tbuckley/cabot-search huggingface dataset:
Abstract 2243: Preclinical studies of BB-1709, a CD73-targeting ADC potentially suppresses tumor growth through dual mechanisms
Authors: Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Ziping Wei, Yuhong Zhou
Journal: Cancer Research (2025)

Abstract CD73, also known as ecto-5'-nucleotidase, is a cell surface enzyme that catalyzes the conversion of AMP to adenosine. It is highly expressed in various types of cancers, including gastric, glioblastoma, non-small cell lung, and colorectal cancers. Elevated CD73 expression is highly correlated with poor prognosis, increased metastasis, and resistance to chemotherapy. In the tumor microenvironment, CD73-derived adenosine exerts multiple immunosuppressive effects, promoting tumor growth and metastasis. Currently, there are no approved antibody-drug conjugates (ADCs) targeting CD73. In this study, we introduce BB-1709, a CD73-targeting ADC that incorporates MMAE as its cytotoxic payload, demonstrating its antitumor activity through direct cytotoxicity against CD73-expressing tumor cells and its ability to inhibit CD73 enzyme activity. A comprehensive set of studies was conducted to assess its in vitro cytotoxicity, in vivo antitumor activity as well as its ability to inhibit CD73 enzyme activity. In vitro studies demonstrated that BB-1709 exhibited potent and selective cytotoxicity against various CD73-positive cancer cells and significantly inhibited CD73 enzyme activity, effectively blocking the conversion of AMP into adenosine. In vivo studies using xenograft models showed that a single dose of BB-1709 resulted in substantial antitumor activity. Pharmacokinetic and toxicology assessments in non-human primates revealed a favorable safety profile for BB-1709 at clinically relevant dosages and administration schedules. In summary, these results suggest that BB-1709 not only exhibits good preclinical efficacy and safety, but also has the potential to promote anti-tumor immune responses by inhibiting CD73 enzymatic activity. A phase I clinical trial of BB-1709 is currently underway to further explore its therapeutic potential in cancer treatment. Citation Format: Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Ziping Wei, Yuhong Zhou. Preclinical studies of BB-1709, a CD73-targeting ADC potentially suppresses tumor growth through dual mechanisms. [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 2243.
Abstract 2790: Identification of tumor suppressor miRNA to regulate FXYD3 in pancreatic cancer cells
Authors: Ke Xin Yee, Kuen-Haur Lee
Journal: Cancer Research (2025)

Abstract Pancreatic cancer (PC) continues to be one of the deadliest cancers globally, ranking among the top causes of cancer-related mortality. Despite significant progress in medical research, effective methods for early diagnosis and treatment remain challenging, contributing to poor survival rates. MicroRNAs (miRNAs), small non-coding RNA molecules that consist of 18-25 nucleotides, have emerged as critical regulators of gene expression as therapeutic agents and diagnostic biomarkers. Recently, the oncogene FXYD3 has gained attention as a candidate for early detection, offering a promising result for research. In this study, we applied bioinformatic analyses to identify potential interactions between tumor-suppressing miRNAs and the oncogene FXYD3. Our findings revealed that several miRNAs directly target FXYD3, highlighting their role in regulating its expression. To validate these predictions, we performed immunohistochemistry (IHC) analysis. The results confirmed that these miRNAs were significantly overexpressed in normal pancreatic tissues compared to PC tissues. These observations suggested that the loss of specific miRNAs could contribute to the upregulation of FXYD3, promoting tumor progression. Interestingly, our study also found differential expression patterns of these miRNAs across various pancreatic cancer cell lines, indicating cell-type-specific regulatory mechanisms. The findings of the functional assays using miRNA mimics or inhibitors provide a foundation for developing miRNA-based therapeutic strategies targeting FXYD3. In summary, this study emphasizes the importance of miRNAs that target FXYD3 in pancreatic cancer. Our research supports their role as tumor suppressors and underscores their therapeutic potential in combating one of the most aggressive and challenging cancers. Citation Format: Alejandra Ke Xin Yee, Kuen-Haur Lee. Identification of tumor suppressor miRNA to regulate FXYD3 in pancreatic 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 2790.
Abstract 2720: Investigating the functional role of SUV420H1 in HPV-negative head and neck squamous cell carcinoma
Authors: Arfa Moshiri, Sohyoung Kim, Marie Luff, Vassiliki Saloura
Journal: Cancer Research (2025)

Abstract Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a significant clinical challenge due to limited treatment options and poor prognosis. SUV420H1, encoding a protein lysine methyltransferase (PMT) responsible for H4K20 trimethylation (H4K20me3), is recurrently amplified in approximately 5% of HPV-negative HNSCC tumors, indicating a potential oncogenic role. Our previous studies demonstrated that while SUV420H1 depletion using siRNAs reduced the proliferation and colony-forming capacity in HPV-negative HNSCC cell lines, enzymatic inhibition with the SUV420H1 inhibitor A-196 induced only a modest effect in these phenotypes. In this study, we generated enzymatically inactive SUV420H1 mutants with a confirmed decrease in global H4K20me3 levels and conducted proliferation and colony-forming assays which concordantly showed only a modest effect in these phenotypes. GSEA analysis of RNA-seq obtained from HPV-negative HNSCC cells treated with SUV420H1 siRNAs or the SUV420H1 inhibitor A-196 showed commonly enriched pathways, including EMT, cell cycle and proliferation, and interferon alpha response pathways. In vivo experiments using Suv420h1 knockout (KO) MOC1 mouse cell lines in a syngeneic HPV-negative HNSCC flank mouse model demonstrated a marked decrease in tumor size. Furthermore, tumor flow cytometry revealed increased CD8+ T-cell, B-cell and macrophage infiltration. These findings provide strong evidence for the role of SUV420H1 in modulating immune responses. Ongoing studies aim to evaluate the combinatorial impact of SUV420H1 depletion and anti-PD-1 therapy in vivo to determine whether SUV420H1 loss sensitizes tumors to immune checkpoint blockade. Collectively, our data supports SUV420H1 as a potential therapeutic target in HPV-negative HNSCC. Citation Format: Arfa Moshiri, Sohyoung Kim, Marie Luff, Vassiliki Saloura. Investigating the functional role of SUV420H1 in HPV-negative head and neck squamous cell carcinoma [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 2720.
Abstract 3592: Hospital-treated infectious diseases and pancreatic cancer risk: Findings from a large population-based cohort
Authors: Kiera R. Murison, Rayjean J. Hung
Journal: Cancer Research (2025)

Abstract Rationale: Inflammation has been established as a mechanism for pancreatic cancer development. The longitudinal relationship between infection, and the resulting inflammation, and pancreatic cancer risk has yet to be elucidated. A large population-based cohort, such as the United Kingdom (UK) Biobank, offers a unique opportunity to assess these relationships with long follow-up time and a large number of infections. Objectives: Estimate the effect of hospital-treated infection on pancreatic cancer risk by infection type and infection burden. Methods: UK Biobank participants with no record of pancreatic cancer at cohort entry were included. Follow-up was to February 29, 2020 and January 31, 2021 for participants from England and Wales, and Scotland, respectively. Hospital-treated infection status was obtained through linkage to hospital inpatient data and allowed for characterization of exposure to over 900 infectious diseases using the International Classification of Diseases and Related Health Problems 10th Revision. Incident pancreatic cancer diagnosis was obtained through linkage to national cancer registries. Relative risk (RR) and associated 95% confidence intervals (CI) were estimated for infectious disease groups and infectious disease burden categories using negative binomial regression models. Results: From cohort entry to the end of follow up, 502, 219 people were included in the cohort. 93, 123 participants had at least one recorded exposure to hospital-treated infection preceding pancreatic cancer diagnosis and 1, 255 were diagnosed with pancreatic cancer throughout the follow up period. Exposure to any hospital-treated infection was associated with increased risk of pancreatic cancer (aRR 2.56 [95% CI 2.27, 2.88]). When considering infection burden, a dose-response relationship was seen (ptrend &amp;lt; 0.001) where a greater number of infections was associated with a greater risk of pancreatic cancer. When compared to those with no infection, participants had increasing risk with 1 infection (aRR 1.99 [95% CI 1.69, 2.35]), 2 infections (aRR 2.84 [95% CI 2.34, 3.43]), and &amp;gt;3 infections (aRR 3.21 [95% CI 2.72, 3.78]). Conclusions: Infections which require treatment in hospital are associated with risk of pancreatic cancer. This association was strongest when considering bacterial infection and its impact on longitudinal risk of pancreatic cancer. Further, the dose-response relationship observed when investigating infection burden may suggest a cumulative risk of pancreatic cancer conferred with severe infections. Citation Format: Kiera R. Murison, Rayjean J. Hung. Hospital-treated infectious diseases and pancreatic cancer risk: Findings from a large population-based cohort [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 3592.
Abstract 3104: The mechanism of action of ADCs are dependent on Rab GTPases
Authors: Astrid Medhus, Kay Oliver Schink, Ane Sager Longva, Olav Engebraaten, Kristian Berg, Anette Weyergang
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) are therapeutic compounds designed to exert targeted toxicity as compared to conventional chemotherapy. The conjugation of a cytotoxic payload to an antibody trough a chemical linker serves to lower the systemic toxicity and thereby increase the therapeutic window. However, an enhanced understanding of the mechanism of action of ADCs is needed, as little is known about how these drugs are trafficked and processed within the cell. The tumor-targeted activity of ADCs depend on the presence of target molecules on the tumor cell surfaces, and the overall response of ADCs is generally dependent on the expression level of these surface receptors. However, ADCs are dependent on cellular uptake and intracellular trafficking for the cytotoxic payload to be released and reach its target within the cell. This process of endocytosis and subsequent intracellular trafficking is regulated by a group of small molecular switches called Rab GTPases. These proteins acts as key regulators of the endo/lysosomal machinery, and we hypothesized them to impact ADC efficacy. We used cell lines from breast and lung cancer origin to study the mechanism of action of different ADCs dependent on RAB5 and RAB4 expression. We have found that the makeup of the ADC - comprising the antibody moiety, linker design, and choice of payload - dictates how it is taken up and processed, and thereby determines which Rab GTPases are critical for its therapeutic effect. Our results demonstrate how ADC design influences intracellular trafficking and processing, and points towards linker design as a major regulator of the intracellular fate of an ADC. Citation Format: Astrid Medhus, Kay Oliver Schink, Ane Sager Longva, Olav Engebraaten, Kristian Berg, Anette Weyergang. The mechanism of action of ADCs are dependent on Rab GTPases. [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 3104.
Abstract 2803: Genome-wide CRISPR-Cas9 functional screens map long noncoding RNA dependencies in triple-negative breast cancer
Authors: Nehad M. Alajez
Journal: Cancer Research (2025)

Abstract Long noncoding RNAs (lncRNAs) are increasingly recognized as crucial regulators of gene expression, significantly influencing complex biological processes and disease progression, including cancer. Their transformative potential was underscored by the awarding of the 2024 Nobel Prize in noncoding RNA research, spotlighting lncRNAs as powerful modulators of biological regulation and therapeutic innovation. However, the precise functions of most lncRNAs remain largely unexplored. While GENCODE has cataloged over 20, 000 lncRNA genes, the true diversity of lncRNAs is likely much greater. To address this, we constructed an expanded lncRNA reference by integrating GENCODE, BIGTranscriptome, and MiTranscriptome databases. This enhanced reference enabled a comprehensive mapping of lncRNA dependencies in aggressive triple-negative breast cancer (TNBC) using a genome-wide CRISPR-Cas9 screen. Our screen specifically targeted the transcription start sites of over 1, 000 TNBC-associated lncRNAs, encompassing both annotated and novel transcripts. By employing a dual-excision CRISPR strategy in two TNBC cell models, we identified lncRNAs that are essential for TNBC cell growth and chemoresistance, validating several candidates using antisense oligonucleotides (ASOs). In total, 102 lncRNA hits were identified across both MDA-MB-231 and BT-549 TNBC models. Of these, three novel lncRNAs were found to be indispensable for TNBC survival in both two-dimensional and three-dimensional cultures. Analysis of a large TNBC cohort (n=360) further associated the expression of these lncRNAs with more aggressive TNBC subtypes. Loss-of-function studies with ASO Gapmers underscored the roles of these novel lncRNAs in regulating key cellular processes, including extracellular matrix organization, lipid metabolism, and GTPase signaling. Our study provides the first comprehensive map of lncRNA vulnerabilities in TNBC, highlighting their potential as therapeutic targets. This approach, while focused on TNBC, is adaptable for exploring lncRNA functions in other biological settings, paving the way for novel RNA-based therapies and clinical applications. Citation Format: Nehad M. Alajez. Genome-wide CRISPR-Cas9 functional screens map long noncoding RNA dependencies in triple-negative 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 2803.
Abstract 1498: SELENOF maintains proteostasis through UPR-IRE1α axis in breast cancer
Authors: An Zhang, Irida Kastrati
Journal: Cancer Research (2025)

Abstract Background: SELENOF is an understudied selenoprotein that incorporates selenium in the form of selenocysteine. Our lab’s investigation into SELENOF’s function in breast cancer indicates that it is likely a tumor suppressor. SELENOF resides in the endoplasmic reticulum (ER) and has been hypothesized to assist in protein folding, specifically disulfide-bond formation. Disruption of protein folding efficiency leads to the accumulation of misfolded proteins, a process referred as EnR stress. In turn, the unfolded protein response (UPR) is triggered to relieve EnR stress and to restore protein processing functions. In cancer, UPR is a double edge sword. To meet the challenges of rapid proliferation, cancer cells exploit this intrinsic adaptive mechanism of UPR. However, with prolonged and unresolved EnR stress, the cell switches UPR from an adaptive response to a terminal death-inducing response. We hypothesize that SELENOF may play a role in UPR stress resolution, and how this affects breast cancer initiation of progression remains to be determined. Objective: Our study aims to determine the crosstalk between SELENOF and EnR using normal mammary gland tissue and breast cancer models. Results: SELENOF levels were manipulated by overexpression or knockout in normal breast epithelial cells and in breast cancer cell lines. Loss of SELENOF does not change baseline UPR measured by Thioflavin T staining and EnR stress markers include IRE1a phosphorylation and XBP1 mRNA splicing. Instead, overexpression of SELENOF increased UPR. We also determined that the IRE1-XPB1 axis required, but not the other two, Upon induction of EnR stress using Tunicamycin, Thapsigargin, we find that SELENOF levels is increased via IRE1-XBP1, thus uncovering a crosstalk between UPR and SELENOF. Furthermore, loss of SELENOF reduces the overall UPR. These findings were validated in vivo using wild type and SELENOF knockout mice. Conclusion: Our findings establish a feed-forward model between UPR and SELENOF; SELENOF level increase upon UPR induction to amplify the UPR response towards terminal UPR. Loss of SELENOF restricts UPR response within adaptive levels to bypass cell death. This may provide a mechanism for cancer cells to survive while coping with higher proteotoxic stress. Citation Format: An Zhang, Irida Kastrati. SELENOF maintains proteostasis through UPR-IRE1α axis in 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 1498.
Abstract 3283: RNAi mediated silencing of <i>STAT3 or PD-L1</i> in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors
Authors: Shanthi Ganesh, Minju KIm, Jenny Lee, Xudong Feng, Harini Krishnan, Amber Beaudry, Jennifer A. Lockridge, John Hanrahan, Sam Moskowitz, Vinita Uttamsingh
Journal: Cancer Research (2025)

Abstract Most refractory malignant solid tumors create an immunosuppressive tumor microenvironment (TME), rendering them resistant to standard-of-care immune checkpoint inhibitors (CPIs). We investigated the feasibility of applying systemically delivered RNAi agent to silence the mRNA of a historically undruggable target, that involved in mediating immune suppression in TME, directly in tumor-associated immune cells. In preclinical rodent tumor models, GalXC-PlusTM conjugates selectively silenced the Stat3 mRNA in multiple relevant cell types, reduced the protein levels, and increased cytotoxic T-cell infiltration. In immunotherapy resistant tumors, RNAi-mediated silencing resulted in tumor growth inhibition, which was further enhanced in combination with CPIs. We also demonstrated that silencing Cd274 (PD-L1) in antigen-presenting cells using another GalXC-PlusTM conjugate was effective in treating tumors that are resistant to PD-L1 antibody therapy. Currently, both human active STAT3 and PDL1 conjugates are in Phase 1 clinical trials for treating immunotherapy-refractory cancer types (NCT06098651, NCT06504368). Citation Format: Shanthi Ganesh, Minju KIm, Jenny Lee, Xudong Feng, Harini Krishnan, Amber Beaudry, Jennifer A. Lockridge, John Hanrahan, Sam Moskowitz, Vinita Uttamsingh. RNAi mediated silencing of STAT3 or PD-L1 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors [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 3283.
Abstract 280: ALDH2 knockout dysregulates arginine and proline metabolism in SK-BR-3 breast cancer cells
Authors: Ming Zhao, Blake R. Rushing, Zhikun Ma, Rachel A. Coble, Amanda B. Parris, Sergey Krupenko, Susan J. Sumner, Xiaohe Yang
Journal: Cancer Research (2025)

Abstract Aldehyde dehydrogenase 2 (ALDH2) mitigates cellular stress by detoxifying reactive aldehydes produced during alcohol exposure and endogenous metabolic processes. The ALDH2*2 variant, prevalent in East Asian populations, has decreased catalytic activity, which is linked to an increased risk of cancer and other diseases. While the effects of ALDH2 deficiency on cellular stress responses are well documented, the specific metabolic dysregulations arising from this deficiency require further investigation. To explore the impact of ALDH2 deficiency on metabolism and cellular stress in breast cancer, we generated the ALDH2 knockout subline of the SKBR-3 cell line (SKBR-3/ADKO) using CRISPR/Cas9 technology. Our findings indicate that ALDH2 knockout leads to heightened cellular stress, evidenced by elevated levels of 8-OHdG, reactive oxygen species (ROS), and malondialdehyde (MDA). Untargeted metabolomic analysis of SKBR-3 and SKBR-3/ADKO cells using Ultra High Performance Liquid Chromatography/High Resolution Mass Spectrometry assigned a total of 5, 033 metabolites, with 615 metabolites being significantly different (fold change ≥ 2, p-value &amp;lt; 0.05) between the two cell lines. The Mummichog approach has identified six key metabolic pathways altered upon ALDH2 knockout, including: arginine biosynthesis; D-amino acid metabolism; arginine and proline metabolism; alanine, aspartate and glutamate metabolism; pentose and glucuronate interconversions; pantothenate and CoA biosynthesis. The most significantly dysregulated pathway in response to the ALDH2 loss was arginine and proline metabolism, which is an integral pathway to redox homeostasis, ROS production, and cellular stress responses. Our study provides a novel insight into the role of ALDH2 in cancer metabolism, which might have a broader implication for cancer biology. Citation Format: Ming Zhao, Blake R. Rushing, Zhikun Ma, Rachel A. Coble, Amanda B. Parris, Sergey Krupenko, Susan J. Sumner, Xiaohe Yang. ALDH2 knockout dysregulates arginine and proline metabolism in SK-BR-3 breast 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 280.