tbuckley/cabot-search huggingface dataset:
Abstract 2351: Genomics annotation and interpretation in somatic oncology using structured data from a clinical knowledgebase
Authors: Jian Li, Lili Niu, Shuba krishna, Fnu Kinshuk, Martin Jones, Carlos Hernandez, Michael Clark, Sandra Balladares
Journal: Cancer Research (2024)

Abstract Accurate and comprehensive interpretation of genomic variants has become a bottleneck in clinical sequencing applications due to the accelerating precision oncology and biomedical information explosion. This motivated us to build Ephesus, a framework enabling curation of predictive, prognostic and diagnostic evidence for clinical biomarkers in cancers. Currently Ephesus is the primary content source for Roche navify Mutation Profiler (nMP). The Ephesus’ data model ensures adherence to best practices in clinical genomic content curation. Variant classification follows the AMP guidelines for somatic variant interpretation. Variant interpretations are derived from international regulatory approvals and clinical practice guidelines (FDA, EMA, TGA, eVIQ, etc.) and recommendations (NCCN, ESMO). The data model is mapped to a set of relational tables. To enforce data integrity and validity, strategies such as data normalization based on standard nomenclatural ontologies, a submit-review-approval workflow, and biological constraints are adopted. Ephesus is deployed as a web application used by curators inside and outside Roche. The UI allows users to conduct edits, filtering, sorting and bulk operations on entities by attributes. In order to minimize manual effort and maximize content coverage, inference rules are applied before ingesting into nMP. Currently Ephesus is developed for data collection, browsing and summarizing primary entities such as biomarkers, evidence items, genes, variants, variant groups, and drugs. The content from the 2023-Aug snapshot contains 11,596 directly curated biomarker profiles (including biomarker combinations), and 6M+ expanded profiles for 41 major cancer types. To evaluate the clinical reporting value of the curated knowledge, ~160k real cancer patient samples of the AACR GENIE project were queried on Ephesus. Compared with three other major knowledgebases, Ephesus/NMP is observed showing the highest performance. Table 1. Percentage of patients or biomarkers with at least one interpretation from each knowledgebase CGI (2022-10-17) CIVIC(2023-09-01) ClinVar(2023-09-09) NMP(2023-08-11) AACR-Genie-v14.0 Total patient % with any interpretation 25% (40,545) 46% (73,835) 81% (130,882) 89% (142,905) 160,965 biomarker % (including combos) with any interpretation 0.03% (256) 0.06% (526) 13.26% (122,424) 73.79% (681,128) 923,093 Citation Format: Jian Li, Lili Niu, Shuba krishna, Fnu Kinshuk, Martin Jones, Carlos Hernandez, Michael Clark, Sandra Balladares. Genomics annotation and interpretation in somatic oncology using structured data from a clinical knowledgebase [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 2351.
Abstract 2044: A live cell PRMT5 NanoBRET Target Engagement Assay querying competitive and uncompetitive modes of inhibition
Authors: Ani Michaud, Elisabeth Rothweiler, Cesear Corona, Michael Beck, Jennifer Wilkinson, James Vasta, Kilian Huber, Matthew Robers
Journal: Cancer Research (2024)

Abstract PRMT5 is an essential arginine methyltransferase that regulates a wide spectrum of cellular processes through the methylation of histone and non-histone substrates. In PRMT5 catalysis, SAM serves as the cofactor and methyl group donor, generating a methylated guanidinium moiety on the target substrate. In normal cells, the SAM pools are maintained through the methionine salvage pathway. In 15% of cancers, a key enzyme in this pathway (MTAP) is deleted, leading to an accumulation of the intermediate MTA, which inhibits PRMT5 activity. This genetic loss of function has therefore been pursued as a collateral vulnerability in MTAP deleted cancers. To exploit this synthetic lethality, a number of novel inhibitors have been developed that bind cooperatively at the PRMT5/MTA complex, offering a compelling pathway to precision medicine. Here we describe a novel, live cell NanoBRET Target Engagement assay that enables mechanistic studies on a variety of PRMT5 inhibitors. Using a cell-permeable NanoBRET probe directed to the substrate pocket of PRMT5, both substrate- and cofactor-competitive engagement can be quantified in cells. Moreover, this method can be used to quantify MTA-uncompetitive target engagement in cells, providing a platform to measure the potency of PRMT5-MTA-drug ternary complex formation. This method serves as a first-in-class method to quantify uncompetitive target engagement in live cells, which can be applied to other model systems. Citation Format: Ani Michaud, Elisabeth Rothweiler, Cesear Corona, Michael Beck, Jennifer Wilkinson, James Vasta, Kilian Huber, Matthew Robers. A live cell PRMT5 NanoBRET Target Engagement Assay querying competitive and uncompetitive modes of inhibition [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 2044.
Abstract 204: Quantitative evaluation of biomarkers for TGF-β-induced epithelial-mesenchymal transition in biochemical, cellular, and 3D spheroid model systems
Authors: Antony W. Wood, Ernest Heimsath
Journal: Cancer Research (2024)

Abstract Epithelial-mesenchymal transition (EMT) is a cellular differentiation process whereby epithelial cells lose epithelial features and acquire mesenchymal, fibroblast-like properties, leading to reduced cell-cell contacts and increased motility. EMT is a fundamental biological process required for normal embryonic development, but may be co-opted by malignant epithelial tumors to facilitate metastatic spread. A known driver of EMT is the TGF-β superfamily of growth factor ligands, which elicit receptor-mediated responses in cells, primarily via TGF-β/SMAD signaling pathways. In these pathways, receptor-mediated SMAD (R-SMAD) proteins serve as the primary downstream effector molecules, the activities of which are regulated through receptor-mediated phosphorylation. The magnitude and duration of ligand-induced receptor activation influences the level of SMAD phosphorylation, which in turn influences the magnitude of the downstream cellular response(s). In this study, we describe high-throughput methods to quantitatively evaluate the biochemical and cellular responses to TGF-β/SMAD pathway activation in a cellular model of TGF-β-induced EMT. Effects of pathway activation are examined at different levels of biological complexity (biochemical, cellular, and multicellular), using 2D and 3D (spheroid) models. Collectively, these approaches enable a comprehensive evaluation of TGF-β/SMAD pathway activation that is amenable to high-throughput analysis platforms. Citation Format: Antony W. Wood, Ernest Heimsath. Quantitative evaluation of biomarkers for TGF-β-induced epithelial-mesenchymal transition in biochemical, cellular, and 3D spheroid model systems [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 204.
Abstract 2036: Characterizing PARP inhibitor and next-generation anti-androgen therapy responses in advanced prostate cancer
Authors: Love A. Moore, Bryan Correa Gonzalez, Allen C. Gao, Alan P. Lombard
Journal: Cancer Research (2024)

Abstract PARP inhibitors (PARPi) have been shown to be effective in prostate cancer patients with certain DNA repair defects, thus ushering in the era of precision medicine for this disease. Despite this advance, barriers remain which impede further progress including an incomplete understanding of therapeutic response. Our previous and on-going work shows that PARP inhibition leads to both cell death and a more cytostatic, senescence-like arrest. We hypothesize that persistent cells may later promote progression and treatment resistance. Recent clinical trials such as PROpel and TALAPRO-2 have demonstrated success in combining PARPi’s with next-generation anti-androgen therapies (NGAT) including abiraterone and enzalutamide. Whether NGAT’s are synthetic lethal and cell death promoting with PARP inhibition is poorly understood. Additionally, given the evolving clinical landscape for prostate cancer, it is important to test whether prior NGAT exposure may preclude response to combination therapy. In this study, we sought to characterize these combinations to better understand tumor cell response to treatment and the placement of treatment within the overall therapeutic paradigm. We’ve previously used the C4-2B metastatic castration-resistant prostate cancer cell line as a model which responds well to PARP inhibition. Here, we additionally utilize the C4-2B-derived enzalutamide and abiraterone resistant lines MDVR and AbiR, respectively. The combination of olaparib with abiraterone (recently approved from results of PROpel) was significantly more efficacious than either monotherapy in all three models. Additionally, combination of talazoparib and enzalutamide (approved from results of TALAPRO-2) was also more effective than monotherapy. These data suggest that prior development of NGAT resistance does not prevent benefit from NGAT and PARPi combinations. Although both combinations were found to cause significantly less cell growth, cells appeared more cytostatic rather than apoptotic, suggesting NGAT’s do not induce significant synthetic lethality with PARPi’s. Our work suggests that combining a PARPi with an NGAT promotes a persistent cytostasis which may give rise to eventual tumor progression and the development of resistance. Future studies are directed at further characterizing combinations with PARPi’s and the development of novel strategies to enhance their efficacy. Citation Format: Love A. Moore, Bryan Correa Gonzalez, Allen C. Gao, Alan P. Lombard. Characterizing PARP inhibitor and next-generation anti-androgen therapy responses in advanced prostate 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 2036.
Abstract 3288: Identification of Annexin A1 as a novel driver of lenvatinib resistance in hepatocellular carcinoma
Authors: Catherine Yujia GU, Carmen Oi Ning LEUNG, Terence Kin Wah LEE
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Lenvatinib has recently been approved by the FDA for front-line treatment of HCC patients at advanced stages. However, the survival benefit of lenvatinib is modest due to the development of acquired drug resistance. In this study, we aimed to investigate the mechanisms underlying lenvatinib resistance in HCC and to identify potential therapeutic targets to combat lenvatinib resistance. For this purpose, we established a lenvatinib-resistant (LenR) HCC patient-derived tumor xenograft (PDTX) by administering four rounds of lenvatinib treatment, and their genetic profiles were analyzed using single-cell RNA sequencing (scRNA-seq). Based on single-cell regulatory network inference and clustering (SCENIC) analysis, Annexin A1 (ANXA1), the top gene that was enriched in the HCC cell-like cluster of LenR tumors, was identified and was consistently observed in LenR HCC cell lines and LenR tumors derived from Tp53KO/C-MycOE and RIL175 HCC mouse models. Using an in vitro differentiation model, limiting dilution assay, apoptosis assay and correlation analysis, we demonstrated the role of ANXA1 in the regulation of cancer stemness-driven lenvatinib resistance. Mechanistically, ANXA1 regulates cancer stemness and drug resistance by driving the STAT3/S100A6 signaling cascade, and ANXA1 expression is regulated by SOX2 via promoter activation, as demonstrated by a chromatin immunoprecipitation (ChIP) assay. Using the same set of scRNA-seq data, we showed that LenR HCC tumors reshaped the tumor microenvironment (TME) by inducing M2 macrophage polarization, as evidenced by a higher M2/M1 ratio of tumor-associated macrophages (TAM) in LenR HCC tumors than in their mock counterparts. Based on this observation, we further demonstrated the in vitro role of secretory ANXA1 in LenR HCC cells in inducing macrophage polarization towards the M2 phenotype. In conclusion, ANXA1 may regulate lenvatinib resistance intrinsically via the promotion of cancer stemness and extrinsically via the induction of an immunosuppressive TME. Citation Format: Catherine Yujia GU, Carmen Oi Ning LEUNG, Terence Kin Wah LEE. Identification of Annexin A1 as a novel driver of lenvatinib resistance in hepatocellular carcinoma [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 3288.
Abstract 2371: BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and &amp;lt; for vivo antitumor activity and &amp;lt; for superior safety profile in preclinical models
Authors: Zhuo Li, Liang Qu, Xin Chen, Liu Xue, Jie Li, Qi Liu, Jian Sun, Hanzi Sun, Yun Chen, Yuanyuan Xie, Wanyi Wang, Lin Zhu, Penghao Wang, Xiaosui Zhou, Hongjia Hou, Jie Chen, Xinyi Liu, Yilu Zhang, Ning Liu, Xinyi Liang, Shuo Zhang, Xiaoyan Tang, Jing Song, Tong Zhang, Xiaomin Song, Xuesong Liu, Kang Li, Chichi Huang
Journal: Cancer Research (2024)

Abstract 4-1BB (CD137) is a key costimulatory immunoreceptor and a promising therapeutic target in cancer. CEACAM5 (CEA) is a well-established tumor associated antigen overexpressed in many cancers, including colorectal, gastric, lung, pancreatic cancer, liver, breast and thyroid cancers. BGB-B167 is a novel immunoglobulin G (IgG)-based bispecific antibody targeting 4-1BB and CEA and is under clinical development for the treatment of advanced or metastatic solid tumors in humans. BGB-B167 binds to its target proteins with high specificity and affinity. Potent and CEA-dependent functional activities were demonstrated using peripheral blood mononuclear cell (PBMC)-based immune cell activation and cytotoxicity assays. In humanized 4-1BB knock-in mice bearing human CEA-expressing tumors, BGB-B167 exhibited potent, dose-associated single-agent efficacy as well as synergistic antitumor activity in combination with anti-PD-1 antibody. BGB-B167 was well tolerated in 1-month repeat-dose toxicology study in cynomolgus monkeys. Here, we describe the characterization of BGB-B167 with regard to preclinical proof-of-concept and basic drug-like properties. The combined dataset provides an overview on the design, mode of action, preclinical pharmacology and safety profile of BGB-B167. Citation Format: Zhuo Li, Liang Qu, Xin Chen, Liu Xue, Jie Li, Qi Liu, Jian Sun, Hanzi Sun, Yun Chen, Yuanyuan Xie, Wanyi Wang, Lin Zhu, Penghao Wang, Xiaosui Zhou, Hongjia Hou, Jie Chen, Xinyi Liu, Yilu Zhang, Ning Liu, Xinyi Liang, Shuo Zhang, Xiaoyan Tang, Jing Song, Tong Zhang, Xiaomin Song, Xuesong Liu, Kang Li, Chichi Huang. BGB-B167, a first-in-class 4-1BB/CEACAM5 bispecific antibody, exhibits potent in vitro and &amp;lt; for vivo antitumor activity and &amp;lt; for superior safety profile in preclinical models [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 2371.
Abstract 5155: CD8+ T cells and CD4+central memory T cells as biomarkers of perioperative anti-PD-1 therapy in combination with concurrent chemoradiotherapy for locally advanced G/GEJ adenocarcinoma
Authors: Yue Wang, Yawei Chen, Ju Yang, Xiaoyu Zhou, Yutao Wei, Qin Liu, Yang Yang, Wenxian Guan, Baorui Liu, Jia Wei
Journal: Cancer Research (2024)

Abstract Background: Gastric or gastroesophageal junction (G/GEJ) adenocarcinoma is one of the most common lethal malignancies in the world. Near half of the G/GEJ adenocarcinoma are locally advanced at diagnosis and with poor prognosis. Several clinical trials including SHARED (ChiCTR1900024428), which conducted in our center, demonstrated that perioperative anti-PD-1 therapy in combination with concurrent chemoradiotherapy for locally advanced G/GEJ cancers, could raise the pCR rate over 30%. However, the biomarkers for patients with pCR are nor clear. Methods: Baseline tumor biopsies and post-treatment surgical tissues were collected for next-generation sequencing (NGS) and mass cytometry (CyTOF). The overall survival (OS) was measured from the date of surgery to the date of death or the last follow-up visit. Results: 34 patients with locally advanced G/GEJ cancer received anti-PD-1 therapy (Sintilimab) in combination with concurrent chemoradiotherapy in our center. Our results met the pre-specified primary endpoint, with a pCR rate of 38.2% (13/34) and median DFS of 17.0 months. Tumor mutation burden (TMB) analyzed by NGS was higher in the pCR group than those not achieving pCR (non-pCR). Deletion of cytoband 7q35, where TPK1 locates, was significantly enriched in pCR groups. The RNA sequencing data revealed an enrichment of dendritic cells (DC), CD8+ T cells and cytotoxic cell signatures in the pCR group. Conversely, the signature for CD4+ central memory T cells (TCM) was observed to be lower in the pCR group. On the other hand, CyTOF data also demonstrated that the proportion of CD8+ T cells, CD8+ effector memory T cells (TEM) were both higher in pCR group at baseline, while CD4+ TCM was lower. Moreover, the proportion of specific subtype characterized by CD127+CD27+CD45RO+CXCR5-CD4+ TCM was significantly lower in pCR patients and significantly reduced after treatment. As continuous variable, only CD8+ T cells correlated with OS. Conclusions: It seemed that CD8+ T cells and CD4+ TCM cells could be predictive biomarkers of perioperative anti-PD-1 therapy in combination with cCRT for locally advanced G/GEJ. Furthermore, we found a new CD4+ TCM subtype defined with CD127+CD27+CD45RO+CXCR5- could be novel biomarkers. Citation Format: Yue Wang, Yawei Chen, Ju Yang, Xiaoyu Zhou, Yutao Wei, Qin Liu, Yang Yang, Wenxian Guan, Baorui Liu, Jia Wei. CD8+ T cells and CD4+central memory T cells as biomarkers of perioperative anti-PD-1 therapy in combination with concurrent chemoradiotherapy for locally advanced G/GEJ adenocarcinoma [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 5155.
Abstract 467: Genetic ablation of microRNA-10b improves treatment outcomes in mouse models of pancreatic cancer
Authors: Katarzyna Kempinska, Sudhakar Samuel, Saiprashanth Rajesh, Christiane Mallett, Lorenzo Sempere
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant and lethal disease with an overall 5-year survival rate of less than 12%. PDAC is a heterogeneous disease characterized by highly aggressive cancer cells, extensive desmoplastic reaction, and hypovascularity. These unique features endow PDAC tumors with an array of innate resistance mechanisms against standard-of-care (SOC) chemotherapy: gemcitabine/nab-paclitaxel or FOLFIRINOX. Thus, there is clinical need to develop novel targets that enhance treatment efficacy of SOC chemotherapy. microRNA-10b (miR-10b) expression is frequently upregulated in PDAC and correlates with poor outcome. High levels of miR-10b expression within cancer cells correlates with poor treatment response to gemcitabine-containing neoadjuvant chemotherapy and poor overall clinical outcome. We and others reported that miR-10b exerts cancer cell-intrinsic pro-survival, anti-apoptotic, and pro-metastatic functions via downregulation of key target genes (i.e., BIM, PTEN, TIAM1). We hypothesize that upregulation of miR-10b expression is a chemoresistance mechanism to increase cell survival and inhibit apoptosis in PDAC. To test this hypothesis, we generated a KPC model (KrasG12D-driven, p53-deleted by Pdx1-Cre) with global Mir-10b gene knockout (Mir-10bKO). Animals were recruited when their tumor volume reached 200 mm3 by multi-mouse MR imaging and were randomly assigned to control or treatment groups (100 mg/kg of gemcitabine q4d). Tumor growth was monitored by weekly MR imaging sessions throughout the duration of the treatment. Untreated KPC;Mir-10bKO animals survived several weeks longer than untreated KPC animals (21.7 vs. 18 weeks, p = 0.056), suggesting a weak but detectable tumor promoting role of miR-10b. Remarkably, loss of miR-10b activity enhances treatment response to gemcitabine and significantly prolongs survival in this KPC model. Treated KPC animals lived only 5 weeks longer than untreated KPC (23 vs 18 weeks, p = 0.015), whereas KPC;Mir-10bKO lived 9 weeks longer (27 vs 18 weeks, p = 0.002). Notably, we observed a more durable response in treated female KPC;Mir-10bKO animals (n = 4) compared to any other experimental group (n &amp;gt; 5). We are currently performing tissue and molecular analyses to identify direct target genes involved in chemoresistance and sex-specific modulation of treatment response. Citation Format: Katarzyna Kempinska, Sudhakar Samuel, Saiprashanth Rajesh, Christiane Mallett, Lorenzo Sempere. Genetic ablation of microRNA-10b improves treatment outcomes in mouse models of pancreatic 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 467.