tbuckley/cabot-search huggingface dataset:
Abstract 1722: Targeting synaptotagmin 4 to overcome enzalutamide and abiraterone resistance in castration resistant prostate cancer
Authors: Masuda Sharifi, Shu Ning, Amy Rose Leslie, Zachary A. Schaaf, James Patrick Maine, Wei Lou, Allen C. Gao
Journal: Cancer Research (2025)

Abstract Background: Castration-resistant prostate cancers (CRPCs) are predominantly driven by androgen receptor (AR) signaling. Although next-generation anti-androgen therapies (NGATs), such as enzalutamide (Enza) and abiraterone (Abi), have been shown to extend patient survival, resistance to these therapies often develops. The underlying mechanisms driving resistance to these treatments remains unclear. Synaptogamin 4 (SYT4), a membrane protein involved in vesicle trafficking, is highly expressed in our established Enza and Abi resistant CRPC cells. Here, we explore the contribution of SYT4 in disease progression and NGATs resistance in CRPC. Methods: Differences in SYT4 expression were determined in Enza-resistant C4-2B MDVR (MDVR) and Abi-resistant C4-2B AbiR (AbiR) cells versus parental C4-2B cells by RNA-sequencing, real time PCR, western blot and immunofluorescence microscopy. SYT4 expression was analyzed in GEO and cBioPortal databases from patients with prostate cancer. Specific siRNAs were used to inhibit SYT4 expression. The effect of SYT4 knock down on global gene expression, cell growth and sensitivity to Enza and Abi was assessed in our resistant cell lines. Results: SYT4 gene expression was found to be markedly elevated in MDVR and AbiR cells compared to their parental C4-2B counterparts. Analysis of clinical data further revealed that SYT4 expression is significantly upregulated in patients with advanced prostate cancer; with high SYT4 levels being associated with poorer overall survival outcomes. Transcriptomic profiling identified enrichment of genes involved in calcium-mediated cell adhesion in MDVR cells, which is suppressed upon transfection with SYT4-specific siRNA. Additionally, silencing SYT4 expression via siRNA not only inhibited prostate cancer cell growth but also restored sensitivity of MDVR and AbiR cells to their respective treatments, underscoring SYT4 as a promising therapeutic target for treatment-resistant prostate cancer. Conclusions: Our findings indicate that elevated expression of SYT4 promotes resistance to Enza and Abi; correlating with poorer outcomes in prostate cancer patients. Targeting SYT4 reduces the expression of genes involved in calcium-dependent cell adhesion and reduces cellular viability, thereby restoring sensitivity to NGATs like Enza and Abi, offering potential new strategies for overcoming treatment-resistant prostate cancer. Citation Format: Masuda Sharifi, Shu Ning, Amy Rose Leslie, Zachary A. Schaaf, James Patrick Maine, Wei Lou, Allen C. Gao. Targeting synaptotagmin 4 to overcome enzalutamide and abiraterone resistance in castration resistant prostate 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 1722.
Abstract 1540: ADAR1 regulates lipid remodeling through MDM2 to dictate ferroptosis sensitivity
Authors: Che-Pei (Pat) Kung, Nick Terzich, Michael J. Prinsen, Raleigh D. Kladney, Alex Mabry, Luisangely Soto Torres, Jade Weber, Ma Xenia G. Ilagen, Leonard Maggi, Leah P. Shriver, Gary J. Patti, Jason D. Weber
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron-dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analysis led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA-approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC. Citation Format: Che-Pei (Pat) Kung, Nick Terzich, Michael J. Prinsen, Raleigh D. Kladney, Alex Mabry, Luisangely Soto Torres, Jade Weber, Ma Xenia G. Ilagen, Leonard Maggi, Leah P. Shriver, Gary J. Patti, Jason D. Weber. ADAR1 regulates lipid remodeling through MDM2 to dictate ferroptosis sensitivity [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 1540.
Abstract 2250: UCHL1 hijacks tolerogenic DC maturation and promotes mregDC-Treg crosstalk to nullify anti-PD-L1 therapy
Authors: Yufei Zhao, Peiyi Xie, Qinghai Ye, Mien-Chie Hung, Hui Li
Journal: Cancer Research (2025)

Abstract Background: Immune-checkpoint blockade (ICB) therapies have revolutionized cancer treatment, but such immunotherapy regimens fail in a subset of patients. Dendritic cells (DCs) are a heterogeneous group of professional antigen-presenting innate immune cells that activate adaptive immunity and determine the efficacy of immunotherapies. While they can also be hijacked by tumor-mediated factors to contribute to immune tolerance and tumor progression. However, little is known about the molecular mechanisms that drive the tolerance maturation of DCs in the tumor microenvironment (TME). Methods: We enrolled 85 patients with advanced hepatocellular carcinoma (HCC) exhibiting varying response to immunotherapy, and profiled their tumor ecosystems using a single-cell transcriptomes sequencing (scRNA-seq) and mass cytometry by time of flight (CyTOF) for 10 patients, and plasma protein level quantification, conducted both pre-treatment and post-treatment across all patients. We integrated our in-house data and 6 additional published scRNA-seq cohorts of 83 donors to generate a comprehensive landscape of cellular dynamics underlying different responses to immunotherapy. We verified the prognostic value in our in-house tumor microarray of 342 patients. Results: UCHL1 overexpression nullifies anti-PD-L1 therapy by driving conventional DC transformation into mature DCs enriched in immunoregulatory molecule (mregDC) via tolerogenic maturation and promoting mregDC and regulatory T (Treg) cell crosstalk, thereby restrains CD8+ T anti-tumor immunity. Mechanistically, UCHL1 enhances glycolysis by stabilizing HIF1α and lactate accumulation in TME, which further promotes SREBP2 activation and nuclear translocation in DCs. We verified the positive correlations of UCHL1 with HIF1α/VEGFα/LAMP3/FOXP3 in 342 patients with HCC. Genetic ablation or pharmacological inhibition of UCHL1 all reduce the mregDC and Treg accumulation, restore the immuno-surveillance of tumor-infiltrating lymphocytes, and safeguard anti-tumor immunity and efficacy of anti-PD-L1 therapy in mouse models. Conclusions: UCHL1 hijacks tolerogenic DC maturation and promotes mregDC-Treg crosstalk to nullify anti-PD-L1 therapy. Genetic ablation or pharmacological inhibition of UCHL1 unleash the immuno-surveillance of tumor-infiltrating lymphocytes, and safeguard the anti-tumor immunity. Plasma level of UCHL1 predicts the efficacy of anti-PD-L1 therapy. Citation Format: Yufei Zhao, Peiyi Xie, Qinghai Ye, Mien-Chie Hung, Hui Li. UCHL1 hijacks tolerogenic DC maturation and promotes mregDC-Treg crosstalk to nullify anti-PD-L1 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 2250.
Abstract 2883: Cetuximab increases LGR5 expression and enhances efficacy of LGR5 antibody-drug conjugates in patient-derived models of colorectal cancer
Authors: Peyton High, Zhengdong Liang, Cara Guernsey-Biddle, Adela Aldana, Yukimatsu Toh, Qingyun Liu, Kendra S. Carmon
Journal: Cancer Research (2025)

Colorectal cancer (CRC) is the second-leading cause of cancer-associated deaths in the United States with a need for improved therapies. Antibody-drug conjugates (ADCs) are a rapidly expanding class of anticancer drugs that utilize monoclonal antibody (mAb) specificity to hone cytotoxic payloads to cancer cells. We generated ADCs targeting leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a cancer stem cell biomarker that is highly overexpressed in CRC. LGR5 ADCs demonstrated high specificity and efficacy in CRC cells and xenograft models without notable toxicity, although tumors eventually relapsed following treatment cessation. Interestingly, FDA-approved therapies targeting epidermal growth factor receptor (EGFR) have been shown to increase LGR5 expression in patient-derived models of CRC. This study therefore aims to determine the mechanisms of EGFR-mediated regulation of LGR5 expression and evaluate the therapeutic efficacy of EGFR-targeted therapies in combination with LGR5 ADCs for the improved treatment of CRC. We have demonstrated that cetuximab (CTX), an EGFR-targeting mAb approved for KRASWT metastatic CRC (mCRC), increases LGR5 protein levels independent of KRAS/PIK3CA mutational status in CRC cell lines, tumor organoids, and cell line-derived xenografts. Additionally, we identified a novel EGFR-LGR5 interaction that is enhanced by CTX treatment. Furthermore, we have generated a camptothecin-based LGR5 ADC (8E11-CPT2) utilizing site-specific conjugation technology that demonstrates target- and dose-dependent cytotoxicity in CRC cells and was well-tolerated. Importantly, combination treatment of 8E11-CPT2 with CTX in RASmut CRC patient-derived xenograft models significantly reduced tumor burden with notable regression in some mice and extended survival compared to LGR5 ADC and CTX monotherapies. These results demonstrate that combination treatments of LGR5 ADCs with CTX may prove more effective than ADC monotherapies in treating CRC and implicate expanded clinical utility for CTX to treat mCRCs with KRAS and/or PIK3CA mutations. Citation Format: Peyton High, Zhengdong Liang, Cara Guernsey-Biddle, Adela Aldana, Yukimatsu Toh, Qingyun Liu, Kendra S. Carmon. Cetuximab increases LGR5 expression and enhances efficacy of LGR5 antibody-drug conjugates in patient-derived models of 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 2883.
Abstract 1473: POLQ facilitates annealing mediated long deletions at chromosomal break in homologous recombination deficient cancers
Authors: Manisha Jalan, Erika S. Buechelmaier, Jonathan Rafailov, Yingjie Zhu, Xin Pei, Sebastian Brylka, Joan Gomez-Aguilar, Niamh McDermott, Nadeem Riaz, Marcin Imielinski, Simon N. Powell
Journal: Cancer Research (2025)

Tumors deficient in homologous recombination (HRD) predominantly rely on alternative DNA repair pathways for maintaining genome stability, especially once end resection has been initiated after a double strand break (DSB). These back up repair mechanisms, especially microhomology-mediated end-joining (MMEJ) and single-strand annealing (SSA), once considered minor contributors to genome stability, have garnered increased attention as recent evidence supports their significant roles in tumorigenesis and their potential as therapeutic targets. Consequently DNA polymerase theta (POLQ), a key regulator of MMEJ, emerges as an attractive target for the selective treatment of HRD cancers, and recent efforts in the development of POLQ inhibitors have demonstrated their potential to enhance the efficacy of existing therapies and overcome resistance mechanisms. In our study, we investigated the genetic drivers of the under-investigated SSA and its connection to the related MMEJ pathway in human cells. A previously unidentified role for POLQ in regulating the frequency of SSA was observed in addition to its role in MMEJ. Beyond its established role as a gap-filling polymerase, we show that the helicase activity of POLQ is critical for homology-mediated annealing in both MMEJ and SSA. POLQ is shown to be a key facilitator of SSA through its ability to process DNA ends and promote annealing of homologous sequences with at least 80% sequence identity (homeology), resulting in a range of deletion sizes. We also provide evidence for these homeology-dependent SSA-like repair scars in tumor genomes and show that they are associated with HRD and elevated POLQ expression, suggesting the utilization of these mechanisms as a critical repair pathway in these tumors. These findings suggest POLQ is the ideal target for therapies of HRD cancer. Citation Format: Manisha Jalan, Erika S. Buechelmaier, Jonathan Rafailov, Yingjie Zhu, Xin Pei, Sebastian Brylka, Joan Gomez-Aguilar, Niamh McDermott, Nadeem Riaz, Marcin Imielinski, Simon N. Powell. POLQ facilitates annealing mediated long deletions at chromosomal break in homologous recombination deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1473.
Abstract 2528: Bioinspired multispectral imaging for intraoperative detection of metastatic lymph nodes: enhancing precision through UV and NIR fluorescence
Authors: Zhongmin Zhu, Yifei Jin, Brianna Hajek, Shuming Nie, Viktor Gruev
Journal: Cancer Research (2025)

Intraoperative identification of metastatic lymph nodes (LNs) remains a clinical challenge, with current techniques often leading to unnecessary removal of healthy tissue or retention of cancer-positive nodes. To address this issue, we developed a bioinspired multispectral imaging system that integrates ultraviolet (UV) autofluorescence and near-infrared (NIR) fluorescence detection. This platform mimics the mantis shrimp's unique visual system, leveraging vertically stacked photodiodes and pixelated spectral filters to achieve simultaneous imaging across the UV, visible, and NIR spectral ranges without spatial misalignment or loss of resolution. The system uses indocyanine green (ICG) as an FDA-approved NIR fluorescent probe for LN localization and UV excitation to evaluate LN status via autofluorescence. The UV fluorescence leverages endogenous biomarkers, such as tryptophan, commonly enriched in tumor-associated tissues. This dual-modality imaging approach enables real-time identification of both the anatomical location and pathological status of LNs, reducing dependence on postoperative histopathological analysis. In a clinical study involving 33 breast cancer patients, the imaging system achieved a positive predictive value of 96% and a receiver operating characteristic (ROC) area under the curve (AUC) of 89% in distinguishing metastatic from non-metastatic lymph nodes. These results were corroborated by pathology, which served as the ground truth. By providing immediate and accurate feedback to surgeons, this system has the potential to improve surgical precision, reduce unnecessary excisions, and minimize the need for follow-up procedures. Unlike traditional multispectral imaging systems reliant on mechanically rotating filters or dichroic beamsplitters, our bioinspired sensor eliminates co-registration errors and significantly reduces system complexity. Its compact design and capability to perform high-resolution imaging under challenging surgical lighting conditions make it well-suited for widespread clinical adoption. Further studies are underway to validate the system’s efficacy across different cancer types and expand its applications to other surgical scenarios. This novel imaging platform offers a significant step forward in integrating real-time molecular and anatomical imaging into intraoperative workflows, addressing critical gaps in precision oncology. Citation Format: Zhongmin Zhu, Yifei Jin, Brianna Hajek, Shuming Nie, Viktor Gruev. Bioinspired multispectral imaging for intraoperative detection of metastatic lymph nodes: enhancing precision through UV and NIR fluorescence [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 2528.
Abstract 2866: An innovative T cell engager platform with optimized CD3 affinity and formats for targeting hematologic and solid tumors
Authors: Cuicui Guo, Yu Pang, Zhen Han, Fenglin Yun, Ao Li, Hai Wu, Xun Gui
Journal: Cancer Research (2025)

Abstract Background: T-cell engagers (TCEs) are a promising class of immunotherapies that bridge T cells to tumor cells, triggering T-cell activation and subsequent tumor cell cytotoxicity. While TCEs demonstrated substantial efficacy in hematologic malignancies, their clinical benefit in solid tumors remains less established. The development of effective TCEs is hindered by challenges related to the complex interplay between CD3 affinity, TCE format, tumor-associated antigen (TAA) density, and specificity. To address these challenges, we have developed an innovative TCE platform designed to optimize CD3 affinity and TCE format to better match TAA expression profile and improve therapeutic efficacy. Methods: Humanized CD3 and TAA-targeting antibodies were generated by Mabwell’s integrated novel antibody discovery system. CD3 activity was assessed through T-cell binding and activation assays, while TAA binding potency was measured using tumor cell binding assays. Various bispecific and trispecific TCE formats were evaluated and optimized for developability, stability, and functional activity. Tumor-directed cytotoxicity (TDCC) assays were used to assess the efficacy of TCEs in vitro, while cytokine release syndrome (CRS) potential was also evaluated. Results: CD3 parental antibodies with varying T-cell binding and activation potencies, including cross-reactivity with monkey CD3, were generated. TAAs were identified and prioritized using a bioinformatics analysis system, leading to the selection of tumor-specific targets such as LILRB4, CLL-1, CLDN6, MUC16, MSLN, CDH17, GUCY2C, SEZ6, DLL3, and ENPP3. Several optimized 1+1, 1+2, and 2+2 TCE formats were developed, demonstrating excellent developability and potent in vitro tumor cell killing. Importantly, these TCEs exhibited minimal cytokine release syndrome (CRS) potential. Our platform also integrates comprehensive indication analysis, target validation, and TCE format optimization, facilitating the identification of multiple TAAs across a broad range of cancer types. Conclusion: Our innovative TCE platform offers a flexible and powerful approach for designing TCEs with enhanced efficacy and minimal CRS. This platform holds significant promise for developing novel T-cell engagers with robust therapeutic activity and favorable safety profiles for both hematologic and solid tumor indications. Citation Format: Cuicui Guo, Yu Pang, Zhen Han, Fenglin Yun, Ao Li, Hai Wu, Xun Gui. An innovative T cell engager platform with optimized CD3 affinity and formats for targeting hematologic and solid 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 2866.
Abstract 5793: Measurement of basophil activation using a flow cytometry method for applications in clinical research and clinical trials
Authors: Jennifer J. Stewart, Lynette Brown
Journal: Cancer Research (2025)

Abstract Background: Basophils are a type of white blood cell that play a role in the immune system, particularly in defending the body against allergens, pathogens, and parasites. Basophils also can contribute to the immune response directed against cancer cells by releasing histamine and other mediators that can enhance inflammation and recruit other immune cells to the tumor site. They express high-affinity immunoglobulin E (IgE) receptors, which are involved in recognizing and responding to antigens presented by cancer cells. Basophils may also play a role in modulating the tumor microenvironment, potentially influencing the effectiveness of immunotherapies and understanding the exact mechanisms make the study of basophil activation an exciting area for developing novel therapeutics. Methods: Basophil cells can become activated when the antigen loaded IgE antibody recognizes and binds to the Fc receptor (FcεRI) on the basophil surface. Basophil activation also causes certain markers to be upregulated on the surface of the cell that can be measured by flow cytometry to determine basophil activity. The basophil activation test (BAT) was conducted with human whole blood samples using a commercially available basophil activation kit. Whole blood specimens from human donors were collected in EDTA blood collection tubes. Blood was stimulated with FCεR1 and fMLP and staining reagent for 25 - 30 minutes at 37°C. Cells were lysed, washed and acquired on the flow cytometer. Results: CCR3 was used to identify the basophil population in human whole blood. CD63 and CD203c were then used to identify the unstimulated and stimulated state of the cells. Upon stimulation there was an increase in CD63 and CD203c expression on the surface of the basophils. Conclusions: These results showed that the basophil activation can be measured using flow cytometry with the increased expression of CD63 and CD203c on stimulated basophils. This method could be used to help scientists in clinical research and clinical trials to monitor allergic diseases, predict responses to immunotherapy, and assess the effectiveness of treatments, including immunoncology drugs. Citation Format: Jennifer J. Stewart, Lynette Brown. Measurement of basophil activation using a flow cytometry method for applications in clinical research and clinical trials [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 5793.