tbuckley/cabot-search huggingface dataset:
Abstract SY22-01: States of cell-cycle withdrawal
Authors: Sabrina L. Spencer
Journal: Cancer Research (2025)

Abstract A key determinant of tumor recurrence is whether residual cancer cells that remain after treatment are in a reversible state of cell-cycle withdrawal (quiescence/dormancy) or an irreversible state of withdrawal (senescence). This distinction has been difficult to make because quiescent and senescent cells are defined by overlapping biomarkers and because cell-cycle withdrawal is much more poorly characterized than the cell cycle itself. While the reigning model in the field is that senescence and quiescence are entirely distinct states, our data suggest that senescence markers are expressed in a graded fashion, with signals that increase gradually as a function of time spent withdrawn from the cell cycle. We therefore favor an alternative model in which quiescence and senescence exist on a continuum of cell-cycle withdrawal where the probability of cell-cycle re-entry approaches zero at senescence. If we can quantify a cell’s depth-of-withdrawal, we could potentially predict the likelihood of cell-cycle re-entry and tumor recurrence, or push residual cancer cells into a deeper state of withdrawal. Citation Format: Sabrina L. Spencer. States of cell-cycle withdrawal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY22-01.
Abstract LB238: Expanding the TEAD therapeutic potential with degraders: In vitro sensitivity, predictive biomarkers, and in vivo efficacy
Authors: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Melissa M. Ronan, Matthew G. Rees, Jennifer A. Roth, Peter Brandt
Journal: Cancer Research (2025)

Abstract TEAD transcription factors have emerged as clinically validated targets for cancers with dysregulated Hippo signaling, such as mesothelioma driven by NF2 inactivation or deficiency. We have developed a series of novel small-molecule targeted protein degraders of TEAD, designed to bind to TEAD interface 3. These compounds function by forming a ternary complex with the E3 ligase cereblon in cells, resulting in the ubiquitination and subsequent proteasomal degradation of TEAD. P65-047, one of these degraders, was evaluated using a large-scale cellular PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) screen, which revealed sensitivity in a select subset of cell lines beyond mesothelioma. Univariate analysis of the PRISM sensitivity profile and genomic features identified VGLL3 gene expression as the strongest association. A multivariate gene expression biomarker analysis yielded a model that can predict cell line sensitivity to P65-047 (AUC = 0.82). Unlike the more well-known coactivators YAP and TAZ, which bind simultaneously to interfaces 1, 2, and 3, VGLL3 is a TEAD coactivator that binds only to interfaces 1 and 2. Additional findings from lineage enrichments and multivariate biomarker analysis will also be discussed. In pharmacokinetic experiments conducted in mice, intraperitoneal administration of P65-047 resulted in high exposure in both plasma and lung tissue. A dose-dependent degradation of TEAD1 was observed in lung tissue 24 hours after a single dose, with the compound being well tolerated and with no signs of toxicity. P65-047 was further tested in a mouse CDX model of mesothelioma using the NF2-deficient cell line NCI-H226. The results of this study will be discussed. Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Melissa M. Ronan, Matthew G. Rees, Jennifer A. Roth, Peter Brandt. Expanding the TEAD therapeutic potential with degraders: In vitro sensitivity, predictive biomarkers, and in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB238.
Abstract LB395: Neuroprotectin D1 alleviates metastatic bone cancer pain via GPR37/β-arrestin 2 pathway
Authors: Kaiyuan Wang, Limei Yuan, Huifang Tu, Ruichen Shu, Yiqing Yin
Journal: Cancer Research (2025)

Abstract Osteolytic bone cancer pain is a primary concern for cancer patients with bone metastasis, and current therapies offer inadequate pain relief. In the present study, we found that activation of the G protein-coupled receptor 37 (GPR37) by neuroprotectin D1 (NPD1) alleviates both acute and persistent pain in multiple mouse models of bone cancer. GPR37 agonists also protect against cancer-induced bone destruction. Mechanistically, NPD1 binding to GPR37 in macrophages promotes the release of IL-10, which further inhibits cancer-induced osteoclastogenesis. Moreover, direct activation of GPR37 in dorsal root ganglion (DRG) neurons and the spinal dorsal horn reduces action potential firing and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), thereby suppressing cancer-induced neuronal hyperexcitability. Importantly, the analgesic and protective effects of NPD1 are abolished in Gpr37−/− mice, and β arrestin 2 is identified as a key mediator in IL-10 release and neuronal inhibition. In patients with bone metastases, plasma levels of endogenous NPD1 are negatively correlated with both pain intensity and the bone resorption marker CTX-I. Collectively, our findings highlight GPR37 activation by NPD1 as a potential therapeutic strategy for alleviating bone cancer pain through direct and synergistic inhibition of osteoclastogenesis and neuronal hyperexcitability. Citation Format: Kaiyuan Wang, Limei Yuan, Huifang Tu, Ruichen Shu, Yiqing Yin. Neuroprotectin D1 alleviates metastatic bone cancer pain via GPR37/β-arrestin 2 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB395.
Abstract LB347: Telomere-to-telomere long read whole genome sequencing provides novel insights into ovarian cancer genomics
Authors: Shiro Takamatsu, Jian Li, Thomas Welte, Eleonora Khlebus, Veena Vuttaradhi, Allison Brodsky, Barrett Lawson, Robert T. Hillman
Journal: Cancer Research (2025)

Abstract Background: High-grade serous ovarian carcinoma (HGSOC) is driven by chromosomal instability and patterns of genomic rearrangement have predictive and prognostic value in this disease. Nearly all next generation sequencing performed to date rely on short read sequencing, which is unable to resolve complex rearrangements or analyze repetitive centromeric or telomeric regions. Here we combine long-read sequencing (LRS) platform with the recently completed telomere-to-telomere (T2T-CHM13) reference genome to report the first comparison of whole genome variation in BRCA1-mutated and CCNE1-amplified HGSOC. Methods: High-molecular-weight DNA was extracted from cryopreserved, pre-treatment tumor and matched blood samples from six HGSOC patients and sequenced using Oxford Nanopore PromethION platform. Base-called reads were aligned to both the GRCh38 and T2T-CHM13 reference genomes for the analysis of SNVs, indels, allele-specific CNVs, complexed structural variants, transposable element insertions, and CpG methylation patterns. Results: Somatic pathogenic TP53 mutations were identified in all tumors (P1-P6). Germline pathogenic BRCA1 mutations were present in two cases (P1, P2), while CCNE1 amplification was observed in the remaining four cases (P3-P6). Homologous recombination deficiency (HRD) scores were elevated in BRCA1-mutated tumors (73 and 84) compared to CCNE1-amplified tumors (71, 43, 53, and 29, respectively). Complete loss of heterozygosity in chromosome 17 was observed in all tumors. Chromoplexy was detected in five tumors (P1, P2, P4-P6). Focal amplifications associated with extrachromosomal DNA and breakage-fusion-bridge cycles were observed in P2 and P6. Telomere length was significantly shortened in all tumors compared to matched normal samples. Additionally, CpG methylation levels were significantly reduced in centromeric satellite repeats and inserted transposable elements in all tumors than in normal samples. Conclusion: This study establishes the first LRS-based analysis workflow for comprehensive genomic characterization of HGSOC, uncovering novel alterations in previously inaccessible genomic regions. These findings highlight the potential of LRS as a new gold standard for whole genome analysis in HGSOC, warranting further investigation for its clinical and research applications. Citation Format: Shiro Takamatsu, Jian Li, Thomas Welte, Eleonora Khlebus, Veena Vuttaradhi, Allison Brodsky, Barrett Lawson, Robert T. Hillman. Telomere-to-telomere long read whole genome sequencing provides novel insights into ovarian cancer genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB347.
Abstract SY45-01: Characterizing the effects of the tumor microbiome on the response to immunotherapy
Authors: Stephan Spahn, Yaara Zwang, Nancy Gavert, Michal Lotem, Mark Lythgoe, Ayelet Shai, Iris Barshack, Noam Shental, Simon Heidegger, Talia Golan, Jonathan Krell, Ravid Straussman
Journal: Cancer Research (2025)

Abstract The presence of bacteria in solid human tumors has been documented for over 100 years. Still, it has only been in recent years that a more thorough characterization of this low biomass microbiome and its effects has been pursued. We have studied tumor biopsies that were taken before the initiation of treatment with checkpoint inhibitors (CPIs) and compared the tumor microbiome within these samples with the tumor immune landscape and the response to immune therapy. We found a few bacterial taxa and bacteria functions that were highly correlated with the response to CPIs. In my talk, I will present our main findings as well as our follow-up studies to validate the main results and dissect the mechanisms that underlie the effects of intra-tumor bacteria on the response to CPIs. Citation Format: Stephan Spahn, Yaara Zwang, Nancy Gavert, Michal Lotem, Mark Lythgoe, Ayelet Shai, Iris Barshack, Noam Shental, Simon Heidegger, Talia Golan, Jonathan Krell, Ravid Straussman. Characterizing the effects of the tumor microbiome on the response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY45-01.
Abstract LB431: Discovery and characterization of a highly potent and orally available small-molecule inhibitor for diverse KRAS mutations
Authors: Yongxian Zhang, Fei Yang, Zhigang Feng, Meimei Sun, Xinyan Huang, Haibing Deng, Hongping Yu, Yao-chang Xu, Zhui Chen, Haiyan Ying
Journal: Cancer Research (2025)

Abstract KRAS is frequently mutated in human cancers, including pancreatic (∼90%), colorectal (∼35%), and lung cancers (∼25%). While selective inhibitors targeting KRASG12C and KRASG12D mutations have been identified and are either approved or in clinical development, there remains a significant unmet need for therapies targeting other highly prevalent KRAS mutations, such as KRASG12V. This study describes the discovery and preclinical characterization of ABK-KRAS-1, a novel, potent, and highly orally bioavailable small-molecule inhibitor with broad activities against multiple KRAS mutations. ABK-KRAS-1 exhibited high binding affinity and strong biochemical activity against a range of KRAS mutations in vitro. In cellular experiments, treatment with ABK-KRAS-1 effectively inhibited KRAS signaling across a diverse panel of KRAS mutant cancer cell lines, demonstrated by reduced phosphorylation of ERK1/2 (p-ERK). Additionally, ABK-KRAS-1 significantly impaired cell viability at sub-nanomolar to nanomolar concentrations. In vivo efficacy studies further demonstrated robust anti-tumor activity of ABK-KRAS-1 in multiple xenograft models dependent on various KRAS mutations. Preclinical DMPK analyses confirmed excellent bioavailability across multiple animal species. Collectively, the superior preclinical profile of ABK-KRAS-1 supports its advancement into preclinical development. Citation Format: Yongxian Zhang, Fei Yang, Zhigang Feng, Meimei Sun, Xinyan Huang, Haibing Deng, Hongping Yu, Yao-chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of a highly potent and orally available small-molecule inhibitor for diverse KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB431.
Abstract LB321: ACTL6A (SWI/SNF complex subunit) cooperates with EZH2 and maintains a repressive chromatin state to modulate a immune COLD phenotype in squamous cancers
Authors: SrinivasVinod Saladi, Nana Chen
Journal: Cancer Research (2025)

Abstract Squamous cell carcinoma of the head and neck (HNSCC) is a common cancer worldwide with the overall survival rate for patients with HNSCC at 50%. Hippo pathway is altered in 50% of head and neck cancers. Amplification of the SWI/SNF chromatin remodeling factor ACTL6A/BAF53a gene is observed in 20% of HNSCCs and is associated with poor clinical outcomes. However, the mechanisms by which ACTL6A contributes to HNSCC remain unknown. Here, we demonstrate that overexpressed ACTL6A mediates transcriptional repression of a tumor cell-intrinsic immune response program including antigen presentation machinery and chemotactic cytokine genes. Our prior studies have shown that ACTL6A and Hippo pathway collaborate to drive HNSCC. Detailed analysis of this pathway reveals mechanisms by which tumor cell-intrinsic immune response program is inhibited including antigen presentation machinery and chemotactic cytokine genes. We uncover the direct molecular mechanism of ACTL6A-mediated repression, revealing that high-level ACLT6A induces an unanticipated increase in EZH2 chromatin binding and H3K27 tri-methyl deposition, and we show that clinical EZH2 inhibitors mimic the gene expression changes and physiologic effects of ACTL6A loss. Utilizing single cell RNA and single cell ATAC approaches in head and neck, and skin squamous cancer patient tumors that are surgically removed, we uncover the chromatin state indicative of a COLD tumor phenotype and contributing to cellular plasticity and tumor heterogeneity. Conclusively, we identify a therapeutically targetable epigenetic program for immune evasion in head and neck cancers. Citation Format: SrinivasVinod Saladi, Nana Chen. ACTL6A (SWI/SNF complex subunit) cooperates with EZH2 and maintains a repressive chromatin state to modulate a immune COLD phenotype in squamous cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB321.
Abstract LB448: Unveiling novel type of cell death caused by depletion of lncRNA <i>JUNI</i>
Authors: Isha Soni, Vikash Kumar, Eitan Shaulian
Journal: Cancer Research (2025)

Abstract Cellular proliferation and cell death are crucial for the sustenance of organismal wellbeing. Cancer cells evade most of the apoptotic and non-apoptotic cellular death pathways to survive and proliferate. In the last two decades, extensive research has demonstrated the involvement of various long non-coding RNAs (lncRNAs) in cancer development and progression. One such lncRNA is JUNI (LINC01135, JUN-DT), a stress-induced lncRNA upregulated under genotoxic stress, such as exposure to UV irradiation and chemotherapeutic drugs. JUNI is a primate-specific gene and induces the activity of the transcription factor and oncogene c-Jun. Depletion of JUNI sensitizes cancer cells to chemotherapeutic agents, thereby, reducing their survival. However, JUNI’s role in the survival of cancer cells is poorly understood.In our investigation, using melanoma and cervical adenocarcinoma cell lines, we identified and characterized a novel form of cell death caused by depletion of JUNI in cancer cells, even without the exposure to stress. The cell death exhibited a morphology distinct to any previously known cell death types. We showed that silencing of JUNI for 96 hours leads to up to 40-60% cell death in various cell types. Silencing for about two weeks reduces the survival to 20-25% relative to unsilenced cells. The effects of JUNI on cellular survival are more significant than the effects of its regulated gene c-Jun, whose knockdown leads to up to 40% cell death, 96 hours post-knockdown. Silencing of c-Jun for up to two weeks resulted in half the cell death caused by JUNI’s silencing. Transfecting JUNI-silenced cells with c-Jun expression vector improved the survival partially. These results suggest JUNI’s effect on cellular survival to be mostly independent of c-Jun activity. A morphological characterization of JUNI-induced cell death using high-magnification fluorescent microscopy revealed a novel cell death phenotype which does not conform to any known cell death type.Our study reveals the importance of JUNI for the survival of chemotherapy-treated and naïve cancer cells, which, in its absence, die via novel cell death type. Our investigation provides new insights in lncRNA biology, highlighting JUNI as a prospective therapeutic target, potentially bridging the gap between fundamental research and clinical oncology. Citation Format: Isha Soni, Vikash Kumar, Eitan Shaulian. Unveiling novel type of cell death caused by depletion of lncRNA JUNI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB448.
Abstract LB222: Preclinical characterization of IBI3010, a FRα targeting biparatopic antibody-drug conjugate (ADC), for the treatment of FRα expressing tumors
Authors: Bo Wang, Jiakai Xing, Shuaixiang Zhou, Weiwei Wu, Min Wu, Rongmei Zuo, Chenchen Zhu, Menghui Zhao, Li Li, Chengjie Cai, Nan Gao, Zhihai Wu, Ninghuan Li, Zeyu Liu, Jinling Xu, Bingliang Chen, Kaijie He
Journal: Cancer Research (2025)

Abstract Folate Receptor alpha (FRα) is a validated target that is overexpressed in multiple cancers with unmet medical need, including ovarian, lung and breast cancers, while restricted expression in normal tissues. Although mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate (ADC) with a microtubule inhibitor, has been approved from the FDA for the treatment of FRα-expressing platinum-resistant ovarian cancer. There is still a large proportion of patients who do not respond to treatment, especially those with low FRα expression. We have developed a next-generation anti-FRα ADC, IBI3010, which consists of an FRα-targeting biparatopic antibody that is conjugated to a novel topoisomerase I inhibitor, NT1, with a homogeneous drug-to-antibody ratio of 8 (DAR8). Here, we describe the key pharmacological experiments, in vivo efficacy and results from the good laboratory practice (GLP) toxicology studies. In vitro studies have shown that the biparatopic antibody exhibits higher binding and internalization in tumor cells. IBI3010 shows comparable or better cytotoxicity to IMGN853 in various FRα expressing cancer cell lines. In addition, IBI3010 has superior in vitro bystander effect compared to IMGN853. In vivo efficacy was evaluated in various cell line-derived xenograft models with different FRα expression levels. IBI3010 exhibits superior antitumor activity to IMGN853, especially in the FRα low-expression models. In the GLP toxicology study, IBI3010 was tolerated in cynomolgus monkeys at all dose levels, with the highest dose of 60 mg/kg, defined as the highest non-severely toxic dose (HNSTD). Our findings support the clinical development of IBI3010 to evaluate its potential as an ADC therapeutic for FRα-expressing solid tumors. Citation Format: Bo Wang, Jiakai Xing, Shuaixiang Zhou, Weiwei Wu, Min Wu, Rongmei Zuo, Chenchen Zhu, Menghui Zhao, Li Li, Chengjie Cai, Nan Gao, Zhihai Wu, Ninghuan Li, Zeyu Liu, Jinling Xu, Bingliang Chen, Kaijie He. Preclinical characterization of IBI3010, a FRα targeting biparatopic antibody-drug conjugate (ADC), for the treatment of FRα expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB222.
Abstract LB310: Methylation synthetic lethality: <i>SMARCA1</i> methylation and inhibition of pyrimidine synthesis
Authors: Hideyuki Takeshima, Yui Ohashi, Ryoma Mashiko, Toshikazu Ushijima
Journal: Cancer Research (2025)

Abstract Synthetic lethality is a promising therapeutic strategy, but the number of combinations of a mutated gene and a therapeutic target gene is limited. In contrast with a mutation, DNA methylation is frequently present in many types of cancers, and can be a rich source for a synthetic lethality. So far, BRCA1 methylation with a PARP inhibitor is known as a synthetic lethality [Kawachi et al., Breast Cancer Res Treat, 181:323-329, 2020]. We have been searching to identify a novel synthetic lethal combinations by using methylated genes. In this study, as a methylated gene, we focused on SMARCA1, which was often methylated in various types of cancers [Takeshima et al., Cancer Lett, 357:328-338, 2015], and encodes a ISWI-type chromatin remodeling factor. Genes lethal for cancer cell lines with SMARCA1 low expression were screened for using the sgRNA screening database [DepMap], and two of top 3 candidate genes identified were genes related to pyrimidine biosynthesis pathway, DHODH and UMPS. To experimentally validate the usefulness of this combination, five SMARCA1-methylated and seven -unmethylated cell lines were treated with a DHODH inhibitor, and SMARCA1-methylated cell lines showed higher sensitivity. These cell lines included three cell lines not used in the screening, validating the usefulness of the combination. Sensitivity to DHODH inhibition in SMARCA1-methylated cell line, RKO, was reduced by exogenous overexpression of SMARCA1, indicating the causal role of SMARCA1 methylation for the synthetic lethality. We are now evaluating in vivo usefulness of this combination. These results showed that DNA methylation is a rich source for a synthetic lethality, and the inhibition of pyrimidine synthesis is a promising therapeutic strategy for SMARCA1-methylated cancers. Citation Format: Hideyuki Takeshima, Yui Ohashi, Ryoma Mashiko, Toshikazu Ushijima. Methylation synthetic lethality: SMARCA1 methylation and inhibition of pyrimidine synthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB310.