tbuckley/cabot-search huggingface dataset:
Abstract LB361: The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti-tumor immunity
Authors: Junghyun Lim, Ryan Rodriguez, Katherine Williams, John Silva, Alan Gutierrez, Paul Tyler, Faezzah Baharom, Tao Sun, Eva Lin, Scott Martin, Brandon Kayser, Robert J. Johnston, Ira Mellman, Lélia Delamarre, Nathaniel West, Sören Müller, Yan Qu, Klaus Heger
Journal: Cancer Research (2024)

Abstract The DNA exonuclease TREX1 (Three-prime repair exonuclease 1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. Since tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here we show, that in tumor cells TREX1 indeed restricts the spontaneous activation of the cGAS/STING pathway and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8 T cells and NK cells, prevented CD8 T cell exhaustion and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency synergized with T cell directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances anti-tumor immunity by itself and in combination with T cell-targeted therapies. Citation Format: Junghyun Lim, Ryan Rodriguez, Katherine Williams, John Silva, Alan Gutierrez, Paul Tyler, Faezzah Baharom, Tao Sun, Eva Lin, Scott Martin, Brandon Kayser, Robert J. Johnston, Ira Mellman, Lélia Delamarre, Nathaniel West, Sören Müller, Yan Qu, Klaus Heger. The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB361.
Abstract LB160: The mouse mammary tumor virus mediates the antineoplastic action of decitabine
Authors: Sarah Light, Maziar Montazer, Cade Wycoff, Richard Tuttle, Andrew Brola, William Wycoff, Ryan Johnson, Yingguang Liu
Journal: Cancer Research (2024)

Abstract The purpose of this study is to clarify the role of the mouse mammary tumor virus (MMTV) in cancer growth and in mediating the antineoplastic effect of decitabine, a DNA demethylating agent. In vitro studies have shown that decitabine inhibits cancer cell proliferation by stimulating endogenous retroviruses which in turn activates the production of cytostatic interferon beta (IFN-β). We investigated the potential involvement of endogenous MMTV and the mouse IFN-β in the pharmacodynamics of decitabine using stable knockdown cell lines and MMTV hyper-infection. For the first time, we show that knockdown of MMTV or IFN-β in a mouse mammary cancer cell line (4T1) both rendered the cancer cells more resistant to decitabine in mice bearing 4T1-derived mammary cancer. Mechanistically, decitabine enhanced MMTV expression on the RNA level in both control tumors and tumors with MMTV knockdown, although the degree of enhancement was limited in knockdown tumors. Conversely, infection of a mouse colon cancer cell line (MC38) with MMTV released from 4T1 cells rendered the colon cancer cells more sensitive to decitabine. These data confirm the viral mimicry hypothesis as the mechanism of DNA demethylating agents. Practically, our research suggests the possibility of combining the use of an exogenous virus and a DNA demethylating agent as a new approach to cancer treatment. Citation Format: Sarah Light, Maziar Montazer, Cade Wycoff, Richard Tuttle, Andrew Brola, William Wycoff, Ryan Johnson, Yingguang Liu. The mouse mammary tumor virus mediates the antineoplastic action of decitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB160.
Abstract LB291: High-plexy intracellular and surface CITE-Seq offers multiomic insights into cell function
Authors: Tracy L. Campbell, Adam Wright, Ying Wah Lee, Anne Tran, Yan Chen, Joe Olives, Hye-Won Song, Larry Wang
Journal: Cancer Research (2024)

Abstract CITE-Seq allows researchers to combine high-plex protein information with whole transcriptome sequencing to gain insights about individual cell states. Due to the harsh fixation and permeabilization required for intracellular (IC) antibody staining, only a few studies have recovered mRNA expression profiles alongside IC protein detection. This experiment utilized a novel IC CITE-Seq assay that enables robust profiling of multiple IC protein targets in combination with mRNA and high-plex surface proteins. In this study, we stimulated human peripheral blood mononuclear cells (PBMCs) alongside a resting control. After stimulation, we stained the surface proteins with a 40-plex BD® AbSeq Panel, including the Immune Discovery Panel and human Single-Cell Multiplexing Kit (SMK). Resting and stimulated cells were pooled, and a portion of the sample pool immediately underwent cell capture as a live control using a BD Rhapsody™ single-cell microwell system. The other portion of the pool was stored in BD® OMICS-Guard Sample Preservation Buffer for either 5 minutes or 24 hours followed by permeabilization, IC staining with a 10-plex IC AbSeq Panel (50-plex total, surface and IC), and cells captured on the the same system. We show IC protein detection for the expected positive targets, including pH2AX, actCaspase-3, and cPARP in the stimulated population, as well as T-Bet, Granzyme B and Helios in the resting lymphocytes. Analysis shows excellent correspondence between IC CITE-Seq protein and transcriptome for T-Bet, Granzyme B and Helios. The gene expression correlation for surface antigen and mRNA between the IC and live control each had R2 values &amp;gt; 0.9. The mRNA sensitivity for the IC sample compared to live control was within whole transcriptome analysis (WTA) assay variation at 86–89% and 95–97% median molecules and genes per cell. Our data showed that the new IC CITE-Seq assay can provide rich single-cell multiomics information including mRNA and surface and intracellular proteins. For Research Use Only. Not for use in diagnostic or therapeutic procedures.BD, the BD Logo and BD Rhapsody are trademarks of Becton, Dickinson and Company or itsaffiliates. © 2023 BD. All rights reserved. NPM-2532 (v1.0) 1023 Citation Format: Tracy L. Campbell, Adam Wright, Ying Wah Lee, Anne Tran, Yan Chen, Joe Olives, Hye-Won Song, Larry Wang. High-plexy intracellular and surface CITE-Seq offers multiomic insights into cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB291.
Abstract LB057: Pre-clinical characterization of IBI343, a site-specifically conjugated anti-Claundin18.2 ADC, for treating solid tumors
Authors: Shuaixiang Zhou, Xiong Yao, Jian Guan, Keke Fei, Jia Lu, Weiwei Wu, Yang Liu, Tianyu Zhu, Zhuangguang Liao, Shi Chen, Bingliang Chen, Kaijie He
Journal: Cancer Research (2024)

Abstract Claudin18.2 is important for the formation and function of tight junctions between cells in epithelial tissues. Normally expressed only in gastric mucosa, Claudin18.2 is overexpressed in multiple types of solid tumors, including gastric, pancreatic, breast and colon cancers. Despite being a well-established tumor-associated antigen, the clinical value and feasibility of targeting Claudin18.2 by various modalities are yet-to-be fully demonstrated. IBI343 is a fully humanized anti-Claudin18.2 monoclonal antibody conjugated to Exatecan via site-specific glycol-conjugation with an average drug-to-antibody ratio (DAR) of 3.6. IBI343 showed robust antigen-specific in vitro cytotoxicity in cancer cell lines with varying levels of Claudin18.2 expression. In addition, due to the cleavable linker design and high hydrophilicity of the payload, IBI343 demonstrated potent bystander killing effects in vitro. The glycan-based conjugation technology leads to enhanced stability of the conjugated linker-payload and the entire ADC molecule, which results in superior pharmacokinetics. IBI343 showed potent in vivo anti-tumor efficacy with complete tumor regressions in multiple xenograft models. Furthermore, it demonstrated strong in vitro and in vivo synergistic effects with various anti-cancer agents, including immune checkpoint blockers and DNA damage repair pathway inhibitors. IBI343 displayed good safety profile in monkey GLP toxicology study (HNSTD = 30 mg/kg). These pre-clinical findings show that IBI343 is a promising anti-cancer agent with large therapeutic window, and support clinical exploration of IBI343 in patients with Claudin18.2-expressing tumors. A companion late-breaking abstract of clinical phase 1 study results (NCT05458219) will also be presented in AACR 2024. Citation Format: Shuaixiang Zhou, Xiong Yao, Jian Guan, Keke Fei, Jia Lu, Weiwei Wu, Yang Liu, Tianyu Zhu, Zhuangguang Liao, Shi Chen, Bingliang Chen, Kaijie He. Pre-clinical characterization of IBI343, a site-specifically conjugated anti-Claundin18.2 ADC, for treating solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB057.
Abstract LB031: Discovery and Characterization of HH100937, a potent and selective SOS1 inhibitor demonstrates synergistic efficacy in combination with KRAS/MAPK therapies
Authors: Qing Xie, Dongsheng Li, Shujuan Jiang, Jie Zhu, Songda Yu, Maozhi Yang, Yalei Cai, Lei Liu, Bing Yu, Wangyang Tu, Yixiang Zhang, Leping Li
Journal: Cancer Research (2024)

Abstract Besides marketed inhibitors targeting KRAS G12C, novel therapies are needed to effectively treat cancer patients harboring other KRAS mutations. SOS1, a guanine nucleotide-exchange factors (GEFs), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status and represents a promising therapeutic target for all KRAS-driven tumors. Up to date, several SOS1 inhibitors have entered early phase clinical trials. But a more potent SOS1 inhibitor with improved drug-like properties is still needed to prove efficacy as monotherapy or in combination with other drugs targeting the KRAS/MAPK pathway.We discovered a potent SOS1 inhibitor, HH100937 that effectively disrupted the interaction between SOS1 and wild-type KRAS or with G12C, G12D or G12V mutations. HH100937 exhibited lower IC50s than BI-3406 and MTRX0902 in blocking ERK phosphorylation and cancer cell proliferation, leading to better anti-tumor efficacies in xenografts than reference compounds at same doses. HH100937 also showed synergistic effect with AMG510 in cancer cells with KRAS G12C mutation but refractory to AMG510. The combination of HH100937 and AMG510 in xenografts led to tumor regression in all mice, while some tumors did not response well to AMG510 monotherapy. Our SOS1 inhibitor also exhibited synergistic effect with HH2710, a clinical-stage ERK inhibitor, in a broad panel of cancer cells with KRAS mutations.The pharmacological potency of HH100937 was highly selective over SOS2, other kinases tested or other targets in a safety panel of 47 targets. HH100937 was well tolerated in 28-day DRF study in rats and dogs up to 250 mg/kg QD and 30 mg/kg QD, respectively. The AUC of drug exposure in DRF studies was approximately three to six times higher than that at the efficacious dose. HH100937 also showed favorable DMPK properties in mice, rats and dogs, and acceptable safety profiles in vitro.Taken together, HH100937 is a highly potent and selective SOS1 inhibitor with better anti-tumor activities than some SOS1 inhibitors at clinical stage. It can be developed as mono therapy or in combination with other KRAS/MAPK targeting therapies. Citation Format: Qing Xie, Dongsheng Li, Shujuan Jiang, Jie Zhu, Songda Yu, Maozhi Yang, Yalei Cai, Lei Liu, Bing Yu, Wangyang Tu, Yixiang Zhang, Leping Li. Discovery and Characterization of HH100937, a potent and selective SOS1 inhibitor demonstrates synergistic efficacy in combination with KRAS/MAPK therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB031.
Abstract LB144: The short-term associations of air pollutants with inflammation and oxidative stress markers in the Korean population
Authors: Kyoungho Lee, Ji Hyun Kim
Journal: Cancer Research (2024)

Abstract Inflammation and oxidative stress responses induced by air pollutants are major biological mechanisms that can lead to multiple chronic diseases. We investigated the association between short-term exposure to ambient air pollutants and circulating levels of inflammatory cytokines, as well as a urinary marker of oxidative DNA damage in Korean adults (n=2,199) from the Korea Genome and Epidemiology Study. Circulating levels of inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, and TNF-α, as well as urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), were selected as biomarkers of interest. We estimated a range of air pollutants, such as particulate matter (PM, PM10 and PM2.5) and nitrogen dioxide (NO2), utilizing a chemical transport model. The exposure duration was defined based on 1- to 7-day averages. To explore the association between air pollution and biomarkers, we utilized multivariable linear models adjusting for major covariates, including demographic, lifestyle, relative humidity, and temperature. PM10 was linked to increased levels of IL-1β, IL-10, TNF-α, and 8-OHdG, and PM2.5 was associated with elevated levels of IL-1β, IL-10, IL-8, TNF-α, and 8-OHdG. With each 10 μg/m3 increase in the weekly average of PM, the largest magnitude of percent changes were observed for IL-1β levels (PM10: 2.7%, 95% CI 0.6 to 4.8; PM2.5: 6.4%, 95% CI 2.4 to 10.5). NO2 showed statistically non-significant associations with any of the biomarkers. As a result, short-term exposure to ambient PM may trigger oxidative damage and pro-and anti-inflammatory responses. Citation Format: Kyoungho Lee, Ji Hyun Kim. The short-term associations of air pollutants with inflammation and oxidative stress markers in the Korean population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB144.
Abstract LB016: Spatial transcriptomics-based platform for pathological diagnosis and research of colorectal cancer
Authors: Chi Qu, Huaqiang Huang, Yan Quan, Xuqing He, Weifeng Zhang, Tianbi Duan, Jiajun Zhang, Jiang Gu
Journal: Cancer Research (2024)

Abstract The application of spatial transcriptomic (ST) in contemporary pathology is promising yet rarely validated. We herein established a ST-based platform to analyze colorectal cancers following the logic and workflow of routine histopathological diagnosis. By integrating spatial coordinate traits with in-situ gene expression matrix, we reproduced and extended key diagnostic features for tumor diagnosis and molecular analysis including proliferation evaluation, vasculature identification, immune scoring and dMMR/pMMR molecular subtyping. Meanwhile, spatial and morphological distinction ST co-dominated broadened avenues for targeted cancer therapy and research. In hyperplasia/carcinoma confusion sites, we detected mixed cnv patterns in single crypt with distinct spatial distributions; Meanwhile, RNA-based molecular subtypes prevailed with intratumor heterogeneity and concurrently exhibited uniformed histological characteristics; Moreover, landscape of temporal molecular variation during cancer infiltration stages revealed potential metastatic biomarkers and mechanisms. In conclusion, we have herein established a comprehensive platform to perform and extensely extend assessment for tumor diagnosis. Additionally, by aligning histological features and gene expression profiles, we excavated significant opportunity for pathological investigation and coordination of multimodal molecular pathology dimensions, which is suitable and ideal for scientific discoveries and molecular diagnosis. With improvement in efficiency and cost-effectiveness, we foresee that this de novo platform will significantly advance pathological diagnosis and research of cancer tissue. Citation Format: Chi Qu, Huaqiang Huang, Yan Quan, Xuqing He, Weifeng Zhang, Tianbi Duan, Jiajun Zhang, Jiang Gu. Spatial transcriptomics-based platform for pathological diagnosis and research of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB016.
Extracellular Proteins Isolated from <i>L. acidophilus</i> as an Osteomicrobiological Therapeutic Agent to Reduce Pathogenic Biofilm Formation, Regulate Chronic Inflammation, and Augment Bone Formation In Vitro (Adv. Healthcare Mater. 9/2024)
Authors: Abinaya Sindu Pugazhendhi, Anouska Seal, Megan Hughes, Udit Kumar, Elayaraja Kolanthai, Fei Wei, Jonathan D. Schwartzman, Melanie J. Coathup
Journal: Advanced Healthcare Materials (2024)
Abstract CT264: Improved clinical outcomes in patients received treatment beyond tumor progression with AdAPT-001 +/- a checkpoint inhibitor
Authors: Anthony P. Conley, Tony Reid, Chris Larson, Bryan Oronsky, Scott Caroen, Meaghan Stirn, Erica Burbano, Nacer Abrouk, Christina L. Roland, Jeannie Williams, Lucy B. Kennedy
Journal: Cancer Research (2024)

Abstract Background AdAPT-001 is an oncolytic adenovirus with a TGF-β trap. Pseudoprogression (PsP) or transient tumor enlargement from intense T cell infiltration was commonly observed with AdAPT-001 in immune competent mouse models. We evaluated progression-free survival (PFS) and overall survival (OS) in 36 treatment-resistant patients (pts) that received AdAPT +/- an ICI on a Phase 2 clinical trial. Methods RECIST1.1 assessment was performed every 8 weeks. PsP was defined as progressive disease (PD) on RECIST 1.1 with subsequent tumor regression during TBP. The decision to TBP was based on investigator-assessed clinical benefit and the potential for late responses with minimal adverse events. Log rank tests were applied to compare PFS between pts with and without PsP and to compare OS between pts with and without TBP. Results Median (m) PFS was longer in pts with PsP and TBP (3.7, 95% CI: 1.6 - ) than without it (2.0, 95% CI: 1.8 - 3.7, log-rank test p = 0.97). mOS months was significantly longer in pts with TBP (median not reached) vs. no TBP (7.8, 95% CI: 6.1 - log-rank test p = 0.053). Conclusion A high frequency of PsP occurred on this Phase 2 study likely from infiltration of treatment-activated immune cells. AdAPT-001 mediated PsP and TBP may serve as markers of prolonged clinical benefit. Further validation in larger numbers of future patients is warranted. Citation Format: Anthony P. Conley, Tony Reid, Chris Larson, Bryan Oronsky, Scott Caroen, Meaghan Stirn, Erica Burbano, Nacer Abrouk, Christina L. Roland, Jeannie Williams, Lucy B. Kennedy. Improved clinical outcomes in patients received treatment beyond tumor progression with AdAPT-001 +/- a checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT264.
Abstract LB127: A first-in-class bispecific ADC targeting FORL1 and MUC1 exhibits promising anti-tumor activity in a FOLR1low xenograft model
Authors: Yifu Zhang, Chengzhang Shang, Chaoshe Guo, Yi Yang
Journal: Cancer Research (2024)

Abstract Folate receptor alpha (FOLR1) is specifically overexpressed in malignant tumors of epithelial origin, including ovarian, lung and breast cancers. While antibody-drug conjugate (ADC) therapies targeting FOLR1 have shown promise in clinical trials, there is still a large proportion of patients, particularly those with low FOLR1 expression, who do not respond, indicating new therapeutic strategies are needed. MUC1 is another tumor-associated antigen that is likewise overexpressed in epithelial ovarian cancer, breast cancer, and NSCLC, among other cancers; analysis of ovarian PDX tumors by immunohistochemistry (IHC) suggests that FOLR1 and MUC1 are both highly expressed in this cancer type. We therefore hypothesized that dual targeting of FOLR1 and MUC1 could provide therapeutic benefit in ovarian cancer as well as a broad range of tumors. We generated a FOLR1 x MUC1 bispecific antibody (bsAb) from anti-FOLR1 and anti-MUC1 monoclonal antibodies that were produced using RenLite® fully human common light chain mice. These parental monoclonal antibodies recognize both human and cynomolgus monkey antigens. Anti-FOLR1 antibodies were highly specific for FOLR1, as they did not recognize other FOLR family members. The anti-MUC1 antibody was previously confirmed to target MUC1-C, the juxtamembrane domain of MUC1, ensuring tumor cell recognition regardless of MUC1 cleavage. Assessment of the novel FORL1 x MUC1 bsAb indicates binding to several ovarian, breast and NSCLC cell lines, and shows enhanced internalization in MDA-MB-468 and T47D cell lines when compared to parental antibodies. Subsequently, the FORL1 x MUC1 bsAb was conjugated to vcMMAE with a DAR of 4, to generate a bispecific ADC, BCG023. BCG023 exhibited superior tumor growth inhibition compared to benchmark ADCs conjugated with the same payload and DAR in a low FOLR1-expressing NSCLC PDX model. These data suggest that targeting FOLR1 and MUC1 with a bispecific ADC is a promising therapeutic strategy for the treatment of ovarian and other tumors. Citation Format: Yifu Zhang, Chengzhang Shang, Chaoshe Guo, Yi Yang. A first-in-class bispecific ADC targeting FORL1 and MUC1 exhibits promising anti-tumor activity in a FOLR1low xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB127.