clinical models for tailoring therapies. This study is supported by a generous grant (#20) of the Alex’s Lemonade Stand Foundation (ALSF) Crazy8 Program. Citation Format: Utkarsh Kapoor, Christoph Hafemeister, Lisa Shaw, Karin Muelbacher, Julia Moldaschl, Dominik Egger, Stefan Toegel, Cornelia Kasper, Matthias Farlik, Florian Halbritter, Heinrich Kovar. Dedifferentiation unveils origin of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3950.
Abstract 1809: Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs
Authors: Hsing-Pang Hsieh, Mu-Chun Li, Wan-Ching Yen, Su-Ying Wu, Teng-Kuang Yeh, Ching-Chuan Kuo, Shau-Hua Ueng, Han-Chung Wu
Journal: Cancer Research (2024)

Abstract In cancer progression, abnormal AXL expression can promote tumor growth, metastasis, and chemotherapy resistance, while MER can identify apoptotic cancer cells and induce immune suppression in the tumor microenvironment. Combining AXL and MER inhibitors could generate a synergistic effect, enhancing antitumor responses, and further suppressing resistance formed by monotherapy with AXL selective or MER selective inhibitors. According to the explicit function of AXL and MER, the development of dual AXL and MER inhibitors may provide tremendous advantages to cancer patients. Drawing on our experience in the discovery of an anti-EGFR and anti-HER2 clinical candidate, we introduced several AXL-active and MER-active pharmacophores into DBPR112. Furthermore, we modified the scaffold and the solubilizing groups to improve the drug-like properties. Our comprehensive structure-activity relationship study led to the discovery of several potent dual AXL and MER inhibitors. Among approximately 200 synthesized compounds, BPR5K230 demonstrated strong inhibitory activities against AXL and MER, along with favorable oral bioavailability (F% = 55%) and promising in vivo antitumor effects in various mouse xenograft models, including MDA-MB-231, 4T1, and MC-38 tumor models. BPR5K230 effectively addressed sorafenib resistance in the Hepa 1-6 model and exhibited significant synergistic antitumor effects when combined with an anti-PD-L1 antibody in the EMT-6 model. As a result, BPR5K230 represents a promising dual AXL/MER kinase inhibitor, and further preclinical evaluation is underway for its development as a potential anticancer and immune-modulating drug. Citation Format: Hsing-Pang Hsieh, Mu-Chun Li, Wan-Ching Yen, Su-Ying Wu, Teng-Kuang Yeh, Ching-Chuan Kuo, Shau-Hua Ueng, Han-Chung Wu. Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1809.
Abstract 414: Accelerating DDR related drug discovery through a customized cell panel
Authors: Cong Huang, Xiaoqing Li, Zhengtai Li, Yan Tan, Huawei Pan, Lizhen Zhou, Kejun Mao, Yanyan Qin, Zhida An, Wanxiao Song, Yifan Li, Shuyu Jin, Tiejun Bing
Journal: Cancer Research (2024)

Abstract DNA damage is a major threat to cell survival. Not properly repaired DNA damage can lead to cell senescence, apoptosis or tumor development. DDR (DNA Damage Repair) is a collection of bioprocesses which cells utilize in order to identify and correct the DNA damage of the genome. The usage of various compounds for targeting DNA damage responses as well as attenuating DNA repair is also an approach for cancer therapy that has been widely studied in recent years. Despite the success of drug discovery of DDR related inhibitor, drug resistance has become an emerging issue of the field. Here we have constructed multiple cancer cell lines which are either DDR gene, such as XRCC1 and FANCD2, knock-out or resistant to certain DDR inhibitors. Together with the corresponding parental cell lines, we have generated a DDR cell panel which covers 11 different cancer types. We have first validated those DDR inhibitor sensitive or resistant cell lines with functional cell proliferation assays. Additionally, RNAseq has been performed for all constructed resistant cell lines. In combination with a thorough bioinformatic analysis using our in-house generated algorithms, we can provide the genetic background information of the resistant cell lines and top features that potentially contribute to the resistance mechanism. The representative data in this study has shown that LINC02709, BDKRB1, and PRKCQ are the top featured genes in A375 Vemurafenib resistant cell. Meanwhile, cell cycle, ECM-receptor interaction, and DNA replication are the most enriched KEGG terms. Lastly, we have validated this cell panel against multiple inhibitors targeting different DDR vital proteins such as ATM, PARP, POLQ etc. The result has shown that our unique DDR cell panel is capable of providing fast and comprehensive evaluation of DDR related inhibitors, thus facilitate faster and more efficient discovery of DDR inhibitors in the cancer therapy field. Citation Format: Cong Huang, Xiaoqing Li, Zhengtai Li, Yan Tan, Huawei Pan, Lizhen Zhou, Kejun Mao, Yanyan Qin, Zhida An, Wanxiao Song, Yifan Li, Shuyu Jin, Tiejun Bing. Accelerating DDR related drug discovery through a customized cell panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 414.
Abstract 5271: Pseudohypoxia by HIF-PHD inhibitors activates tumor immune response for MSS colorectal cancer
Authors: Toshiaki Ohara, Yuehua Chen, Yusuke Hamada, Seitaro Nishimura, Hotaka Kawai, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara, Akihiro Matsukawa
Journal: Cancer Research (2024)

Abstract Purpose: Microsatellite-stable (MSS) colorectal cancer is resistant for immune therapy, necessitating the exploration of novel modalities for its conquest. Recent revelations have revealed the genetic upregulation of HIF-1α as a potential activator of CD8+ T-cells, enhancing an anti-tumor effect. Pseudohypoxia, characterized by normoxic upregulation of Hypoxia-Inducible Factor (HIF-1α), is known to be induced by iron chelators, including HIF-PHD inhibitors. In this study, we aimed to examine whether pseudohypoxia by HIF-PHD inhibitor can enhance immune response and elucidate the underlying mechanism. Method: Colon 26, SW480 and HT29 were used as murine and human MSS colorectal cancer model. Human and murine CD8+ T-cells were represented by Jurkat cells and isolated splenic CD8+ T-cells, respectively. HIF-PHD inhibitors Roxadustat and Vadadustat were used in the study, and a subcutaneous Colon 26 tumor model was established in BALB/c WT and nude mice. Hypoxic culture conditions were maintained for 48 hours at 2% O2. Results: Roxadustat and Vadadustat did not suppress the proliferation of cancer cells under conditions marked by HIF-1α upregulation. Roxadustat and Vadadustat suppress the colon 26 subcutaneous tumor growth in WT mice, the effect was cancelled in the nude mice. The treatment regimen was associated with an augmentation in the total number and effector-like subtypes of CD8+ T-cells (Tex) infiltrating the tumor. Combination therapy involving Roxadustat and PD-1 antibody synergistically inhibited tumor growth and was accompanied by an increase in PD-1lo, Ly108-, TIM-3+ CD8+ T-cells within the tumor microenvironment. Immunohistochemistry revealed that Interleukin-2 (IL-2) expression of murine spleen was stronger in Roxadustat than control group. Interestingly, HIF-PHD inhibitors induced the secretion of IL-2 from isolated CD3+ T-cells of murine spleens in ELISA, a phenomenon uniquely observed under pseudo-hypoxic conditions created by HIF-PH inhibitors, rather than actual hypoxia. This result indicates that pseudo-hypoxia may induce more robust hypoxic response than real hypoxia. Conclusion: The induction of pseudohypoxia by HIF-PHD inhibitors activates the tumor immune response for MSS colorectal cancer via induction of splenic IL-2. Citation Format: Toshiaki Ohara, Yuehua Chen, Yusuke Hamada, Seitaro Nishimura, Hotaka Kawai, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara, Akihiro Matsukawa. Pseudohypoxia by HIF-PHD inhibitors activates tumor immune response for MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5271.
Abstract 7071: Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature
Authors: Konstantinos V. Floros, Jinxiu Li, Jane L. Roberts, Richard Kurupi, Carter K. Fairchild, Bin Hu, Yanli Xing, Krista M. Dalton, Sosipatros A. Boikos, Angeliki M. Stamatouli, Mikhail G. Dozmorov, Jennifer E. Koblinski, Kevin B. Jones, Senthil K. Radhakrishnan, Anthony C. Faber
Journal: Cancer Research (2024)

Abstract Synovial Sarcoma (SS) is driven by the SS18-SSX translocation event and occurs often in people under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18-SSX does not directly bind to DNA but instead alters BAF complexes away from a wild-type SS18-containing cBAF complex towards a SS18-SSX- containing ncBAF complex to drive a SS-specific transcription program. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here we demonstrate that SS18-SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, subasumstat (TAK-981). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF/PBAF complex member, SMARCE1, leading to stabilization and restoration of cBAF complexes. This phenotypic shift leads to a DNA damage and cell death response, resulting in tumor inhibition across mouse models of SS. As such, TAK-981 combined with standard-of-care chemotherapy enhances SOC-induced DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes, positioning it as a clinical candidate to treat this refractory cancer. Citation Format: Konstantinos V. Floros, Jinxiu Li, Jane L. Roberts, Richard Kurupi, Carter K. Fairchild, Bin Hu, Yanli Xing, Krista M. Dalton, Sosipatros A. Boikos, Angeliki M. Stamatouli, Mikhail G. Dozmorov, Jennifer E. Koblinski, Kevin B. Jones, Senthil K. Radhakrishnan, Anthony C. Faber. Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7071.
Abstract 571: CRISPR/Cas9 screening identifies the proteasome subunit PSMC6 as key for the survival of cisplatin-resistant ovarian carcinoma cells
Authors: Matteo Costantino, Padraig D'arcy, Luca Mirra, Cristina Corno, Giovanni L. Beretta, Johannes Gubat, Pietro Pratesi, Chiara M. Ciniselli, Paolo Verderio, Stig Linder, Paola Perego
Journal: Cancer Research (2024)

Abstract Ovarian carcinoma is a disease with poor prognosis, due to delays in diagnosis and the development of drug resistance. Since deregulation of the ubiquitin proteasome system may contribute to the development of drug resistance, the aim of this study was to investigate the interplay between expression of proteasome subunits and cisplatin resistance by utilizing a CRISPR/Cas9 dropout screen. Paired cisplatin-sensitive and -resistant cells (IGROV-1 and IGROV-1/Pt1) were transfected with Cas9 and transduced with gRNAs against proteasome components. Cells were collected at early (day 4) and late (day 21) time exposure and sequenced to identify genes necessary for survival. Various proteasome subunits were found to be essential for the survival of cisplatin-resistant ovarian carcinoma cells, including PSMA5, PSMC6, PSMD7, PSMD12 and PSMD14. Since PSMC6 knockout produced the greatest growth inhibitory effects, it was selected for functional studies utilizing conventional RNA interference. When IGROV-1 and IGROV-1/Pt1 cells were transfected with small interfering RNAs (siRNAs) targeting PSMC6, efficient down-regulation on the mRNA and protein level was observed. Phenotypic analyses of PSMC6 knockdown cells indicated reduced clonogenicity using both 2D and soft agar assays in parental and resistant cells associated with down-regulation of the canonical MAPK pathway. A slight but not significant increase in sensitivity to cisplatin was observed upon PSMC6 silencing in resistant cells using clonogenic assays. Finally, we carried out a pilot study using ovarian carcinoma specimens (n = 134) obtained through the institutional biobank. The samples were representative of the frequency occurrence of the various histological ovarian carcinoma subtypes. We found that PSMC6 expression, evaluated by qRT-PCR, was associated with tumor stage. These findings suggest that PSMC6 is linked to ovarian carcinoma aggressiveness and that PSMC6 targeting may be an interesting therapeutic strategy. Citation Format: Matteo Costantino, Padraig D'arcy, Luca Mirra, Cristina Corno, Giovanni L. Beretta, Johannes Gubat, Pietro Pratesi, Chiara M. Ciniselli, Paolo Verderio, Stig Linder, Paola Perego. CRISPR/Cas9 screening identifies the proteasome subunit PSMC6 as key for the survival of cisplatin-resistant ovarian carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 571.
Abstract 3727: Synergistic effect of CD47 blockade and EPHA3 treatment on recurrent head and neck cancers
Authors: Song Hee Kim, Myung Woul Han, Ji Won Kim, Seong Who Kim
Journal: Cancer Research (2024)

Abstract CD47 acts as a “don’t eat me “signal and suppresses it through its interaction with signal regulatory protein (SIRP-a) on the macrophage. CD47 is expressed in many human cancer cells, including head and neck cancer. Additionally, we reported in a previous study that EphA3 is overexpressed in radioresistant head and neck cancer and may play an important role in the development of radioresistance in head and neck cancer. In our present study, we demonstrated that the blockade of EPHA3 and CD47 attenuates the function of M2-like macrophages and may contribute to macrophage polarization toward the M1 phenotype. Here, we combined a therapeutic strategy of an anti-EPHA3 and an anti-CD47 antibody. Using mRNA sequencing and fluorescence imaging, we showed that the combination treatment could significantly enhance the effectiveness of anti-EPHA3 and anti-CD47 antibodies, in reactivating macrophages and reversing macrophage polarization. In addition to using flow cytometry in vivo, combination treatments can alter the proportion of tumor-associated macrophages (TAMs). Collectively, our findings suggested that the combination treatment of anti-EphA3 and the anti-CD47 antibodies could significantly improve tumor suppression, increase the proportion of M1 macrophages, and decrease the proportion of M2 macrophages. Citation Format: Song Hee Kim, Myung Woul Han, Ji Won Kim, Seong Who Kim. Synergistic effect of CD47 blockade and EPHA3 treatment on recurrent head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3727.
Characteristic SNPs defining the major multidrug-resistant Mycobacterium tuberculosis clusters identified by EuSeqMyTB to support routine surveillance, EU/EEA, 2017 to 2019
Authors: Albert J de Neeling, Elisa Tagliani, Csaba Ködmön, Marieke J van der Werf, Dick van Soolingen, Daniela Maria Cirillo, Richard M Anthony
Journal: Eurosurveillance (2024)

Background The EUSeqMyTB project, conducted in 2020, used whole genome sequencing (WGS) for surveillance of drug-resistant Mycobacterium tuberculosis in the European Union/European Economic Area (EU/EEA) and identified 56 internationally clustered multidrug-resistant (MDR) tuberculosis (TB) clones. Aim We aimed to define and establish a rapid and computationally simple screening method to identify probable members of the main cross-border MDR-TB clusters in WGS data to facilitate their identification and track their future spread. Methods We screened 34 of the larger cross-border clusters identified in the EuSeqMyTB pilot study (2017–19) for characteristic single nucleotide polymorphism (SNP) signatures that could identify and define members of each cluster. We also linked this analysis with published clusters identified in previous studies and identified more distant genetic relationships between some of the current clusters. Results A panel of 30 characteristic SNPs is presented that can be used as an initial (routine) screen for members of each cluster. For four of the clusters, no unique defining SNP could be identified; three of these are closely related (within approximately 20 SNPs) to one or more other clusters and likely represent a single established MDR-TB clade composed of multiple recent subclusters derived from the previously described ECDC0002 cluster. Conclusion The identified SNP signatures can be integrated into routine pipelines and contribute to the more effective monitoring, rapid and widespread screening for TB. This SNP panel will also support accurate communication between laboratories about previously identified internationally transmitted MDR-TB genotypes.