tbuckley/cabot-search huggingface dataset:
Abstract 2362: Bitter taste receptors detect oral dysbiosis and trigger oral cancer cell death via β-arrestin-biased NLRP3 activation
Authors: Sungmin Joo, Seong Yu, Jeong-Mu Shin, Yeshin Kwon, Na-Young Song
Journal: Cancer Research (2025)

Bitter taste receptors (taste 2 receptors, T2Rs) are a family of G protein-coupled receptors (GPCRs) that transduce bitter taste signals in the taste buds via the gustatory G protein α-gustducin. Recently, T2Rs have emerged as novel regulators in various extraoral physiological processes, including microbial interactions and carcinogenesis. Notably, T2R4 and T2R14 can recognize bacterial quorum sensing (QS) molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12). Reanalysis of oral microbiome datasets from oral squamous cell carcinoma (OSCC) patients, a major subtype of head and neck squamous cell carcinoma (HNSC), revealed an upregulation of bacterial QS pathways associated with oxo-C12 synthesis. Lower expression levels of T2R4 or T2R14 correlated with poor outcomes and impaired bacterial defense responses in OSCC/HNSC patients. We hypothesized that T2R4 and T2R14 mediate the interplay between oral microbial dysbiosis and OSCC in response to the bacterial QS molecule oxo-C12. Our results showed that oxo-C12 induces pyroptosis and apoptosis in human OSCC cells, unlike other T2R agonists such as quinine and apigenin. Unexpectedly, T2R4 and T2R14 mediated oxo-C12-induced cell death independently of α-gustducin, instead activating the NLRP3 inflammasome via β-arrestin-1/2 (β-ARR1/2). This indicates that oxo-C12 acts as a β-ARR1/2-biased ligand, triggering OSCC cell death through the T2R-β-ARR1/2-NLRP3 axis. A positive correlation between β-ARR2 and T2R4, T2R14, or NLRP3 in HNSC patient datasets supports this signaling pathway. Taken together, T2R4 and T2R14 function as crucial interkingdom sensors that detect oral microbiome dysbiosis and trigger defensive cell death mechanisms in OSCC via β-ARR1/2-biased NLRP3 activation. These findings suggest the potential of T2Rs as chemotherapeutic targets, particularly through ligand-specific biased pathways involving either G protein- or β-ARR1/2-dependent signaling. Citation Format: Sungmin Joo, Seong Yu, Jeong-Mu Shin, Yeshin Kwon, Na-Young Song. Bitter taste receptors detect oral dysbiosis and trigger oral cancer cell death via β-arrestin-biased NLRP3 activation [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 2362.
Abstract 5670: Using molecular docking to develop a novel peptide targeting tumor-associated macrophages based on RXRB recognition
Authors: Nianwu Wang, Hong-Bo Pang
Journal: Cancer Research (2025)

Abstract Tumor-associated macrophages (TAMs) play a critical role in tumor progression, and thus have attracted great attention for therapeutic development. However, macrophage-modulating strategies suffer from drawbacks that they may interfere with normal immunity. Therefore, it is desirable to target and modulate macrophages in tumor-specific manner. We previously identified one such peptide, termed CRV, which selectively homes to a variety of solid tumors and bind TAMs within upon systemic administration. This TAM-targeting ability was then attributed to CRV receptor, retinoid X receptor beta (RXRB). While CRV demonstrated desirable properties in tumor homing and TAM recognition in vivo, the actual affinity to RXRB was very weak. We hypothesize that peptide variants with a higher affinity to RXRB may exhibit a more specific targeting of TAMs. To test this hypothesis, we employed molecular docking to optimize the CRV sequence. Seven rounds of optimization were carried out to replace one residue of CRV peptide in each round with nineteen other amino acids, and the binding energy was calculated as the selection criterion. This study identified a novel peptide, termed CRH, with an improved predicted binding affinity compared to CRV (-12.2 kcal/mol vs. -8.9 kcal/mol). In vitro assays verified that CRH possesses a higher affinity to RXRB than CRV. Ongoing studies include surface plasmon resonance (SPR) binding analysis and in vivo homing evaluations. Overall, we showcase here the identification of a novel peptide to target TAMs, which may enable a more precise drug delivery and TAM modulation. Citation Format: Nianwu Wang, Hong-Bo Pang. Using molecular docking to develop a novel peptide targeting tumor-associated macrophages based on RXRB recognition [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 5670.
Abstract 1381: BCL-2 selective inhibitor venetoclax combined with topoisomerase I inhibitor irinotecan is effective in small cell lung cancer (SCLC)
Authors: Yanli Xing, Krista M. Dalton, Jane L. Roberts, Anthony C. Faber
Journal: Cancer Research (2025)

Abstract Background: Lung cancer is the third most common cancers globally, and small cell lung cancer (SCLC) accounts for 10-15% of all lung cancer cases. Extensive stage (ES)-SCLC has an overall five-year survival rate of ∼5%. Although ES-SCLC initially responds well to platinum-based combination chemotherapy, it almost invariably develops resistance over time. Immunotherapy can induce some responses in ES-SCLC, and arlatamab-dlle, a DLL3 targeted bi-specific T-cell engager, was recently given advanced approval to treat relapsed ES-SCLC. However, ES-SCLC remains a dismal prognosis. Venetoclax is a Bcl-2 selective inhibitor that induces apoptosis by binding to the hydrophobic groove of BCL-2. We previously demonstrated that venetoclax is effective in SCLC with high BCL-2 expression (Lochmann et al., Clinical Cancer Research 2018). Irinotecan is an antineoplastic enzyme inhibitor that blocks the topoisomerase I-DNA complex, preventing DNA repair and causing double-strand breaks that lead to cell death. It is often given in the relapsed setting as second-line therapy for ES-SCLC. Aims: We aimed to determine if venetoclax could enhance responses to irinotecan in SCLC preclinical models, and vice versa. Methods: Venetoclax was combined with irinotecan and SCLC cell viability was evaluated including CellTiter-Glo (CTG), immunoblotting, and in mouse models, including patient-derived xenografts, in vivo. Results: Our data showed that combining the BCL-2 selective inhibitor venetoclax with irinotecan demonstrated in many SCLC models, enhanced activity over single-agent alone. In vivo, the combination enhanced survival compared to either single-agent. Conclusion: We demonstrate that combining the BCL-2 selective inhibitor venetoclax with irinotecan could enhance responses and survival in the refractory SCLC setting. Citation Format: Yanli Xing, Krista M. Dalton, Jane L. Roberts, Anthony C. Faber. BCL-2 selective inhibitor venetoclax combined with topoisomerase I inhibitor irinotecan is effective in small cell lung cancer (SCLC) [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 1381.
Abstract 1940: EpCAM and L1CAM expression signatures in circulating tumor cells of advanced colorectal cancer
Authors: Gabriela Felix, Jun Gong, Francesca Aguirre, Lisa Zhou, Rocio Ramirez, Megan P. Hitchins
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is the third most common deadliest cancer among both men and women in the United States. Hence, to improve CRC clinical management, there is an unmet need for affordable and personalized approaches, such as non-invasive blood tests that analyze circulating tumor cells (CTCs). However, there is limited data about the expression of markers associated with epithelial-mesenchymal transition (EMT) of CTCs in advanced CRC. In this study, we sought to evaluate EMT markers signatures in CTCs of advanced cases of CRC. Method: Peripheral blood samples (10-20 mL) were collected from five patients with metastatic CRC. CTCs were isolated using the Single-cell CellSelect Slides™ enrichment or in-house protocol, followed by FACS (Fluorescence-Activated Cell Sorting). The following markers were analyzed: Ghost Dye™, CD45, CD133, LGR5, L1CAM, CD326 (EpCAM), CD325 (CDH2), CD274 (PD-L1), CD87 (VIM), and Cytokeratin-7/-8. FACS data analysis was done in FlowJo and plugins needed. Results: The average age of diagnosis was 51.6 years. At the time of blood collection, all CRC patients had stage IV disease and were progressing. Self-organizing map clustering and dimensionality reduction algorithm analysis of 10, 197 sorted CD45 negative living cells showed that LGR5 was the least expressed marker. The highest expression of CD133 was associated with highest expression of either EpCAM or L1CAM, which were both inversely correlated with LGR5. Co-expression of EpCAM and L1CAM were negatively associated with CD133, but positively associated with LGR5. EpCAM and L1CAM expression had significant association with CDH2, VIM, Cytokeratin-7/-8 and PD-L1. Conclusion: In advanced CRC, the mutually exclusive expression of EpCAM and L1CAM in the presence of CD133, and absence of LGR5 could be linked to increased plasticity leading to EMT, and increased risk of metastasis and recurrence. In addition, it is important to consider other markers alongside EpCAM for the identification of CTCs in advanced CRC. Citation Format: Gabriela Felix, Jun Gong, Francesca Aguirre, Lisa Zhou, Rocio Ramirez, Megan P. Hitchins. EpCAM and L1CAM expression signatures in circulating tumor cells of advanced 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 1940.
Abstract 6472: Integrative multi-omic analysis of the multiple myeloma bone marrow reveals alterations of the immune microenvironment in treatment naïve patients
Authors: Siobhan B. Cashman, Aruna Ayer, Teresa Swift
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) is defined by the uncontrolled clonal proliferation of plasma cells in the bone marrow (BM). It is one of the most frequent hematological cancers, representing 10% of hematological malignancies in the US. Although recent advancements in therapies have led to improved outcomes, MM remains incurable. Disease development and progression are impacted by alterations in the local immune microenvironment, and dysfunction in both the innate and adaptive immune responses are characteristic of the MM BM microenvironment. With the increasing use of immunotherapeutic strategies to treat MM, there is a growing need to understand the existing immune landscape in these patients. We sought to gain a greater understanding of the immune cell diversity in MM by sampling BM from healthy and newly diagnosed cohorts. A combination of traditional flow cytometry, spectral flow cytometry, and single-cell RNA sequencing (scRNA-seq) with the addition of CITE-seq, enabled the high-resolution analysis of surface protein and targeted immune response-related transcriptomic changes within individual cells. In this study, we found a high degree of inter-patient heterogeneity within the aberrant plasma cell population. We report an expanded population of CD57+ effector memory expressing CD45-RA (TEMRA) cytotoxic T cells, and an overall reduction in T cell effector responses. Our scRNA-seq approach demonstrated a strong correlation of CITE-seq signal with key cell identifying markers. Investigation of the suppressive cell subsets found that overall, these cell frequencies were maintained across health and disease. However, we found altered TREG phenotypes with an increased frequency of a highly suppressive TREG subset in MM patients. In summary, our study provided insight into the significant differences observed in the frequency and functionality of the principal immune populations of the BM microenvironment. By combining flow cytometry with scRNA-seq and CITE-seq, the changes in the immune landscape in the BM of treatment naïve MM patients can be mapped more comprehensively, allowing correlation of surface marker expression with gene expression profiles. For Research-Use Only. Not for use in diagnostic or therapeutic procedures. BD and the BD Logo are trademarks of Becton, Dickinson and Company. © 2024 BD. All rights reserved. NPM-5205 Citation Format: Siobhan B. Cashman, Aruna Ayer, Teresa Swift. Integrative multi-omic analysis of the multiple myeloma bone marrow reveals alterations of the immune microenvironment in treatment naïve patients [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 6472.
Coordinated regulation of self-renewal and cell cycle during human lympho-myeloid lineage restriction
Authors: Fangwu Wang, Laura Gonzalez, Qiuyu Lian, Colin A Hammond, Yasmine Y.M. Lau, Benjamin D. Simons, Martin Hirst, Connie J Eaves
Journal: Blood (2025)

Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and its use to elucidate the biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of these changes revealed that the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal potential. Single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. By applying a novel culture system that supports early human lymphoid differentiation, we uncover a shared mechanism of proliferation control, along with persistent biological and transcriptional heterogeneity in cells undergoing B and NM lineage restriction.
Abstract 3039: Elucidating hsa_circ_0001038 and circRNA_400029 circular RNAs mechanisms in response to splicing factor 3 inhibitor in cervical cancer cells
Authors: Amahle Nyalambisa, Zodwa Dlamini, Rahaba Makgotso Marima
Journal: Cancer Research (2025)

Abstract Cervical cancer (CCa) is the fourth leading cause of cancer-related death among women worldwide. Around 90% of CCa cases are reported in low- and middle-income countries (LMICs), with Sub-Saharan Africa (SSA) bearing over 80% of the global burden. CircRNAs hsa_circ_0001038 and circRNA_400029 have been implicated in cervical cancer. Splicing factor 3 key a key factor in circRNA generation. However, mechanisms of these ceRNAs in CCa is poorly understood. This study aimed at elucidating hsa_circ_0001038 and circRNA_400029 mechanisms in response to splicing factor 3 inhibitor, theophylline in CCa. Using bioinformatics, CircAtlas, the study identified miRNA binding sites for hsa_circ_0001038, selecting miR-205-5p for further analysis due to its tumor-suppressive role. Similarly, miRTarBase predicted miR-16-5p as a key interacting miRNA for circRNA_400029. The downstream gene targets of these miRNAs were explored, focusing on those associated with CCa. Cell cycle FACS analysis and apoptosis assay were used to study cell biological response of theophylline to CCa cells SiHa and C33A. Furthermore, gene specific primers of hsa_circ_0001038, circRNA_400029 and SRSF3 were used to study gene expression in drug treated and control groups. Interestingly, ceRNA network was constructed, showing that one gene can be targeted by more than one miRNA. Additionally, pathway analysis using KEGG, STRING, and Reactome highlighted key signaling pathways, such as the HPV E5-EGFR-RAS-ERK and HPV E6-Notch pathways, which are implicated in cell proliferation, survival, and oncogenesis in CCa. Cell cycle analysis revealed G2/M arrest in response to theophylline treatment, while there was no significant cytotoxic effects of the drug, as revealed by apoptosis FACS analysis. hsa_circ_0001038, circRNA_400029 and SRSF3 were downregulated by theophylline treatment. Understanding circular RNAs and their interaction with splicing factors holds potential translational and clinical applications. Citation Format: Amahle Nyalambisa, Zodwa Dlamini, Rahaba Makgotso Marima. Elucidating hsa_circ_0001038 and circRNA_400029 circular RNAs mechanisms in response to splicing factor 3 inhibitor in cervical cancer 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 3039.
Abstract 6879: Inhibition of triple-negative breast cancer progression via ribosomal protein(s) modulation
Authors: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Praveen Kumar, Benedikt Grau, Carrsyn B. Haley, Sharon Pitteri, Sanjay V. Malhotra
Journal: Cancer Research (2025)

Abstract Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with distinct features at the pathological, molecular and clinical levels that are associated with lower survival rates than other subtypes of breast cancer (BC). TNBC is a highly aggressive subtype of breast cancer and represents for 15-20% of all breast cancer cases. TNBC cancers present myriad clinical challenges due to their heterogeneity, poor prognosis, high recurrence, and high incidence of metastasis. Dysregulation of protein translation is a frequent feature of cancer. Translation of mRNAs to proteins i.e., protein synthesis via ribosomes, is a fundamental cellular activity. Increased levels of translation, necessary to support rapid cell proliferation, have been reported across different cancer types including TNBC. Methods: Cell viability and clonogenic assays were performed on a range of TNBC cells, including MDA-MB-231, MDA-MB-468, SUM159, HCC1395, HCC1806, EMT6, and 4T1. Cell cycle distribution was assessed through flow cytometry. LC-MS/MS analysis was performed on TMT-labeled samples for global proteome profiling. CETSA assay was performed to identify the target of CET019. The efficacy of CET019 (30 mg/kg) was tested using tumor (mouse and human cells) and patient derived xenograft studies. Results: Our studies show CET019 suppresses the clonogenic potential and growth of various triple-negative breast cancer cells. The CET019 treatment causes cell cycle arrest in TNBC cells at the G2/M phase. Proteomics analysis suggests that CET019 specifically affects the protein translation associated pathways. CETSA assay identified the thermal shift of various translation associated proteins, including RPLs and RPS. In vivo studies with CET019 found an inhibition of tumor growth kinetics in the mouse xenograft study with different TNBC models, as compared to the control group. We also observed that CET019 inhibited metastatic lung nodules. The results were further substantiated in four Patient Derived Xenograft (PDX) models. Conclusion: In summary, our study has strong preclinical evidence of CET019 as a promising lead candidate for TNBC treatment. “The complete chemical structures of the compounds used will be disclosed at the time of presentation at the meeting.” Citation Format: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Praveen Kumar, Benedikt Grau, Carrsyn B. Haley, Sharon Pitteri, Sanjay V. Malhotra. Inhibition of triple-negative breast cancer progression via ribosomal protein(s) modulation [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 6879.
Abstract 6881: Discovery of ACE-232: a novel and highly potent non-steroidal CYP11A1 inhibitor
Authors: Kuo-Long Yu, Hongbin Yuan, Sanjeev Kumar, Kai Kang, Wenming Li, Manhua Li, Weitao Pan, Wenqian Li, Junmei Wang, Zhiming Wen, Genshi Zhao, Tinggui Yin
Journal: Cancer Research (2025)

Abstract CYP11A1 is the first and rate-limiting enzyme in steroid hormone biosynthesis, catalyzing the conversion of cholesterol to pregnenolone and isocaproic aldehyde. Inhibition of this enzyme blocks the entire steroid hormone biosynthesis pathway, including androgens and their precursors, which activate the androgen receptor (AR) and promote prostate cancer growth. Targeting CYP11A1 has led to therapies like ODM-208 (MK-5684), which shows antitumor activity in heavily pretreated mCRPC patients, especially those with AR ligand binding domain (LBD) mutations. Here we report the discovery of ACE-232, a novel, highly potent, and selective CYP11A1 inhibitor. ACE-232 is significantly more potent than ODM-208 (&amp;gt;15x) in inhibiting CYP11A1 in human adrenal adenocarcinoma H295R cells, with an IC50 of 0.17 nM compared to ODM-208's IC50 of 2.82 nM. Additionally, ACE-232 demonstrates superior potency (&amp;gt;10x) in suppressing testosterone biosynthesis in H295R cells. Preclinical pharmacokinetic studies show that ACE-232 has significantly lower clearance and a longer half-life across multiple species (mouse, rat, and dog), resulting in a flatter pharmacokinetic (PK) curve compared to ODM-208. Together, these properties may enable sustained target engagement with once-daily dosing while minimizing hormone level fluctuations in patients. In castrated mouse models, ACE-232 showed equal or superior efficacy in inhibiting tumor growth at 0.3 mg/kg QD in both VCaP and enzalutamide-resistant xLNCaP models, compared to ODM-208 at 30 mg/kg BID. Furthermore, in a non-castrated mouse model, ACE-232 showed significant efficacy at 1.5 mg/kg BID, whereas ODM-208 at 30 mg/kg BID did not. ACE-232 also demonstrates favorable ADME properties suitable for drug development. In a safety panel screening across 93 targets at 5 µM, ACE-232 exhibited minimal off-target effects. GLP toxicology studies demonstrated a wide safety margin in both rats and dogs, with primary effects observed in the endocrine and reproductive organs, consistent with CYP11A1 inhibition. Based on these findings, an IND filing for ACE-232 with the FDA is planned for December 2024. Citation Format: Kuo-Long Yu, Hongbin Yuan, Sanjeev Kumar, Kai Kang, Wenming Li, Manhua Li, Weitao Pan, Wenqian Li, Junmei Wang, Zhiming Wen, Genshi Zhao, Tinggui Yin. Discovery of ACE-232: a novel and highly potent non-steroidal CYP11A1 inhibitor [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 6881.