tbuckley/cabot-search huggingface dataset:
Abstract 3498: Generation of an NG2 targeting bispecific antibody for induction of T cell immunity against melanoma
Authors: Nisha Prakash, Sebastian Hörner, Ilona Hagelstein, Gundram Jung, Helmut R. Salih
Journal: Cancer Research (2025)

Abstract Analysis of mRNA levels using The Cancer Genome Atlas (TCGA) identifies high expression of neuron-glial antigen 2 (NG2) in several tumor tissues, particularly in melanoma, where it is selectively overexpressed in 90% of cases. NG2, also known as Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP) was originally identified on the surface of cutaneous melanoma. Due to its tumor-restricted expression, NG2 is an attractive target for immunotherapeutic approaches. Strategies that aim at the direct and specific lysis of malignant cells are needed in melanoma treatment despite the advent of immune checkpoint inhibiting antibodies. The latter lack tumor-specific activity and the capacity to directly recruit T cells to the tumor site. As a consequence, a considerable proportion of patients do not respond to immune checkpoint inhibitors, or for a limited time only. Here we report on the generation and characterization of two NG2 bispecific antibodies (bsAbs) with differing T cell binding properties. NG2xUCHT-1 contains a CD3 binder with high affinity, whereas NG2xM18 was generated using a modified UCHT-1 with approximately 100-fold lower CD3 affinity. The purity and integrity of the generated bsAbs were biochemically confirmed using SDS-PAGE and size exclusion chromatography. Dose titration of the two bsAbs on NG2 expressing cell lines documented dose-dependent binding with similar EC50 values of ∼0.5nM. Functional analysis in-vitro revealed that both bsAbs potently induce T cell activation and proliferation, resulting in strictly target-dependent tumor cell lysis. Of note, despite the significantly reduced binding affinity to T cells, NG2xM18 mediated comparable antitumor efficacy as NG2xUCHT-1, but induced substantially lower secretion of cytokines like IL-2, IFN-γ, and TNF, pointing to an optimized ratio of efficacy and potentially dose limiting side effects caused by cytokine release syndrome (CRS). Our findings indicate that NG2xM18 is a promising therapeutic compound that may allow for effective clinical dosing with reduced side effects. Citation Format: Nisha Prakash, Sebastian Hörner, Ilona Hagelstein, Gundram Jung, Helmut R. Salih. Generation of an NG2 targeting bispecific antibody for induction of T cell immunity against melanoma [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 3498.
Abstract 2266: Evaluations of more than 1500 blood metabolite biomarkers with risk of eight common cancers and their subtypes using genetic instruments
Authors: Zheng Guo, Guochong Jia, Fangcheng Yuan, Lili Liu, Shuai Xu, Jirong Long, Wei Zheng
Journal: Cancer Research (2025)

Abstract Background: Many epidemiologic studies have measured blood metabolites and evaluated their associations with risk of cancers. However, conventional epidemiologic studies may suffer from various biases, limiting their ability for causal inferences. We performed a large Mendelian randomization (MR) study to systematically evaluate blood metabolite biomarkers in relation to cancer risk, including large numbers of associations not previously investigated in either convention epidemiologic or MR studies. Methods: We systematically searched the literature and obtained data from 29 genome-wide association studies (GWAS) to identify blood metabolite-associated genetic loci (mQTLs) among 324, 771 individuals of European ancestry. After systematically evaluating all metabolites and mQTLs evaluated in these studies, we selected 1630 metabolite biomarkers for MR analyses using summary statistic data generated from GWAS conducted among 2, 068, 121 individuals of European ancestry for eight common cancers (breast, colorectal, endometrial, kidney, lung, ovarian, pancreatic, and prostate) and 19 subtypes of breast, kidney, lung, and ovarian cancers. The inverse variance weighted (IVW) method was used as the primary approach for MR analyses. Other methods, including MR-Egger, and MR-PRESSO, were used to evaluate possible pleiotropic effects and robustness of study findings. Statistical significance was judged using Bonferroni and FDR corrected P-value to reduce type 1 errors. Results: We identified 106 biomarker-cancer associations under the significant threshold after Bonferroni correction. Among these, 68 were associated with an increased risk of cancer, while 38 were associated with a decreased risk of cancer. Under an FDR-corrected P &amp;lt; 0.05 but not reaching the Bonferroni-adjusted significant threshold, we identified 119 additional associations, including 65 metabolite biomarkers as potential risk factors and 54 as potential protective factors. Conclusion: Our MR analysis uncovered large numbers of novel associations and provided strong evidence for causal inferences of blood metabolite biomarkers with cancer risk. Citation Format: Zheng Guo, Guochong Jia, Fangcheng Yuan, Lili Liu, Shuai Xu, Jirong Long, Wei Zheng. Evaluations of more than 1500 blood metabolite biomarkers with risk of eight common cancers and their subtypes using genetic instruments [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 2266.
Abstract 2316: Young-onset cancer incidence trends: Cohort effects on onset versus period effects on diagnosis
Authors: Lukas Owens, Jonathan Shuhendler, Marc D. Ryser, Ruth D. Etzioni
Journal: Cancer Research (2025)

Background: The disproportionate increase in the diagnosis of certain cancers among younger individuals is generating intense concern. Many studies attribute the increase in so-called “young-onset” cancer to an etiologic cause but questions have also arisen about the role of earlier diagnosis. Methods: We simulate incidence trends from a natural history model that includes healthy, preclinical, and clinical disease states, where the clinical state represents diagnosis. We superimpose birth cohort effects on the rate of disease onset and period effects on the rate of transitioning to the clinical state. We examine patterns of relative incidence by age group and five-year calendar interval from 2000-2019 for six “young-onset” cancers (colon, rectum, female breast, gastric, pancreas, kidney), and identify cohort and period effects that lead to matching relative incidence patterns. Results: Two types of effects are broadly consistent with the trends in younger individuals: (1) A birth-cohort effect on disease onset that begins around 1970 and becomes more pronounced with later birth years, or (2) A progressive reduction over time in the duration of preclinical disease. An earlier, protective birth cohort effect is consistent with recent trends in incidence in older individuals that are the reverse of those in younger individuals for colon, rectal, and gastric cancers. Discussion: A disease model provides clues about the possible drivers of cancer incidence trends, suggests constraints on the patterns of exposures that might be implicated etiologically, and indicates that consideration of the role of diagnostic changes is warranted alongside potential etiologic explanations. Citation Format: Lukas Owens, Jonathan Shuhendler, Marc D. Ryser, Ruth D. Etzioni. Young-onset cancer incidence trends: Cohort effects on onset versus period effects on diagnosis [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 2316.
Abstract 1481: Targeting DNA damage responsive pathways in cancer therapy
Authors: Junjie Chen
Journal: Cancer Research (2025)

Abstract DNA double strand breaks (DSBs) result in activation of several key DNA damage response (DDR) kinases including ATM, ATR, and DNA-PK. These protein kinases not only promote DNA damage-induced checkpoint control, but also facilitate DSB repair in humans. Thus, these DDR kinases have become promising drug targets for cancer therapy. However, the benefits of targeting DDR kinases remain to be realized, in part due to the lack of predictive biomarkers. By undertaking CRISPR screens with inhibitors targeting key DDR kinases, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that ATM and PARP inhibitors showed remarkable synergy, which depends on the dominant negative function of ATM inhibition. Moreover, to provide comprehensive and unbiased perspective of DDR signaling pathways, we performed 30 fluorescence-activated cell sorting-based genome-wide CRISPR screens with antibodies recognizing distinct endogenous DNA damage-signaling proteins to identify new regulators involved in DNA damage response (DDR). We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as new modulators that regulate ATM protein level. Additionally, we discovered that GNB1L is a master regulator of DDR signaling via its role as a co-chaperone for PIKK proteins. Collectively, these screens offer a rich resource for further investigation of DDR, which may provide insight into strategies of targeting these DDR pathways to improve therapeutic outcomes. More recently, we have adopted dTAG technology for the investigation of many essential DDR and replication proteins, which provide mechanistic insights into the roles of these essential proteins in genome maintenance. Additionally, we have expanded FACS-based screens for the studies of other cancer-associated pathways and explored key biological processes critical for cancer progression in vivo. These studies will facilitate the development of better therapies for cancer patients. Citation Format: Junjie Chen. Targeting DNA damage responsive pathways in cancer therapy [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 1481.
Abstract 1657: HZ-S109, a potent and selective HPK1 degrader with enhanced T cell modulation efficacy and improved bioavailability
Authors: Yizhe Wu, Jiangfeng Xie, Jinglai Huang, Mengchao Zheng, Xinglu Zhou
Journal: Cancer Research (2025)

Abstract Background: Hematopoietic Progenitor Kinase 1 (HPK1/MAP4K1) has been demonstrated to restrain T cell activation through phosphorylating SLP-76 at Serine 376 during the T-cell activation process. Given its irreplaceable negative regulation role in TCR pathway, HPK1 is considered as a promising target in immuno-oncology. Recently, HPK1 has been shown to function as scaffolding protein and bind to adaptor proteins to promote JNK signaling and actin cytoskeleton rearrangement involved in lymphocyte adhesion. Additionally, the turnover rate of HPK1 is low. These evidences suggest that HPK1 is a suitable target to develop protein-degrader. Objective: Accordingly, we described our state-of-the-art work in discovery and identification of HPK1 degrader HZ-S109. We asked if this degrader could exhibit stronger engagement with the HPK1 target, leading to the restoration of suppressed T-cell function and inhibition of tumor growth. Methods: HZ-S109 was identified based on our in-house unique DaTProD® platform. CCK-8, ELISA and WB detection were performed by PEG2, NECA and TGF-β induced depleted cell model in vitro.PK/PD detection and tumor measurement were performed by oral gavage of CT-26 subcutaneously transplanted tumor models in C57BL/c mice. Results: HZ-S109 exhibits potent HPK1 degradation with DC50 values lower than 10 nM across various cell types, including Jurkat, Ramos, PBMC, and CAR-T cells. Importantly, HZ-S109 demonstrated no significant effect on other family members, such as GCK, GLK, HGK, or KHS. HZ-S109 can significantly enhance the activation of primary T cell at nanomolar level concentrations, with the maximum activation fold exceeding 15-fold. Furthermore, HZ-S109 restores T cell function in the presence of multiple immune-suppressed conditions including NECA/ PGE2/ TGF-β or their combination. Despite its higher molecular weight, HZ-S109 boasts superior oral bioavailability. In in-vivo anti-tumor efficacy evaluation, oral administration of HZ-S109, either as a single agent or in combination with PD-L1 antibody, robustly suppressed the tumor growth in CT26, A20 and MC38 syngenic mice model, achieving a tumor growth inhibition (TGI) of over 90%. These results suggest that HZ-S109 stands out as a potent and distinct HPK1 modulator, exhibiting enhanced potency and oral bioavailability. At present, HZ-S109 is in the IND-enabling study stage. Citation Format: Yizhe Wu, Jiangfeng Xie, Jinglai Huang, Mengchao Zheng, Xinglu Zhou. HZ-S109, a potent and selective HPK1 degrader with enhanced T cell modulation efficacy and improved bioavailability [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 1657.
Abstract 4245: Targeting ERalpha disorder-function mechanisms in ER-positive breast cancer
Authors: Zhanwen Du, Shuqi Luo, Sichun Yang
Journal: Cancer Research (2025)

Background: The estrogen receptor (ER or ERalpha) is commonly activated by phosphorylation at serine 118 (Ser118) within its intrinsically disordered N-terminal transactivation domain (NTD), enabling estrogen-independent function in breast cancer. While kinase inhibitors targeting this modification are in clinical trials, understanding the molecular mechanism of activation is essential for developing direct therapeutic strategies. Methods: We combined small-angle X-ray scattering and NMR spectroscopy with functional assays to characterize conformational changes in the ER-NTD. We then conducted activity-guided screening to identify small molecules directly targeting the disordered NTD. Results: Ser118 phosphorylation triggers an unexpected conformational expansion by disrupting specific hydrophobic clusters between aromatic-rich regions within the NTD - a mechanism extending beyond simple electrostatic effects (Nature 2024, in press). Leveraging this insight, we developed selective small molecules that directly bind the disordered NTD and potently inhibit growth of hormone-independent breast cancer models. Conclusions: Our work establishes both the mechanistic basis of ER regulation and a therapeutic framework for targeting intrinsically disordered regions in treatment-resistant breast cancer. These findings open a new avenue for first-in-class drugs that modulate protein disorder in cancer. Citation Format: Zhanwen Du, Shuqi Luo, Sichun Yang. Targeting ERalpha disorder-function mechanisms in ER-positive breast 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 4245.
Abstract 3168: High-throughput hybridoma monoclonality characterization using the Celigo™ Image Cytometer
Authors: Mong-Shang Lin, Carolina Franco Nitta, Mackenzie Pierce, Bo Lin, Leo L. Chan, Jessie Ni
Journal: Cancer Research (2025)

Abstract Hybridomas are hybrid cells produced by fusing an antibody producing B cell with a myeloma cell to produce a specific monoclonal antibody. In the process of generating stable clones, developers are often required to perform several rounds of subcloning by plating cultures with a density of a single cell per well. The wells with a single colony are then selected to produce the target antibodies. Traditionally, this lengthy process was heavily relied on researchers with extensive training and experience; however, even experienced researchers may suffer from human error of selecting clones that are not truly monoclonal, thus potentially delaying antibody development and increasing costs. In this work, we demonstrate a high-throughput solution that has successfully established monoclonality of our hybridoma by employing the Celigo™ Image Cytometer (Revvity Health Sciences, Inc., Lawrence, MA) with the robotic arm accessory to screen potential candidates for downstream antibody production under a GMP environment. The Celigo™ is a plate-based, whole well, high-throughput image cytometry system with brightfield and fluorescence imaging capabilities. In combination with the robotic arm, automation can be implemented to further streamline the monoclonality workflow, and subsequently reduce subcloning personnel time by 25-50%, while also minimizing human handling errors by at least 10-fold. Following imaging acquisition, an in-house monoclonality analytical software was utilized to provide concrete documentation for every clone selected for production. Lastly, we demonstrated that time for hybridoma development in clone confirmation screening as well as subcloning could be further improved by incorporating ClonePix technology. Citation Format: Mong-Shang Lin, Carolina Franco Nitta, Mackenzie Pierce, Bo Lin, Leo L. Chan, Jessie Ni. High-throughput hybridoma monoclonality characterization using the Celigo™ Image Cytometer [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 3168.
Abstract 1425: Transcriptional and epigenomic landscape of paclitaxel resistant MCF-7 cells
Authors: Julie Hanson Ostrander, Thu Truong, Marygrace Trousdell, Kyla Hagen, Nuri Alpay Temiz, Michael Ciccone, Fatemah Iman Dewji, Camila dos Santos, Carol A. Lange
Journal: Cancer Research (2025)

PELP1 and SRC-3 function as essential coregulatory proteins in normal development and cancer. Overexpression of SRC-3 and PELP1 independently influence cancer cell biology through the regulation of 1) proliferation; 2) apoptosis and autophagy; 3) migration, invasion, and metastasis; and 4) therapy resistance. PELP1 and SRC-3 have both nuclear and cytoplasmic functions, and prior reports indicate that cytoplasmic localization of SRC-3 is necessary for SRC-3 phosphorylation that impacts the transcriptional coregulatory function of SRC-3. Cytoplasmic localization of PELP1 promotes tamoxifen and paclitaxel resistance, and breast cancer stem-like cell (CSC) phenotypes. We previously showed that cytoplasmic and nuclear PELP1/SRC-3 complexes are enriched in ER+ therapy resistant breast cancer. Our published data suggests that altered PELP1/SRC-3 signaling leads to altered gene expression that contributes to the expansion of breast CSC population in therapy resistant ER+ breast cancer. To better understand the transcription and epigenomic landscape of this therapy resistant model, we used a combination of RNA-seq and CUT&amp;RUN. Genes previously shown to be associated with paclitaxel resistance were found upregulated in MCF7 TaxR CSC-enriched tumorspheres (i.e. ABCB1, TUBB2B), with ABCB1 being the most differentially expressed gene compared to parental MCF7 cells. RNA-seq analysis suggests that an upregulation of genes involved in interferon and inflammatory response, as well and Ras signaling and EMT in TaxR cells. We also identified 114 overlapping genes from our TaxR model and our previously published cytoplasmic PELP1 model. Pathway analysis indicates that these genes are regulated by nuclear receptors (i.e. ER and PR), which is supported by an increase in PR expression in TaxR CSC-enriched 3D cultures. CUT&amp;RUN data indicates an enrichment in PELP1/SRC-3 overlapping peaks in TaxR cells. Genes associated with overlapping peaks are associated with androgen response, cholesterol homeostasis, notch signaling, protein secretion and TGF-beta signaling MSigDB Hallmark pathways. Together these data support our hypothesis that PELP1/SRC-3 complexes are reprogrammed to promote therapy resistances and CSC phenotypes. We aim to use these studies to identify pathways that can be targeted within CSCs to eliminate this quiescent population and prevent breast cancer metastasis. Citation Format: Julie Hanson Ostrander, Thu Truong, Marygrace Trousdell, Kyla Hagen, Nuri Alpay Temiz, Michael Ciccone, Fatemah Iman Dewji, Camila dos Santos, Carol A. Lange. Transcriptional and epigenomic landscape of paclitaxel resistant MCF-7 cells [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 1425.
Abstract 2586: PAI-1 promotes tumor angiogenesis and metastasis via crosstalk between NSCLC cells and CAFs
Authors: Kazuhiro Okada, Ken Suzawa, Yin Min Thu, Ryunosuke Fujii, Kousei Ishimura, Ryota Fujiwara, Kazuya Hisamatsu, Ryo Yoshichika, Tomoaki Higashihara, Naohiro Hayashi, Fumiaki Mukohara, Mao Yoshikawa, Yuma Fukumoto, Keiichi Date, Hidejiro Torigoe, Kazuhiko Shien, Shinichi Toyooka
Journal: Cancer Research (2025)

Plasminogen activator inhibitor -1 (PAI-1) plays a multifaceted role in the tumor microenvironment, with its high expression correlated with poor prognosis in multiple cancers, including non-small cell lung cancer (NSCLC). Our group’s previous studies have shown that cancer-associated fibroblasts (CAFs) induced PAI-1 in lung cancer cells and that PAI-1 mediated the MET-targeted therapy resistance in NSCLC. In this study, we discovered that CAFs promoted PAI-1 as a secretory protein and its expression in cancer cells themselves and into the conditioned medium by the stimulation of CAF-derived stimulatory factors of transforming growth factor beta-1 (TGFb-1) and -3. Next, we used several lung cancer cell lines with different mutational profiles to assess the effect of PAI-1 in the tumor microenvironment. We investigated the phenotypic changes of lung cancer cells by recombinant human PAI-1 administration and the PAI-1 overexpressed lung cancer cell lines. PAI-1 increased the migratory ability of cancer cells and promoted epithelial to mesenchymal transition (EMT). PAI-1 contributed to tumor progression via the enrichment of EMT, extracellular matrix signaling, and inflammatory and immune responses according to gene set enrichment analysis (GSEA) revealed by the PAI-1 overexpressed lung cancer cells. Moreover, PAI-1 also promoted angiogenesis via the vascular endothelial growth factor (VEGF) pathway supported by the tube formation assay, western blot pathway analysis, and the GSEA. This impact is further validated through vivo study, in which the inhibition of PAI-1 improves the anti-cancer targeted therapy in vivo, where the tumor growth is inhibited by the combination of target therapy and the PAI-1 inhibitor, tiplaxtinin. The tumors from PAI-1 overexpressed lung cancer cells xenograft models also showed high expression of CD31 compared to control, confirming that angiogenesis is being promoted in these tumors. These findings underscore the clinical importance of PAI-1 as an important target for personalized anti-cancer drug therapy. Citation Format: Kazuhiro Okada, Ken Suzawa, Yin Min Thu, Ryunosuke Fujii, Kousei Ishimura, Ryota Fujiwara, Kazuya Hisamatsu, Ryo Yoshichika, Tomoaki Higashihara, Naohiro Hayashi, Fumiaki Mukohara, Mao Yoshikawa, Yuma Fukumoto, Keiichi Date, Hidejiro Torigoe, Kazuhiko Shien, Shinichi Toyooka. PAI-1 promotes tumor angiogenesis and metastasis via crosstalk between NSCLC cells and CAFs [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 2586.