tbuckley/cabot-search huggingface dataset:
Abstract 1873: Deep plasma proteome profiling to discover drug treatment related novel biomarkers in non-small cell lung cancer
Authors: Cui Liu, Ruiqi Huang, Xiaopeng Ma, Wenting Du, Cunjing Yu, Xikun Wu, Yongchun Tong, Lanjun Xu, Si Mou
Journal: Cancer Research (2025)

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers. A better understanding of ICI induced dynamics and response / resistance mechanisms may contribute to the optimization of treatment strategies. In early-stage non-small cell lung cancer (NSCLC) cohort with neoadjuvant chemoimmunotherapy, we utilized the plasma proteomics platform to deepen the understanding of disease biology and explore potential response and resistance biomarkers. Methods: Plasma samples collected at various time points during neoadjuvant chemoimmunotherapy were analyzed using an unbiased mass spectrometry-based plasma proteomics platform. Taking advantage of the protein corona formed on the surface of nanoparticles, low-abundant proteins related to immunomodulation and signal transduction were enriched and identified. A comprehensive statistical analysis framework was adapted to reveal mechanism and explore predictive and prognostic biomarkers. Immunotherapy-induced changes of blood proteins were estimated by linear mixed model. Molecular insights were studied through mediation analysis. In the association analysis with clinical outcomes, classic logistic regression was applied for binary clinical outcomes, while cox proportional hazard model for survival outcomes. Results: 180 plasma samples from 92 individuals were profiled, resulting in the quantification of 2303 proteins in peripheral blood. The consistency between quantitative proteomics and established techniques were demonstrated by known biomarker CA125, CRP and gender related proteins. A total of 541 upregulated proteins and 504 downregulated proteins after neoadjuvant chemoimmunotherapy were identified. Pathway enrichment analysis revealed that neoadjuvant chemoimmunotherapy promoted immune activation. Conclusion: Deep plasma proteome profiling enables a deeper understanding of the dynamics and mechanisms induced by ICI treatment. Citation Format: Cui Liu, Ruiqi Huang, Xiaopeng Ma, Wenting Du, Cunjing Yu, Xikun Wu, Yongchun Tong, Lanjun Xu, Si Mou. Deep plasma proteome profiling to discover drug treatment related novel biomarkers in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1873.
Abstract 7170: Differential prognostic impacts of the germline APOBEC3B deletion polymorphism in hepato-pancreato-biliary and genitourinary cancers
Authors: Ahmadreza Niavarani, Peyvand Parhizkar Roudsari, Roya Noorbakhsh, Melineh Markarian, Reza Malekzadeh
Journal: Cancer Research (2025)

Abstract The mutational signatures related to apolipoprotein B mRNA-editing enzyme catalytic polypeptides (APOBECs) are found in many cancers. We aimed to assess the impact of APOBEC3B deletion variant on the risk and prognosis of various cancers in the Golestan Cohort Study, Iran, comprising 1, 393 cancer cases and 1, 806 controls (median age: 69.2 years). The population predominantly consisted of the Turkmen ethnicity (77.5%), with 49.6% of individuals deceased during the study period. The TaqMan genotyping assay was used as a proxy to identify the rs12628403-A/C (linked to intact/deleted APOBEC3B) alleles. The APOBEC3B deletion was identified in 29.8% of individuals. Cancer cases exhibited a higher frequency of APOBEC3B deletion compared to controls, particularly among Turkmen individuals (32.9% vs. 28.5%, OR = 1.23, P = 0.019). Increased frequencies were observed for gastric cancer (OR = 1.61, P = 0.001) and collective gastrointestinal (esophageal, gastric, small intestinal, and colorectal) cancers (OR = 1.31, P = 0.012) among APOBEC3B-deleted individuals. In head and neck cancer, APOBEC3B deletion was more prevalent among cases of all origins (OR = 1.83, P = 0.036). Survival analyses revealed contrasting effects of the APOBEC3B deletion. APOBEC3B deletion was significantly associated with longer survival in pancreatic (4.0 vs. 2.7 months; P = 0.025) and biliary (29.3 vs. 3.1 months; P = 0.047) cancers, as well as the collective hepato-pancreato-biliary (hepatocellular, pancreatic, gallbladder, and biliary) cancers (4.2 vs. 2.5 months; P = 0.002). By contrast, it was predictive of shorter survival in bladder (2.1 vs. 32.8 months; P = 1.1e-4) and cervical (5.7 vs. 53.7 months; P = 0.017) cancers, and the collective genitourinary (bladder, cervical, uterus, and prostate) cancers (5.7 vs. 32.8 months; P = 1.9e-5). Multivariate Cox regression analyses confirmed a favorable prognostic impact of the APOBEC3B deletion in the collective hepato-pancreato-biliary cancers (HR = 0.634; P = 0.039), while an adverse prognostic impact in the genitourinary cancers (HR = 2.45; P = 1.9e-4) and meningioma (HR = 6.750; P = 0.025). These findings suggest the APOBEC3B deletion as a susceptibility and prognostic biomarker in specific cancers, with differential effects based on tumor type. Further studies are warranted to elucidate underlying mechanisms and potential therapeutic implications. Citation Format: Ahmadreza Niavarani, Peyvand Parhizkar Roudsari, Roya Noorbakhsh, Melineh Markarian, Reza Malekzadeh. Differential prognostic impacts of the germline APOBEC3B deletion polymorphism in hepato-pancreato-biliary and genitourinary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7170.
Abstract 6742: High-affinity human IgG1 antibody against GUCY2C for ADC development: Identification, characterization, and efficacy
Authors: Yunxia Zheng, Xiafen Wu, Junxiang Jia, Huihui Guo, Xiangfei Kong, Gengxiang Zhao, Yuanyuan Huang, Hangbo Ye, Xiaolei Liu, Yi Luo, Xiaoqiang Xie, Xia Zhou, Lu Bai, Wenjun Li, Binbin Chen, Qingliang Yang, Robert Yongxin Zhao
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer mortality worldwide. Despite the early disease screening techniques could reduce the number of deaths, the treatments for metastatic CRC still remains limited. GUCY2C, a receptor predominantly found in the intestinal epithelium, is a tumor-associated antigen that is overexpressed in gastrointestinal malignancies, particularly colorectal cancer (CRC). GUCY2C offers a super clean therapeutic target, due to restricted expression in normal tissues and high expression in CRC cells, with significantly reduced the on-target-off-tumor toxicities. A high-affinity, high-specificity human IgG1 monoclonal antibody against GUCY2C was obtained from a 100 billion-capacity human Fab phage display library. This antibody, after recombinant expression in CHO cells, was extensively validated both in vitro and in vivo for its suitability in antibody-drug conjugate (ADC) development. The recombinant antibody demonstrated high affinity for its specific antigen, as confirmed by Bio-Layer Interferometry (BLI) and Enzyme-Linked Immunosorbent Assay (ELISA) methods. Flow cytometry further confirmed that the antibody had picomolar (pM) affinity for gastric and colorectal cancer cell lines expressing high levels of GUCY2C. Cellular internalization experiments indicated that the antibody possesses excellent endocytic capabilities, making it particularly suitable for ADC development. The antibody was then conjugated with a linker-payload complex containing a topoisomerase I inhibitor and an antimetabolite moiety, and subjected to a series of in vitro and in vivo evaluations. The ADC achieved in vitro proliferation inhibition in the picomolar range of IC50. Several in vivo CDX model experiments also demonstrated significant tumor suppression efficacy. Moreover, acute toxicity evaluation of the GUCY2C-ADC in diverse preclinical models indicated favorable safety profiles and tolerability. Overall, these compelling preclinical data supports the promising therapeutic potential of this ADC in targeted treatment of CRC. Citation Format: Yunxia Zheng, Xiafen Wu, Junxiang Jia, Huihui Guo, Xiangfei Kong, Gengxiang Zhao, Yuanyuan Huang, Hangbo Ye, Xiaolei Liu, Yi Luo, Xiaoqiang Xie, Xia Zhou, Lu Bai, Wenjun Li, Binbin Chen, Qingliang Yang, Robert Yongxin Zhao. High-affinity human IgG1 antibody against GUCY2C for ADC development: Identification, characterization, and efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6742.
Abstract 6047: YTHDF proteins modulate gastric cancer immunity by regulating the IFN-γ response through the m6A-dependent degradation of IRF1
Authors: Dongjun Jang, Sung-Yup Cho
Journal: Cancer Research (2025)

Abstract N6-methyladenosine (m6A) RNA methylation is one of the most abundant post-transcriptional modifications in eukaryotic messenger RNAs and plays crucial roles in carcinogenesis and immune responses. YTHDF proteins including YTHDF1, 2, and 3 are ‘reader’ proteins of m6A methylated RNAs and have individual role. A recent report suggests that YTHDFs act redundantly to promote RNA decay. In this study, we found that YTHDF1 was overexpressed in gastric cancer (GC) tissues and correlating with the suppression of cancer immunity, particularly the responsiveness to interferon-gamma (IFN-γ). Overexpression of YTHDF1 reduced the responsiveness to IFN-γ in GC cells, while knockdown studies showed that YTHDF2 and YTHDF3 redundantly affect IFN-γ responsiveness alongside YTHDF1. Analysis of RNA immunoprecipitation (RIP)-sequencing data revealed that IRF1 mRNA, key regulator of IFN-γ signaling, is a direct target of YTHDFs and is degraded in an m6A-dependent manner. Likewise, downregulation of METTL3, which is a major component of m6A methyltransferase complex, using small interfering RNA or catalytic inhibitor increase IRF1 levels and IFN-γ responsiveness. Furthermore, depletion of Ythdf1 reduced tumor growth and increased immune cell infiltration into the tumor, dependent on IFN-γ signaling in mouse syngeneic tumor models. Collectively, our study suggests that YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation. Citation Format: Dongjun Jang, Sung-Yup Cho. YTHDF proteins modulate gastric cancer immunity by regulating the IFN-γ response through the m6A-dependent degradation of IRF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6047.
Abstract 3509: ATG-110, a novel “2+1” LY6G6D-targeted T-cell engager (TCE) for the treatment of MSS colorectal cancer
Authors: Gang Bian, Jiahui Hua, Ge Lin, Xueli Chen, Huiling Liu, Peng Chen, Jay Mei, Bing Hou
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and requires more effective and safer therapies to improve its poor survival outcome. LY6G6D is a GPI-anchored cell surface protein with expression that is particularly specific to colorectal cancer (CRC). LY6G6D exhibits significantly elevated expression levels in colorectal cancer (CRC) tissue comparing to normal tissue, particularly in pMMR/MSS CRC, which demonstrates primary resistance to immune checkpoint inhibitor (ICI) therapy. T cell engagers have shown encouraging efficacy in treating hematological malignancies, while exhibiting suboptimal performance in solid tumors. The potential of cytokine release syndrome (CRS) remains significant issues. We present a novel 2+1 LY6G6DxCD3 T cell engager, ATG-110, which demonstrated LY6G6D-dependent CD3 binding and significant anti-tumor activity with reduced cytokine release. Methods: ATG-110 was constructed by introducing a novel conformational epitope-targeted anti-CD3 single chain fragment variable (scFv) to the hinge region of one of the heavy chains of a LY6G6D monoclonal antibody. It was evaluated in a series of preclinical in vitro studies for binding affinity, T cell activation and cytokine release, T cell dependent cytotoxicity (TDCC), and drug developability. The in vivo anti-tumor efficacy was evaluated in PBMC-humanized immunodeficient NDG mice engrafted with LY6G6Dmedium-expression HT55 or LY6G6Dvery low-expression SW480 MSS CRC cells. Results: ATG-110 bound to LY6G6D-positive cell lines, LY6G6D-overexpression 293T, HT55, LS1034, with the nanomolar grade EC50. The CD3 binding site of ATG-110 is concealed by the LY6G6D Fab arm before binding to LY6G6D, due to the steric hindrance. Therefore, ATG-110 demonstrated limited binding capability to CD3+ cells before LY6G6D crosslinking. It activated T cells and induces cytokine release only in the presence of LY6G6D+ cells. In vitro, ATG-110 resulted in potent T cell dependent cytotoxicity with single-digit pM IC50 values on HT55 and SW480 cells. ATG-110 also showed potent anti-tumor activity in PBMC-humanized SW480 xenograft model and exhibited complete response (CR) in PBMC-humanized HT55 xenograft model. ATG-110 demonstrated good drug developability. Conclusion: ATG-110 demonstrated LY6G6D-dependent CD3 binding and activation with low risk of CRS. It showed powerful in vitro and in vivo anti-tumor efficacy against colorectal cancer, which warrants further clinical evaluation. Citation Format: Gang Bian, Jiahui Hua, Ge Lin, Xueli Chen, Huiling Liu, Peng Chen, Jay Mei, Bing Hou. ATG-110, a novel “2+1” LY6G6D-targeted T-cell engager (TCE) for the treatment of MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3509.
Abstract 6751: AT2604 is a highly efficacious ADC targeting alkaline phosphatases ALPP and ALPPL2
Authors: Bryan K.S. Yeung, Wei Qi Tan, You Xue Wu, Xi Yun Zhang, Yin Wen Cheng, Shao Jun Liu, Chen Zhong, Bin Zou
Journal: Cancer Research (2025)

Abstract Placental alkaline phosphatases, ALPP and ALPPL2, are highly homologous, membrane-bound proteins involved in fetal development. Despite having limited expression in normal tissues, they are highly differentiated in multiple tumor cells making them ideal targets for antibody drug conjugate (ADC) development. AT2604 is an ADC incorporating an anti-ALPP/ALPPL2 antibody conjugated to monomethyl auristatin E (MMAE) with high DAR 4 homogeneity; and displays strong tumor growth inhibition at low doses in CDX models of gastric and pancreatic cancer. In patient-derived xenograft models of gastric cancer with moderate- and low-antigen expression, AT2604 achieves near-complete tumor regression at 3 and 6 mg/kg (QWx3), respectively. A preliminary toxicity assessment in non-human primates concluded a well-tolerated dose of 10 mg/kg (Q3Wx3) without exhibiting any non-reversible adverse effects.and good plasma stability; implying that AT2604 possesses an improved safety profile over other vedotin-based ADCs. Citation Format: Bryan K.S. Yeung, Wei Qi Tan, You Xue Wu, Xi Yun Zhang, Yin Wen Cheng, Shao Jun Liu, Chen Zhong, Bin Zou. AT2604 is a highly efficacious ADC targeting alkaline phosphatases ALPP and ALPPL2​ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6751.
Abstract 6087: A novel Ly6G6D/4-1BB bispecific antibody targeting DNA mismatch repair proficient colorectal cancers shows potent antitumor activities
Authors: Zhiheng Ren, Xiang Li, Shushan Lin, Kuo Zhang, Zhaofeng Li, Xiao Lin, Kaifeng Li, Ju Peng, Mi Zheng, Wen Yang, LiJia Li, Xiaoping Li, Stewart Leung
Journal: Cancer Research (2025)

Abstract HEC921 is a novel bispecific agonistic antibody targeting Lymphocyte Antigen 6 Family Member G6D (Ly6G6D) and the immune agonistic receptor 4-1BB for the treatment of colorectal cancers. Ly6G6D is a tumor associated antigen highly expressed in DNA mismatch repair proficient (pMMR) colorectal cancers frequently resistant to immune check-point therapies. Activating monoclonal antibodies against 4-1BB have shown clinical efficacy but was limited by systemic toxicity. The design of HEC921 enables Ly6G6D-dependent agonism of 4-1BB in the presence of Ly6G6D positive tumor cells, enabling tumor specific T cell activation while minimizing systemic immune toxicity. A high affinity antibody against Ly6G6D and a nanobody against 4-1BB were identified for the construction of HEC921 containing an ADCC-silenced Fc. HEC921 shows potent co-binding to both Ly6G6D and 4-1BB targets and is cross reactive to the cynomolgus orthologues. In an assay using 4-1BB high expression 293 cells with NFκB-luciferase reporter, HEC921 mediated 4-1BB activation in the presence of Ly6G6D positive cells but not Ly6G6D negative cells. HEC921 promoted the production of cytokines IFN-γ, IL-2, and IL-4 in co-cultures of human T cells and Ly6G6D positive tumor cell lines. HEC921 demonstrated effective tumor growth inhibition in xenograft models of Ly6G6D positive tumor lines. Initial drug feasibility and toxicity studies results of HEC921 were favorable. Overall result demonstrated that HEC921 is a promising candidate for Ly6G6D positive cancer immunotherapy. Citation Format: Zhiheng Ren, Xiang Li, Shushan Lin, Kuo Zhang, Zhaofeng Li, Xiao Lin, Kaifeng Li, Ju Peng, Mi Zheng, Wen Yang, LiJia Li, Xiaoping Li, Stewart Leung. A novel Ly6G6D/4-1BB bispecific antibody targeting DNA mismatch repair proficient colorectal cancers shows potent antitumor activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6087.
Abstract 6048: Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy
Authors: Yumi Oh, Sung-Yup Cho, Sujeong Kim, Yunjae Kim, Hyun Kim, Hansoo Park, Yongsoo Jang, Soobin Park, Yong-Chul Kim
Journal: Cancer Research (2025)

Abstract Immune checkpoint therapy (ICT) offers durable responses in select cancer patients, yet resistance remains a significant challenge, prompting the exploration of underlying molecular mechanisms. We propose tyrosylprotein sulfotransferase-2 (TPST2), known for its role in protein tyrosine O-sulfation, as a suppressor of cancer immunity. Through in vivo genome-wide CRISPR screening, TPST2 loss-of-function emerged as a potential enhancer of anti-PD1 treatment efficacy. TPST2 suppressed interferon-γ (IFNγ) signaling by sulfating IFNγ receptor 1 at Y397 residue, while its downregulation boosted IFNγ-mediated signaling and antigen presentation. Depletion of TPST2 in cancer cells augmented anti-PD1 antibody efficacy in syngeneic mouse tumor models by enhancing tumor-infiltrating lymphocytes. RNA sequencing data revealed TPST2's inverse correlation with antigen presentation, and increased TPST2 expression is associated with poor prognosis and altered cancer immunity across cancer types. In an effort to develop novel cancer immunotherapies targeting TPST2, we have discovered LDD-5557, a lead compound with potent enzyme inhibitory activity through library screening and structure-based hit to lead optimization process. The lead compound showed an excellent in-vivo PK profile including high oral bioavailability and immunotherapeutic efficacies of significant upregulations of CD8 positive T-cells and antigen processing related genes in a dose-dependent manner by co-treatment with anti-PD1 in a MC38 syngeneic mouse model. These findings underscore TPST2's novel role in cancer immunity and advocate for its consideration as a therapeutic target in ICT-based treatments. Citation Format: Yumi Oh, Sung-Yup Cho, Sujeong Kim, Yunjae Kim, Hyun Kim, Hansoo Park, Yongsoo Jang, Soobin Park, Yong-Chul Kim. Genome-wide CRISPR screening identifies tyrosylprotein sulfotransferase-2 as a target for augmenting anti-PD1 efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6048.
Abstract 5828: Development of NK humanized mice models for the in vivo evaluation of NK cell-based therapeutics
Authors: Dong Wang, zhixiang zhang, zhongbao song, xiangnan qiang, qingyang gu
Journal: Cancer Research (2025)

With the recent advancements in anti-tumor immunotherapy, novel treatments have emerged and progressed rapidly. Several strategies are now being employed to enhance the efficacy of natural killer (NK) cells in tumor immunotherapy, including the use of monoclonal and multi-specific antibodies, as well as immune modulator molecules. Given these developments, there is an urgent need for the establishment of appropriate mouse models to effectively evaluate the therapeutic potential of these emerging immunotherapies. In this study, we developed a humanized mouse model for the specific reconstitution of functional and durable human NK cells within a murine system. In this model, human NK cells were purified from peripheral blood mononuclear cells (PBMCs) using magnetic bead separation, expanded in vitro, and subsequently engrafted into human IL-15 transgenic NOG mice. We collected blood samples from these mice to monitor human NK cell kinetics and profile using flow cytometry. The therapeutic efficacy of an anti-CD20 antibody was then evaluated in NK-humanized model using the SU-DHL-2 subcutaneous xenograft tumor model. Results indicated that anti-CD20 treatment was ineffective in non-NK-humanized mice. In contrast, in NK-humanized mice, human NK cells significantly inhibited tumor growth via antibody-dependent cellular cytotoxicity (ADCC). Additionally, we assessed NK cell intratumoral infiltration and the expression of activation markers at the end of the in vivo efficacy study, providing further insights into the immune response in the tumor microenvironment. In summary, we have developed a humanized mouse model capable of sustaining functional human NK cells for extended periods, ranging from weeks to months. This NK-humanized model provides a valuable preclinical platform for evaluating NK-modulating therapies and hold promise as a tool to accelerate the development of novel NK-based immunotherapeutics. Citation Format: Dong Wang, zhixiang zhang, zhongbao song, xiangnan qiang, qingyang gu. Development of NK humanized mice models for the in vivo evaluation of NK cell-based therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5828.