tbuckley/cabot-search huggingface dataset:
Abstract 4522: Old dog, new tricks: The role of capecitabine in HPV-negative head and neck cancer
Authors: Marco Antonio Mascarella, Nisha Suarez, Keith Richardson, Alex Mlynarek, Michael Hier, Nader Sadeghi, Khalil Sultanem, Derin Caglar, Marc Pusztaszeri, Livia Florianova, Nathaniel Bouganim, Khashayar Esfahani
Journal: Cancer Research (2025)

Abstract Objective: Treatment for HPV-negative head and neck squamous cell carcinoma (HNSCC) has seen little innovation, particularly in advanced-stage disease, where outcomes remain suboptimal. The public healthcare system's delays in access to care can exacerbate this issue, allowing tumors to progress prior to treatment initiation. This study explores the use of capecitabine, an oral chemotherapy agent, in both preoperative and recurrent settings for HPV-negative HNSCC. Study Design: We conducted a prospective cohort study of patients with stage III/IV HPV-negative HNSCC at two academic centers in Montreal, Canada. The study evaluated clinical and pathological responses in patients receiving capecitabine in a preoperative setting, with radiological and clinical outcomes assessed for those with unresectable recurrent disease. Results: Among the 34 patients included in the study (23 oral cavity, 1 oropharynx, 5 skin, 5 larynx), 31 received capecitabine preoperatively, while 3 had recurrent, unresectable disease. Of the 31 patients undergoing surgery, 16 exhibited clinical tumor reduction, 13 remained stable, and 2 experienced tumor growth. Pathological responses were observed in 15 patients, including 1 complete response (skin) and 6 major responses based on the modified Ryan criteria. Two non-responders developed recurrences within one year. The mean follow-up for surgical patients was 6 months. In the non-surgical cohort, all three patients showed reduced pain and radiological improvements, with a mean follow-up of 8 months. No significant toxicity related to capecitabine was reported. Conclusion: Capecitabine, used either in a preoperative window of opportunity or in the recurrent setting, demonstrated measurable clinical and pathological responses in patients with HPV-negative HNSCC. Given its efficacy and low toxicity, further investigation of this oral agent is warranted, particularly in resource-constrained settings where timely access to treatment may be a challenge. Citation Format: Marco Antonio Mascarella, Nisha Suarez, Keith Richardson, Alex Mlynarek, Michael Hier, Nader Sadeghi, Khalil Sultanem, Derin Caglar, Marc Pusztaszeri, Livia Florianova, Nathaniel Bouganim, Khashayar Esfahani. Old dog, new tricks: The role of capecitabine in HPV-negative head and neck 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 4522.
Abstract 5318: Identifying immune cell phenotypes and their function by using high throughput spatial multiomics
Authors: Debia Wakhloo, Julia Yu, Sonali Deshpande, Donald Allen, Anne Hellebust, Anushka Dikshit
Journal: Cancer Research (2025)

Abstract Advances in our understanding of the tumor microenvironment (TME) will help inform the development of next generation immunotherapies and engineered immune-cell therapies. Spatially characterizing immune cells with cell marker protein and activation marker RNAs is crucial to determine therapeutic efficacy and potential therapeutic toxicity. To address this, we have developed a high throughput RNAscope™ assay on the BOND RX to spatially visualize RNA and protein markers on the same slide. We utilized the new RNAscope™ Multiomic LS assay that can detect up to 6 RNA and protein targets on the same slide. The TSA-based amplification strategy offers signal boost for both RNA and protein targets. To optimize protein detection, the workflow is completely protease-free there by preserving antigen integrity and tissue morphology. The assay can be customized to include any target RNA and proteins of interest. Here, we demonstrate the use of our pre-conjugated antibody panel which includes CD8, CD4, FoxP3 and PanCK to visualize tumor infiltrating lymphocytes (TILs). We also utilized unconjugated primary antibodies for CD68 and CD163 to detect tumor macrophages in multiple tumor tissues. Using the HALO® image analysis software from Indica Labs, we performed RNA and protein quantification as well as cell phenotyping and spatial analysis. Infiltrating Cytotoxic T cell lymphocytes were detected using CD8, GZMB and IFNG co-expression. Regulatory T cells were detected using CD4, FOXP3 co-expression. PanCK was used as a tumor marker to delineate tumor from stroma. Similarly, tumor associated macrophages were detected using CD163, CD68 , IL10 and IL-1B expression. We were also able to identify distinct M1 and M2 macrophage populations in the tumor samples. The protease-free RNAscope Multiomic LS assay was successfully able to interrogate different subpopulation of immune cells with high fidelity RNA and protein signal while maintaining tissue morphology. The higher plex capability provides detection of more markers simultaneously, in turn enabling immune phenotype profiling while maintaining the sensitivity and specificity. Finally, the assay affords a very high throughput on the BOND Rx allowing large-scale pre-clinical and patient sample analysis. Citation Format: Debia Wakhloo, Julia Yu, Sonali Deshpande, Donald Allen, Anne Hellebust, Anushka Dikshit. Identifying immune cell phenotypes and their function by using high throughput spatial multiomics [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 5318.
Abstract 7225: The secreted cytokine Chitinase 3-like-1 promotes breast cancer metastasis
Authors: Adeline Masse, Tarek Taifour, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Hailey Proud, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Rinath Jeselsohn, William J. Muller
Journal: Cancer Research (2025)

Abstract Breast cancer is the second most common cancer and a major cause of mortality affecting women worldwide. Immunosuppression is a key hallmark of cancer progression, whereby cancer cells suppress the immune system that is programmed to fight the disease. This suppressed tumor immune microenvironment (TIME) facilitates cancer metastatic spread to distant organs, which is associated with treatment resistance, recurrence, and poor prognosis. The Signal transducer and activator of transcription 3 (Stat3) suppresses the immune system, drives cancer progression and metastasis. Genetic ablation of Stat3 in the murine inducible breast tumor model expressing polyoma virus middle T (PyMT), results in delayed tumor onset and reduced tumor growth and metastasis. We have also previously demonstrated that the secreted protein Chitinase 3-like-1 (Chi3l1) is a direct target of Stat3 which promotes immunosuppression through its actions on neutrophils. Chi3l1 recruits neutrophils and induces the formation of Neutrophil Extracellular Traps (NETs) that block T cells from infiltrating the tumor. Targeting both Chi3l1 or neutrophils resulted in increased T cell infiltration and delayed tumor onset. However, the roles of Chi3l1 during the metastatic cascade remained unclear. To further investigate the role of Chi3l1 in metastasis, we generated a novel inducible mouse model that overexpresses Chi3l1 specifically in the mammary epithelial cells. Overexpression of the Chi3l1 protein in the Stat3 knockout PyMT model showed a rescue of the delay in tumor onset. Consistent with our previous studies, Chi3l1 overexpression caused a dramatic influx of neutrophils and the generation of an immune suppressed TIME. In addition, we observe an increase in circulating tumor cells which correlated with a quicker onset and increased incidence of pulmonary metastasis. These results hint that in breast cancer, Chi3l1 overexpression creates a pro-tumorigenic TIME which favorizes tumor initiation and progression as well as induces intravasation of tumor cells into the blood stream, which leads to metastasis to distant sites. Our future studies will investigate whether this phenotype is driven through neutrophils and whether targeting neutrophils would inhibit Chi3l1-mediated metastasis. Citation Format: Adeline Masse, Tarek Taifour, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Hailey Proud, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Rinath Jeselsohn, William J. Muller. The secreted cytokine Chitinase 3-like-1 promotes breast cancer metastasis [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 7225.
Abstract 7197: Targeting FAK exhibits therapeutic effects on interstitial lung disease induced by trastuzumab deruxtecan
Authors: Baoyuan Zhang, Ran Pang, Jingwen Cheng, Jiaming Gao, Natasha Qin, Leo Liu, Zaiqi Wang
Journal: Cancer Research (2025)

Abstract Interstitial lung disease (ILD) is a common pulmonary complication associated with cancer therapy. Several antibody-drug conjugates (ADCs), including trastuzumab deruxtecan (Enhertu), have been implicated in the induction of ILD, thereby limiting their clinical application. Treatment with ADCs must be permanently discontinued if grade 2 or higher ILD-related adverse effects occur. The standard approach for managing Enhertu-induced ILD involves the use of corticosteroids, which can exacerbate the toxicities faced by cancer patients. Our previous studies demonstrated that targeting focal adhesion kinase (FAK) enhances the efficacy of Enhertu and other ADCs in solid tumor treatment. Notably, we have now identified that FAK inhibition by the small molecule inhibitor Ifebemtinib (aka IN10018, Ifebe) can mitigate Enhertu-induced ILD. In an animal model of Enhertu-induced ILD, Ifebe showed recovery trends comparable to those observed with corticosteroids across multiple physiological parameters of mouse respiration. Both inflammatory and ILD injury biomarkers which were activated by Enhertu were significantly reduced with Ifebe monotherapy. Collectively, the combination of FAK inhibition and Enhertu may offer improved therapeutic efficacy while mitigating ILD-related toxicities. These findings warrant further clinical investigation. Citation Format: Baoyuan Zhang, Ran Pang, Jingwen Cheng, Jiaming Gao, Natasha Qin, Leo Liu, Zaiqi Wang. Targeting FAK exhibits therapeutic effects on interstitial lung disease induced by trastuzumab deruxtecan [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 7197.
Abstract 6865: Discovery and characterization of small molecule inhibitors targeting EXO1 for BRCAness cancer therapy
Authors: Yixing Wang, Jessica Hess, Li Zheng, Binghui Shen
Journal: Cancer Research (2025)

Abstract Human exonuclease 1 (EXO1), a member of the structure specific nuclease family, plays a critical role in maintaining genome stability by processing DNA double-strand breaks (DSBs), nicks, and replication intermediates during DNA replication and repair. As its exonuclease activity is essential for homology-directed repair and replication fork processing, EXO1 has emerged as a compelling therapeutic target, especially in cancers marked by heightened DNA damage and replication stress. Through high-throughput screening of 45, 000 compounds, we identified eight distinct scaffolds of EXO1 inhibitors that demonstrated effective and selective inhibition. Two lead compounds, C200 and F684, underwent structural and mutagenesis studies, which confirmed their binding mechanisms. Biochemical assays further validated their potent and selective inhibition of EXO1 activity. Tumor cell profiling revealed that these inhibitors exploit synthetic lethality in BRCA1-deficient cells, emphasizing their specificity and therapeutic potential for targeting BRCAness cancers. Mechanistically, EXO1 inhibition suppressed DNA end resection, increased the accumulation of DSBs, and triggered S-phase PARylation, effectively disrupting DNA repair pathways essential for cancer cell survival. These findings establish EXO1 inhibitors as promising candidates for the treatment of BRCAness cancers and lay the groundwork for further optimization and development of these compounds as targeted therapeutics. Citation Format: Yixing Wang, Jessica Hess, Li Zheng, Binghui Shen. Discovery and characterization of small molecule inhibitors targeting EXO1 for BRCAness cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6865.
Abstract 6863: Development of MYCN/MYC inhibitors
Authors: Satyanarayana Gadde, Sin Wi Ng, Natalie Chung, Qian Wang, Larissa Doughty, Tracey Nero, Maria Tsoli, David Ziegler, Louis Chesler, Michael Parker, Naresh Kumar, Belamy Cheung, Glenn Marshall
Journal: Cancer Research (2025)

Abstract Background: Deregulated expression of MYC family transcription factors is present in more than 70% of human cancers. MYC is an intrinsically disordered protein without known drug binding pockets and is essential for adult cell replication, making clinical development of MYC inhibitors challenging. MYCN amplification and overexpression generate driver signals in the childhood cancers, neuroblastoma (NB), medulloblastoma (MB) and diffuse intrinsic pontine glioma (DIPG). Methods and Results: We previously reported a small molecule compound, SE486-11, which reduced MYCN protein levels in combination with suberoylanilide hydroxamic acid. We developed more potent analogues of SE486-11 with improved single agent potency, selectivity towards cancer cells and solubility (UNSW-SC compounds). Our lead compound, UNSW-SC-22 is highly effective in vitro against MYCN-driven NB and MB cells with sub-micromolar IC50 values and displayed a wide therapeutic index. UNSW-SC-22 displayed MYCN- and c-MYC-dependent cytotoxicity and decreased MYCN and c-MYC protein levels in NB and MB cell lines. MYCN and c-MYC protein half-life was decreased ∼2-fold, while K-48-linked ubiquitination of MYCN protein was increased by UNSW-SC-22. We show UNSW-SC-22 bound to full length MYCN and c-MYC proteins directly, with KDs of 62.7 µM and 60.5 µM, respectively, by surface plasmon resonance. In-cell target engagement was further confirmed by drug affinity responsive target stability and cellular thermal shift assays. Total RNA from NB and MB cells treated with UNSW-SC-22 showed down-regulation of MYC target genes on GSEA analyses. On in-vitro pharmacology profiling against 47 intracellular signalling targets (78 assays) known to cause adverse drug reactions in humans, UNSW-SC-22 demonstrated no significant target activation at &amp;lt;20 µM. UNSW-SC-22 freely crossed the blood-brain barrier, reaching a concentration of 10.8 µM in brain tissue, with a half-life of 1.22 hours. UNSW-SC-22 significantly reduced the tumour burden and improved overall survival of MYCN-driven NB and MB mice. MYCN protein expression was downregulated in tumours collected from mice treated with UNSW-SC-22. Conclusion: Collectively, our data suggest that MYCN and c-MYC are the direct molecular targets of UNSW-SC compounds. These compounds have strong potential to serve as specific targeted therapy to treat MYCN/c-MYC driven paediatric and adult cancers. Citation Format: Satyanarayana Gadde, Sin Wi Ng, Natalie Chung, Qian Wang, Larissa Doughty, Tracey Nero, Maria Tsoli, David Ziegler, Louis Chesler, Michael Parker, Naresh Kumar, Belamy Cheung, Glenn Marshall. Development of MYCN/MYC inhibitors [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 6863.
Abstract 5075: Detection and spatial analysis of mRNA delivered by lipid nanoparticles through spatial transcriptomics
Authors: Jeongbin Park, Yuchang Seong, Dongjoo Lee, Jinyeong Choi, Hanna Jung, Somin Lee, Hongyoon Choi, Hyungjun Im
Journal: Cancer Research (2025)

Abstract Background: Lipid nanoparticle (LNP) platforms are widely used for mRNA delivery, but the precise distribution of mRNA within tissues remains poorly understood. Spatial transcriptomics technologies have enabled detailed mapping of RNA localization in tissues. In this study, LNPs targeting the spleen were used to encapsulate tdTomato mRNA, and spatial transcriptomics was employed to analyze its distribution and interactions within the spleen microenvironment. Methods: Spleen-targeting LNPs were developed to deliver codon-optimized tdTomato mRNA. Space Ranger and advanced alignment algorithms were used to distinguish endogenous and externally delivered mRNA. Overlapping sequences with mouse hemoglobin genes were excluded to ensure accurate analysis. After mapping tdTomato mRNA onto the ST data, we performed colocalization analysis with the ST data of the mouse spleen to demonstrate the precise distribution of tdTomato mRNA within the tissues. Results: The transcriptomic analysis of mouse spleen tissues revealed distinct red pulp, white pulp, and marginal zone morphologies. Similar gene expression profiles between control (‘Con’) and experimental (‘Exp’) samples indicated comparable tissue conditions. tdTomato mRNA was observed exclusively in the ‘Exp’ sample, predominantly localized in the red pulp, aligning with the expected LNP delivery pathway via blood circulation. Spatial correlation analysis in the ‘Exp’ sample revealed that hemoglobin genes were highly correlated with tdTomato mRNA, while ribosome-related genes showed the lowest correlation. RNA degradation analysis demonstrated intact tdTomato mRNA in the medulla, whereas significant degradation was observed in the cortex. Compared to fluorescence imaging, the platform used provides distinct advantages, such as absence of autofluorescence, offering PCR-level sensitivity, and enabling absolute quantification, thereby enhancing the precision of these findings. Conclusion: Using spatial transcriptomics, the study successfully mapped the distribution of externally delivered tdTomato mRNA within tissue and analyzed its spatial interactions with the surrounding microenvironment. RNA degradation patterns revealed distinct microenvironments affecting mRNA stability. These findings provide insights into the pharmacokinetics of mRNA-loaded LNPs and support the development of optimized nucleic acid delivery systems. Citation Format: Jeongbin Park, Yuchang Seong, Dongjoo Lee, Jinyeong Choi, Hanna Jung, Somin Lee, Hongyoon Choi, Hyungjun Im. Detection and spatial analysis of mRNA delivered by lipid nanoparticles through spatial transcriptomics [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 5075.
Abstract 4331: Collaboration between p63 and ZNF148 in regulating squamous cell carcinoma progression
Authors: Artem Smirnov, Eleonora Candi
Journal: Cancer Research (2025)

Abstract p63, a member of the p53 family of transcription factors, is essential for the development and maintenance of squamous epithelium. In squamous cell carcinomas, including head and neck squamous cell carcinoma (HNSCC), p63 is the most frequently amplified transcription factor at the genomic level and is often overexpressed. HNSCC is a prevalent and aggressive form of cancer and treating advanced stages of the disease remains a significant challenge. Using a proteomics-based approach, we identified new binding partners of the oncogenic variant DNp63. Among these, the zinc finger protein ZNF148 was found to be co-expressed with DNp63 and to physically interact with it in carcinoma cells. Genome-wide binding studies revealed a functional enhancer-derived RNA (eRNA) located upstream of the CCND1 gene, which is bound by both DNp63 and ZNF148. This interaction regulates the transcription of the eRNA, leading to increased cyclin D1 expression, thereby promoting tumor cell proliferation. Notably, this pathway is specific to cancer cells and remains inactive in normal epithelial cells. The expression levels of DNp63, ZNF148, and the eRNA are positively correlated in cancer, with higher levels linked to advanced disease and metastasis. Furthermore, ZNF148 also independently influences cell migration and inflammatory responses in HNSCC by regulating genes involved in actin cytoskeleton remodeling and type I and II interferon signaling pathways. Together, these findings uncover a novel molecular mechanism driving HNSCC progression and highlight potential targets for selective cancer therapies. Citation Format: Artem Smirnov, Eleonora Candi. Collaboration between p63 and ZNF148 in regulating squamous cell carcinoma progression [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 4331.