tbuckley/cabot-search huggingface dataset:
Abstract 5793: Functional DKK1 antibodies binding to cysteine-rich domain 1 or 2 of hDKK1 demonstrate antagonistic activities on tumor suppression or TCF/LEF signaling
Authors: Linya Wang, Zhen Han, Marisa Yang, Ana G. Lujan Hernandez, Vishwas Prabhu, Cameron F. Hu, Tammy Htoy, Mouna Villalta, Tom Z. Yuan, Hoa Giang, Aaron Sato
Journal: Cancer Research (2024)

Abstract Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects are exerted by activation of the β-catenin/TCF transcription complex and consequent regulation of a set of downstream genes. DKK1 has been shown to be a potent inhibitor of Wnt signaling via competing Wnt binding to LRP5/6. DKK1 is tumorigenic in multiple cancer types and also immunosuppressive via MDSCs and NK cells. Emerging evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. With Twist’s precision DNA writing technologies, we have created phage display libraries with diversity greater than 1 × 1010, and utilized machine learning model for optimal discovery. In this study, we discovered anti-DKK1 antibodies bind to different cysteine-rich domain (CRD) of hDKK1 by epitope binning and mapping, and block the binding of DKK1 to the receptor. Binding of the antibodies to different CRDs of hDKK1 lead to different activation effect. The in vitro functional assays showed that the interaction of Wnt to its receptor was restored in the presence of anti-DKK1 antibodies binding to DKK1 CRD2, resulting in TCF/LEF signaling upregulation. Moreover, anti-DKK1 antibodies binding to DKK1 CRD1 induced immune cell activation and led to tumor cell cytotoxicity. In vivo study indicated anti-DKK1 antibody lead is potent in tumor regression. Our anti-DKK1 lead shows promising efficacy in cancer immunotherapy without influencing Wnt canonical pathway. Citation Format: Linya Wang, Zhen Han, Marisa Yang, Ana G. Lujan Hernandez, Vishwas Prabhu, Cameron F. Hu, Tammy Htoy, Mouna Villalta, Tom Z. Yuan, Hoa Giang, Aaron Sato. Functional DKK1 antibodies binding to cysteine-rich domain 1 or 2 of hDKK1 demonstrate antagonistic activities on tumor suppression or TCF/LEF signaling [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 5793.
Abstract 5850: Multiomics analysis unravels tumor metabolic reprogramming and potential resistance mechanism(s) to curative therapy in TNBC
Authors: Zuen Ren, Kiran Kurmi, Robert Morris, Shakchhi Joshi, Eric Zaniewski, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Laura M. Spring, Wilhelm Haas, Marcia C. Haigis, Leif W. Ellisen
Journal: Cancer Research (2024)

Abstract Drug resistance is the leading cause of treatment failure to completely eliminate viable tumor cells in ~40% of patients with triple negative breast cancer (TNBC). Making a major impact on the treatment and prognosis for TNBC patients requires a better understanding of drug resistance mechanism(s). Combining clinical data with high-throughput metabolomic and proteomic analyses, we probed the molecular basis for chemotherapy resistance in treatment-naive TNBC primary tumors, reflected by pathological complete response (pCR) and non-pCR after neoadjuvant chemotherapy (NAC). Metabolic profiling uncovered that glycolysis and oxidative phosphorylation (OXPHOS) co-exist in TNBC primary tumors compared to benign lesions regardless of pCR status, indicating metabolic reprogramming. However, non-pCR tumors were more enriched in OXPHOS and less in glycolysis relative to pCR tumors, pointing to the potential importance of OXPHOS in drug resistance. Moreover, parallel proteomic profiling of these same TNBC tumors supported the results from metabolic profiling, showing that OXPHOS was indeed highly enriched at the protein level, and may be regulated by SIRT5-mediated sirtuin signaling. In alignment with these findings, non-pCR tumors were abundantly enriched in immune-inhibitory metabolites that may be due to the products of SIRT5-mediated mitochondrial metabolism. Thus, these findings led me to hypothesize that SIRT5 may play an important role in chemoresistance through regulation of mitochondrial metabolism and ROS detoxification. Together, the metabolite resulted from SIRT5-mediated mitochondrial metabolism led to the suppression of immune cell infiltration in non-pCR tumors. Understanding SIRT5-mediated chemoresistance mechanism may uncover a metabolic and therapeutic vulnerability to resistant TNBCs. Citation Format: Zuen Ren, Kiran Kurmi, Robert Morris, Shakchhi Joshi, Eric Zaniewski, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Laura M. Spring, Wilhelm Haas, Marcia C. Haigis, Leif W. Ellisen. Multiomics analysis unravels tumor metabolic reprogramming and potential resistance mechanism(s) to curative therapy in TNBC [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 5850.
Abstract 62: Intra-tumor persistence of activated anti-mesothelin hYP218 CAR T cells is associated with increased efficacy in gastric and colorectal cancers
Authors: Sameer A. Mir, Abhilash Venugopalan, Jingli Zhang, Mana Kamana Khanal, Chaido Stathopoulou, Manjistha Sengupta, Qun Jiang, Raffit Hassan
Journal: Cancer Research (2024)

Abstract Purpose: Patients with gastric and colorectal cancers that have progressed after standard therapies have poor prognosis. Given the high expression of mesothelin in these tumor types, we examined the potential utility of the anti-mesothelin hYP218 CAR T cells to treat these cancers. Experimental Design: Cell surface mesothelin expression in a panel of gastric and colorectal cancer cell-lines was analyzed using flow cytometry. In vitro efficacy of hYP218 CAR T cells against these cell lines was evaluated using cytotoxicity and cytokine release assays. In vivo efficacy of hYP218 CAR T cells was studied using gastric (HGC27) and colorectal (SW48) tumor xenografts in NSG mice. NSG mice were injected with 1 × 106 cancer cells and the tumors were allowed to grow until they reached a volume of 80-100mm³, after which the mice were treated with either 5 × 106 hYP218 CAR T cells, 5 × 106 untransduced T cells, or saline and monitored over time. Persistence of CAR T cells in the tumor was evaluated over time and expression of activation and exhaustion markers were studied. Results: hYP218 CAR T cells demonstrated strong cytotoxic activity against mesothelin positive gastric and colorectal cancer cell lines and exhibited increased pro-inflammatory cytokine production. In both the HGC27 and SW48 tumor models hYP218 CAR T cells demonstrated significant reduction in tumor volume and overall survival compared to mice treated with untransduced T cells or saline. CAR T cells isolated from tumors of both the xenograft models, at day 40 after treatment, displayed higher expression levels of activation markers CD39 and CD69 when compared to the infused product. Furthermore, a concomitant elevation in the levels of effector cytokines, TNF-α and IFN-γ, was detected in the blood of treated mice demonstrating the functional capacity of the CAR T cells to not only persist but also to maintain an activated state. Conclusions: hYP218 CAR T cells show anti-tumor efficacy against gastric and colorectal tumor xenografts due to increased accumulation of activated CAR T cells in the tumor and warrants further investigation for treatment of patients with these cancers. Citation Format: Sameer A. Mir, Abhilash Venugopalan, Jingli Zhang, Mana Kamana Khanal, Chaido Stathopoulou, Manjistha Sengupta, Qun Jiang, Raffit Hassan. Intra-tumor persistence of activated anti-mesothelin hYP218 CAR T cells is associated with increased efficacy in gastric and colorectal 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 62.
Abstract 5830: A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation
Authors: Priyanka Gopal, Mohamed Abazeed
Journal: Cancer Research (2024)

Abstract Introduction: Lung tumors treated with targeted therapies ultimately relapse due to intra-genic resistance mutations, bypass pathway activation, or cellular lineage changes. Newer precision therapies have higher selectivity and potency against both resistant and activating gene mutations, resulting in a significant increase in incidence of cellular transdifferentiation. The most common form of transdifferentiation is the change from lung adenocarcinomas (LUADs) to small cell lung cancer (t-SCLC) upon drug treatment which remains very poorly understood. Methods: We have combined patient derived xenografts (PDX) and ex vivo lines with multi-omic characterization, high-content image-based morphometry and fluorescence tracking, and single-cell barcode tracing to better understand the process of lung tumor transdifferentiation. Results: We have developed a first-of-its-kind t-SCLC model that reconstitutes ex vivo LUAD to SCLC transdifferentiation. Genomic and transcriptomic analyses of our NSCLC PDX collection identified tumors with mutation in TP53 and RB1, two genes that are altered in virtually all de novo SCLCs. PDX sample CBX336 was identified as having mutations in both TP53 and RB1, in addition to expressing the KRASG12C oncogene. Upon treatment with Sotorasib, CBX336 tumors initially demonstrated slow tumor growth, followed by a dramatic increase in the growth after prolonged drug exposure. Our experimental and computational data suggest a highly coordinated procession toward transdifferentiation with the parallel upregulation of the neuroendocrine transcription factor NEUROD1 across numerous epithelial cellular clones. Conclusions: Our new experimental system allows characterization at the single-cell level. Ongoing work includes the integration of new resources to study lineage reprogramming, and advancing new therapeutic strategies. Citation Format: Priyanka Gopal, Mohamed Abazeed. A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation [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 5830.
Abstract 7420: Optimizing proteomic data access and analysis in the cloud: Leveraging Terra's integration with the Proteomic Data Commons
Authors: Emily LaPlante, Bingxing Huo, DR Mani, Ratna R. Thangudu
Journal: Cancer Research (2024)

Abstract The Proteomic Data Commons (PDC) hosts cancer proteomics data with the goal of making this data available to the public to support development of cancer diagnostics, treatment, and progression tracking. As a part of the Cancer Research Data Commons (CRDC), the Terra platform provides a cloud workbench for the PDC data. FireCloud is a Broad Institute project funded by NCI to empower cancer researchers to access data, run analysis tools and collaborate securely in the cloud. It is powered by Terra, a secure, scalable cloud-native platform developed by the Broad Institute, Microsoft, and Verily, an Alphabet company. It provides batch workflow execution, interactive analysis including data visualization, and ~2,900 publicly available tools with the ability to import more tools from Dockstore. The integration of PDC and Terra enables researchers to leverage the data navigation and file-level search capabilities on the PDC web browser (pdc.cancer.gov) and export selected data manifests to a Terra workspace. This integrated hand-off specifically allows metadata and cloud links to PDC data in Portable Format for Bioinformatics (PFB) to be transferred to Terra and used in analysis with cloud resources. A featured workspace for Terra-PDC integration includes tools for (i) downloading data files and relevant additional metadata; (ii) organizing the data and metadata for running the FragPipe workflow, a comprehensive collection of tools for reading and processing raw Mass Spec (MS) data; and (iii) implementing a pre-configured FragPipe workflow to process isobarically labeled MS data from Tandem Mass Tag (TMT) or Isobaric tags for relative and absolute quantitation (iTRAQ) experiments using information automatically imported from PDC via the PFB import. The pipelines can also be customized as needed to process any type of raw MS data the PDC supports. In addition, Terra connects to the NCI Genomic Data Commons (GDC) and hosts The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets allowing users to pull in other data types for co-analysis. As a whole, using the CRDC cloud resources, in conjunction with Terra, allows analysis of data on a massive scale, enabling multi-omic integration spanning the genomic and proteomic commons data, with easy sharing of data and tools. Citation Format: Emily LaPlante, Bingxing Huo, DR Mani, Ratna R. Thangudu. Optimizing proteomic data access and analysis in the cloud: Leveraging Terra's integration with the Proteomic Data Commons [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 7420.
Abstract 5773: Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma
Authors: Chih-Yi Chen, Yu-Ching Huang, Wen-Hsiu Su, Yi-Ting Liu, Chi-Sheng Chen, Chia-Yang Li, Kun-Che Chang, Chia-Yen Dai, Shu-Chi Wang
Journal: Cancer Research (2024)

Abstract Brain cancer is a deadly disease with low survival rates for over 70 % of patients. Therefore, there is a critical need to develop better treatment methods and strategies to improve patient outcomes. In this study, we explored the tumor microenvironment and discovered unique characteristics of microglia to interact with astrocytoma cells and promote proliferation and migration of collisions. The conditioned medium from the collisions expressed cell chemoattraction and anti-inflammatory responses. To further understand the interactions between microglia and astrocytoma cells, we used flow sorting and protein analysis found that the protein alterations were related to biogenesis in the astrocytoma cells and metabolic processes in the microglia. Both types of cells were involved in binding and activity in cell-cell interactions. Using STRING to demonstrate the protein cross-interaction between the cells. Furthermore, PHB and RDX interact with oncogenic proteins, which were significantly expressed in patients with Glioblastoma Multiforme (GBM) and low-grade glioma (LGG) according to GEPIA. To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment. Citation Format: Chih-Yi Chen, Yu-Ching Huang, Wen-Hsiu Su, Yi-Ting Liu, Chi-Sheng Chen, Chia-Yang Li, Kun-Che Chang, Chia-Yen Dai, Shu-Chi Wang. Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma [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 5773.
Abstract 5819: An anti-TROP2-CPT113 ADC, exhibits potent targeted antitumor activity and favorable pharmacokinetic properties
Authors: Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Yongxiang Chen, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Juan Wang, Miaomiao Chen, Qingliang Yang, Robert Y. Zhao
Journal: Cancer Research (2024)

Abstract Trophoblast cell surface antigen 2 (TROP2) is highly expressed in a number of epithelial cancer types and is considered to be a poor prognostic marker. We have developed an anti-TROP2 antibody-drug conjugate, DXC1002, that contains a potent inhibitor of DNA topoisomerase I payload (CPT113) attached to the antibody mainly in the Fab region via a unique hydrophilic CrossConju™ linker. The anti-tumor activities of DXC1002 were studied in various human cancer cell lines and xenograft mouse models and pharmacokinetic profile of DXC1002 were evaluated in cynomolgus monkeys and rats. DXC1002 demonstrated potent anti-tumor activity in TROP2 tumor cells of various expression levels in vitro, and at low dose of 1 mg/kg for one injection, in both high and moderate Trop2 expression xenograft models. In plasma stability studies, wherein DXC1002 was incubated in the plasma of five different species for 168 hours (7 days) at 37 oC, over 90% ADC was intact, exhibiting good stability of the CrossConju™ linker. Pharmacokinetic studies of DXC1002 in monkeys (TROP2 cross-species) and rats (non-TROP2 cross-species) showed half-lives of about 61.27 and 236.77 hours, respectively. Systemic clearance in monkey and rat was 0.41-0.67 and 0.279-0.309 mL/h/kg, respectively. The longer half-lives and slower clearance observed in rats the results offered a more direct assessment of the linker stability as target-mediated clearance played no role in rats. In summary, with the conjugation of a DNA topoisomerase I inhibitor payload to Trop2 antibody via the CrossConju™ linker, DXC1002 demonstrates remarkable anti-tumor properties and pharmacokinetic profile, with a potential to be further validated in clinical applications. Citation Format: Huihui Guo, Xiangfei Kong, Yong Du, Zhicang Ye, Yongxiang Chen, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Juan Wang, Miaomiao Chen, Qingliang Yang, Robert Y. Zhao. An anti-TROP2-CPT113 ADC, exhibits potent targeted antitumor activity and favorable pharmacokinetic properties [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 5819.
Abstract 7378: Using game theory to investigate the therapeutic potential of disrupting tumor-microenvironment interactions
Authors: Debra Van Egeren, Andrew Chen, Madison Stoddard, Lin Yuan, Arijit Chakravarty
Journal: Cancer Research (2024)

Abstract Cancer is a complex disease involving the interplay of several types of malignant and nonmalignant cells. The growth of tumors and surrounding stromal cells can be modeled as an ecosystem, where populations of cancerous and healthy cells interact and compete for resources. In this work, we have explored the application of game theoretic models of cancer to the design of novel anticancer therapies. Notably, a game theoretic-model of tumor-stromal interactions can capture the impact of interactions between cell types and can be used to investigate frequency-dependent parameters describing the impact of drug action during the initiation and growth of metastatic cancers. Previous studies using game theoretic models to describe cancer have focused on explaining progression patterns of specific tumors with known tumor-stromal interactions. This study takes a more general approach to cancer growth dynamics, modeling cancer as a simple game between healthy and cancer cells. This simplified model is used to make general predictions about cancer progression and the efficacy of treatment strategies. Our work suggests that disruption of beneficial interactions between healthy and cancer cells may be a viable treatment strategy for small tumors and preventing metastasis by ensuring that the healthy cell strategy is evolutionarily stable. The efficacy of treatment strategies that disrupt cancer cell cooperation or tumor-stromal dynamics changes as the cancer cell frequency changes. Our work suggests that drugs that target tumor-stromal cell interactions would need to be combined with other types of treatments to be effective against large tumors. Although based on a simplistic model of cancer initiation and progression, the framework derived here can be extended to the real-world design of experimental anticancer therapeutics, and fundamental analyses of this nature can be of practical utility in setting strategy for Target Product Profile design. Citation Format: Debra Van Egeren, Andrew Chen, Madison Stoddard, Lin Yuan, Arijit Chakravarty. Using game theory to investigate the therapeutic potential of disrupting tumor-microenvironment interactions [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 7378.