tbuckley/cabot-search huggingface dataset:
Abstract 7186: Anti-cancer activity of potent and selective EP300 degradation in hematological malignancies
Authors: Claudia Dominici, Qianhe Zhou, Laura La Bonte, Mark Zimmerman, Mei Yun Lin, Wesley Austin
Journal: Cancer Research (2025)

Abstract E1A binding protein (EP300) and CREB binding protein (CBP) are highly homologous acetyltransferase paralogs with demonstrated roles as transcriptional co-activators. Dual inhibition of EP300 and CBP has been reported to have anti-proliferative effects in several cancer types. However, it has also been reported to elicit thrombocytopenia, a toxic reduction in the number of platelets in the blood (Nicosia et al., 2023). Hematological malignancy lineages are particularly susceptible to EP300 loss (DepMap, Broad 2024), therefore, developing chemical matter that selectively targets EP300 has the potential to broaden the therapeutic window and improve tolerability. Historically, selectivity has been difficult to engineer due to the high sequence similarity between EP300 and CBP. Using the targeted degradation approach, we have developed a potent and selective heterobifunctional degrader of EP300 with biological activity in hematological malignancy. We observed that selective degradation of EP300 has anti-proliferative activity in a broad range of hematological malignancies in vitro, including diffuse large B-cell lymphoma, multiple myeloma, and follicular lymphoma. We also achieved in vivo efficacy in a Karpas422 GCB-DLBCL xenograft model. Importantly, an investigational safety study was performed in mice at efficacious doses, and no thrombocytopenia was observed. Therefore, leveraging targeted protein degradation to achieve selective EP300 degradation shows promise to be a well-tolerated and effective treatment strategy for advanced hematological malignancies. Citation Format: Claudia Dominici, Qianhe Zhou, Laura La Bonte, Mark Zimmerman, Mei Yun Lin, Wesley Austin. Anti-cancer activity of potent and selective EP300 degradation in hematological malignancies [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 7186.
Abstract 2294: Association of analgesic use with risk of renal cell cancer in the Nurses’ Health Studies
Authors: Jinhui Li, Minji Jung, Benjamin Chung, Mark Preston, Marvin Langston, Rebecca Graff
Journal: Cancer Research (2025)

Abstract Objectives: This study aims to investigate the association between commonly utilized analgesics—aspirin, non-aspirin nonsteroidal anti-inflammatory medications (NSAIDs), and acetaminophen and the risk of renal cell cancer (RCC) in women. Methods: In 1980, the Nurses’ Health Study (NHS) collected data on aspirin usage from 92, 125 women. Additional non-aspirin NSAIDs and acetaminophen were included in 1990. In 1989, 112, 292 women were collected data in the NHS II and followed up since 1989. The association was also further investigated by stratification of histological subtypes, pathologic stage, and differentiation subtypes for RCC. Cox proportional hazards models were employed to generate cohort-specific, multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for each analgesic. Results from both cohorts were aggregated by random-effects meta-analyses. Results: For the over 20-year follow-up period, there are 11, 978, 22, 838, and 28, 350 women currently use acetaminophen, aspirin, and NSAIDs from the NHS study, and 25, 416, 12, 958, and 22, 407 women currently use these analgesic medications individually. 575 RCC and 142 fatal RCC cases were identified across the two cohorts. For RCC, in NHS II. We observed a significantly increased risk of RCC among the current acetaminophen users (Relative risk (RR): 1.56, 95%CI:1.13, 2.15). Pooled results showed positive associations: acetaminophen (RR:1.02, 95%CI: 0.75, 1.95); aspirin (RR:1.11, 95%CI: 0.91, 1.31); non-aspirin NSAIDs (RR:1.29, 95%CI:0.90, 1.83). Similar trends were observed for fatal RCC. When stratified the RCC subgroups, aspirin use shows a significantly positive association with the increased risk of different pathologic states (pooled RR: 1.29, 95%CI: 1.02, 1.63), and non-aspirin NSAID use was also associated with increased risk of different histological, pathological and differentiated RCC risk significantly. Conclusions: These data illustrated that the use of analgesics in NHS and NHS II cohorts is potentially associated with an increased risk of RCC among women. Citation Format: Jinhui Li, Minji Jung, Benjamin Chung, Mark Preston, Marvin Langston, Rebecca Graff. Association of analgesic use with risk of renal cell cancer in the Nurses’ Health Studies [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 2294.
Abstract 7175: <i>STAT3/STAT5</i> mutation predicts shorter overall survival in patients with plasma cell myeloma
Authors: Matthew T. Ye, Zhuang Zuo, Steliana Calin, Yaling Yang, M. James You
Journal: Cancer Research (2025)

Abstract Plasma cell myeloma is a heterogeneous hematological neoplasm characterized by clonal expansion of malignant plasma cells in the bone marrow. Mutations in the RAS-MAPK pathway, such as KRAS, NRAS, and BRAF, have been identified as high-risk factors associated with poor prognosis. However, the clinical impact of STAT3/STAT5 mutations in plasma cell myeloma has not been well studied. We assessed the clinicopathologic and molecular genetic features and clinical outcomes of 16 myeloma patients with STAT3/STAT5 mutations identified by next-generation sequencing, including 9 with STAT3 mutation, 5 with STAT5A mutation, and 2 with STAT5B mutation, and compared with 32 matched patients without any mutation. STAT3/STAT5 mutations were detected at initial diagnosis in all 8 patients with initial mutation status available, suggesting STAT3/STAT5 mutation is an early event in pathogenesis in plasma cell myeloma. STAT3/STAT5 mutation was the sole mutation in 5 cases and accompanied by other co-existing mutations in 10 cases, with KRAS/NRAS (n=5) and TP53 (n=3) being the most common; in the latter group, STAT3/STAT5 represented the dominant clone in 4 cases and co-dominant clone in 6 cases. All were missense mutations, with 10 of 16 (63%) located at the SH2 domain. The median variant allele frequency was 9.1%. STAT3/STAT5-mutated patients had higher level of serum lactate dehydrogenase, lower level of serum albumin, higher proportion of IgA type paraprotein, and more advanced R-ISS stage. STAT3/STAT5 mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival was significantly shorter for STAT3/STAT5-mutated patients (42 months vs 72 months, p&amp;lt;0.0001). In summary, STAT3/STAT5 mutations are often early events and represent dominant clones in plasma cell myeloma. These mutations are associated with a complex karyotype, more advanced R-ISS stage, and shorter overall survival. Our findings support the routine testing for STAT3/STAT5 mutations in patients with plasma cell myeloma, highlighting their role in disease pathogenesis and their potential as therapeutic targets. Citation Format: Matthew T. Ye, Zhuang Zuo, Steliana Calin, Yaling Yang, M. James You. STAT3/STAT5 mutation predicts shorter overall survival in patients with plasma cell myeloma [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 7175.
Abstract 5744: Design and synthesis of novel sulfonamide-based simple and vital aromatic amines as anticancer agents
Authors: Mohamed A. Eltokhy, Eman A. Fayed, Moustafa S. Abusaif, Ahmed Rageb, Yousry A. Ammar, Sanjay K. Srivastava
Journal: Cancer Research (2025)

Abstract Cancer remains a leading cause of mortality worldwide, with an increasing incidence driven by the complexity of tumor biology, drug resistance, and limited efficacy of current treatment options. Targeted therapy with small molecules has emerged as a promising approach due to its ability to selectively inhibit cancer cell growth while minimizing off-target effects. In this study, a series of derivatives synthesized from 3-formyl-4-hydroxy benzene sulfonyl chloride (FHS) were evaluated for their cytotoxic effects on various cancer cell lines. The objective was to identify compounds with potent anticancer activity and favorable selectivity profiles for further development. The synthesis process began with FHS as the starting material, subjected to a series of chemical reactions to generate a library of compounds labeled C3 through C10. These compounds were characterized using a combination of analytical techniques, including melting point determination, Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and Infrared (IR) spectroscopy to confirm their structural integrity. Cytotoxic effects were evaluated using Sulforhodamine B (SRB) assay. The assay was applied to an extensive panel of cancer cell lines, categorized into such as colorectal cancer (HT-29, MC38, CT26and COLO 205), hepatic (C3a and PLC/PRF), pancreatic (Suit-2, MiaPaca2, As-PC1 and Panc 02.03, CI66), breast (MDA-MB-468, MDA-MB-231, BT20, MCF7, 4T1, 4T1 paclitaxel resistant, JIMT-1, ZR-75-1, E0771, T47D, and HCC1806) and ovarian (OVCAR-5) cell lines. Normal breast epithelial cell line MCF10a was included as a control. Based on the SRB assay the 7 compounds exhibited variable but significant cytotoxicity in various cancer models. Further experiments are in progress to validate the most effective compounds in selected cancer models. Citation Format: Mohamed A. Eltokhy, Eman A. Fayed, Moustafa S. Abusaif, Ahmed Rageb, Yousry A. Ammar, Sanjay K. Srivastava. Design and synthesis of novel sulfonamide-based simple and vital aromatic amines as anticancer agents [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 5744.
Abstract 6589: Exosomal miR-155-5p from early myeloid-derived suppressor cells promotes breast cancer invasion and metastasis by regulating SIRT1
Authors: Guidong Chen, Jinpu Yu
Journal: Cancer Research (2025)

Abstract Early myeloid-derived suppressor cells (eMDSCs) are a heterogeneous group of myeloid cells and have a critical role in the progression of breast cancer. Therefore, exploring the mechanism of communication between eMDSCs and tumor cells is particularly important. In this study, the results showed that eMDSCs co-incubation improved the migration and invasion ability of breast cancer cells by up-regulating the expression of microRNA(miR)-155-5p. Further, we found that eMDSCS-derived exosomes transfer miR-155-5p to breast cancer cells and down-regulate sirtuin 1(SIRT1) expression to promote breast cancer progression. To overcome this challenge, we developed a nanodelivery platform targeting the tumor microenvironment to co-deliver the oligonucleotide inhibitor of miR-155, which demonstrated significant inhibition of tumor growth, migration and invasion in vivo experiments. Overall, our findings suggest that the eMDSCS-derived exosome miR-155-5p promotes invasion and metastasis of breast cancer by targeting SIRT1 and the construction of a tumor microenvironment responsive nanodelivery platform targeting eMDSCs exosome-derived miR-155-5p provides a promising strategy for overcoming breast cancer progression. Citation Format: Guidong Chen, Jinpu Yu. Exosomal miR-155-5p from early myeloid-derived suppressor cells promotes breast cancer invasion and metastasis by regulating SIRT1 [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 6589.
Abstract 6581: Evaluating the impact of the tumor microenvironment on EV-mediated intercellular exchange of nanoparticles
Authors: Yiqin Li, Hongbo Pang
Journal: Cancer Research (2025)

Abstract The limited delivery efficacy of nanoparticles (NPs) continues to impede their clinical translation for cancer therapy. Recent studies have demonstrated that active trans-endothelial pathways dominate NP delivery. While extensive research has focused on endocytosis and subcellular transport, there remains limited understanding of how NPs undergo exocytosis and subsequently re-enter neighboring cells—a process we termed intercellular exchange. Our previous studies established a collagen-based three-dimensional assay designed to specifically quantify the intercellular exchange of NPs and distinguish the contributions of various potential mechanisms. The findings revealed that a significant portion of NPs are transferred within extracellular vesicles (EVs). By modulating EV biogenesis, we successfully altered tumor accumulation and vascular penetration of various NPs in vivo. Here, we further enhance this assay by incorporating critical tumor microenvironment (TME) factors—such as acidity, hypoxia, and the dense extracellular matrix (ECM). This improved model provides a more physiologically relevant platform to evaluate the impact of TME-specific conditions on EV-mediated NP intercellular exchange. Our findings demonstrate that different TME factors exert varying effects on NP transfer efficiency, with ongoing studies evaluating their implications for in vivo delivery. These investigations not only shed light on the mechanisms by which NPs are transported within tumors but also enhance our understanding of the role of EVs in intercellular communication under highly stressed environments. Citation Format: Yiqin Li, Hongbo Pang. Evaluating the impact of the tumor microenvironment on EV-mediated intercellular exchange of nanoparticles [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 6581.
Abstract 6817: Targeting XPO1 eliminates cancer stem-like cells and abrogate hepatic metastasis in uveal melanoma
Authors: Bei Jin, Hailin Zou, Jingxuan Pan
Journal: Cancer Research (2025)

Abstract Uveal melanoma originating from the uveal tract are a rare form of the malignancy with a biology and clinical feature distinct from its more common cutaneous counterparts. Yet, UM is the most common primary intraocular tumor in adults. Despite effective treatment in primary UM with eye-sparing radiation-based techniques or enucleation, ∼50% of UM patients ultimately develop distant metastasis, most commonly in the liver. UM patients with hepatic metastasis have dismal prognosis owing to the limited efficacy of the available treatments. It is fundamental to find new therapeutic targets and develop novel treatment approaches for metastatic UM. XPO1 (also referred as CRM1), a key member of the importin β superfamily of nuclear transport receptors, mediates nuclear export of tumor suppressors and growth factors. We found that XPO1 was highly overexpressed in UM cells and positively correlated with poor prognosis of UM. Depletion of XPO1 by shRNA or its small molecular inhibitor KPT-330 significantly inhibited growth of UM cells in vitro and in vivo. Treatment with KPT-330 markedly induced apoptosis in UM cells via reducing the protein level of Survivin. Meanwhile, silencing of XPO1 by lentiviral shRNA or incubated with KPT-330 significantly decreased the percentage of ALDH+ cells and dampened self-renewal capacity in UM cells. Targeting XPO1 by KPT-330 profoundly alleviated liver metastasis burden in liver metastasis mouse model. These results suggest XPO1 may be a potential therapeutic target for patients with metastatic UM. Citation Format: Bei Jin, Hailin Zou, Jingxuan Pan. Targeting XPO1 eliminates cancer stem-like cells and abrogate hepatic metastasis in uveal melanoma [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 6817.
Abstract 6816: Synergistic targeting of nonsense-mediated mRNA decay and heat shock protein 90α for treating lethal prostate cancer
Authors: Jinghui Liu, Xinyi Wang, Hamed Maasoumyhaghighi, Mansoureh Nouri, Xiaoqi Liu
Journal: Cancer Research (2025)

Abstract Background: Androgen receptor signaling inhibitors (ARSI) provide modest survival benefits for metastatic castration-resistant prostate cancer (CRPC), but most patients eventually develop resistance, with some progressing to neuroendocrine prostate cancer (NEPC), a highly aggressive form of the disease. There are no effective treatments for ARSI-resistant patients, underscoring the need for new therapeutic strategies. Synthetic lethality, where the combined loss of two genes causes cell death, has shown promise in cancer therapy, as demonstrated by the success of PARP inhibitors. However, synthetic lethal CRISPR-Cas9 screens in prostate cancer (PCa) remain underexplored. Methods: A combinatorial CRISPR-Cas9 knockout screen was employed to identify synthetic lethal (SL) pairs in ARSI-resistant prostate cancer. Identified SL pairs were validated using in vitro cell viability assays and in vivo models, including cell line and patient-derived xenografts. A luminescence-based nonsense-mediated mRNA decay (NMD) sensor system was utilized to investigate the role of heat shock protein 90α (HSP90α) in NMD. The molecular mechanisms by which NMD components and HSP90α maintain protein and RNA homeostasis in advanced PCa were elucidated using immunohistochemistry, immunofluorescence, immunoblotting, and immunoprecipitation assays. Results: (1) The combinatorial CRISPR-Cas9 knockout screening identified NMD components and HSP90α emerged as a top novel synthetic lethal pair in ARSI-resistant PCa. (2) Dual knockout of NMD regulators and HSP90α led to cell death in ARSI-resistant PCa. (3) Inhibitors targeting both NMD and HSP90α synergistically suppressed the growth of advanced PCa cells in both in vitro and in vivo models, with minimal effects on normal cells. (4) HSP90α interacts with the NMD regulator, protecting it from aggregation and facilitating its function. Conclusions: Our research, utilizing an unbiased combinatorial CRISPR-Cas9 double-knockout screen, is the first to identify synthetic lethal pairs in ARSI-resistant prostate cancer. This study not only provides a new therapeutic approach for overcoming drug resistance in advanced PCa but also deepens our understanding of cellular homeostasis by elucidating the interaction between NMD components and heat shock proteins in the context of advanced prostate cancer. Citation Format: Jinghui Liu, Xinyi Wang, Hamed Maasoumyhaghighi, Mansoureh Nouri, Xiaoqi Liu. Synergistic targeting of nonsense-mediated mRNA decay and heat shock protein 90α for treating lethal 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 6816.
Abstract 6597: Optimization of DNA and RNA extraction from tumor FFFPE samples and end-to-end automation and analytical validation of the TSO 500 HT v1 library preparation
Authors: Nripesh Prasad, Supriya Singh, Rebecca Beatty, Rachel Rock, Melanie Robinson, Annamaria Szanto, Sara Hildebrand, Boris Umylny, Thomas Halsey
Journal: Cancer Research (2025)

Abstract Formalin-fixed paraffin-embedded (FFPE) techniques are cost-effective, long-term preservation methods for clinical samples, enabling next-generation sequencing (NGS) for expanded discovery and diagnostic applications. DNA and RNA extraction and library preparation must be optimized to ensure efficient downstream NGS analysis. We first focused on optimizing the quality and quantity of DNA and RNA recovery from FFPE samples representing various oncology conditions, using the truXTRAC® FFPE Tissue Extraction Kits (Covaris) automated on the Kingfisher Flex instrument (Thermo). We then analyzed the extracted DNA and RNA from FFPE tumor samples, including colorectal, kidney, breast, lung, gastric, and endometrial cancer, along with control samples from Horizon Oncospan and Seraseq, for analytical validation of the TSO 500HT v1 assay. RNA inputs were tested at 20ng, 40ng, and 80ng, while DNA inputs were tested at 20ng, 40ng, and 100ng. The TSO 500HT assay targets 523 genes to assess all DNA and RNA variant types, including SNV, CNV, indels, fusions, MSI, and TMB. For library preparation, 72-sample batches were processed using manual and fully automated workflows, with the automation protocol executed on the Biomek i7 (Beckman Coulter). Sequencing was performed on the Illumina NovaSeq 6000 and NovaSeq X Plus, using a 2x100bp paired-end configuration to generate approximately 50 million DNA reads and 8-10 million RNA reads per library. This approach demonstrated an overall inter-run and intra-run variant detection accuracy of over 90%, indicating highly repeatable and reproducible results. Variability between runs, lots, and operators was ≥99%. Our analysis showed high assay performance, with ≥96% of samples passing Illumina's cut-off metrics, particularly with 40ng DNA and 80ng RNA inputs. The analytical sensitivity for the TSO 500HT assay was benchmarked with ≥95% sensitivity for SNVs, ≥85% for InDels, ≥90% for CNVs, ≥90% for MSI, and ≥90% for TMB. These results provide a high-throughput, automated solution for dual DNA and RNA extraction from FFPE samples, demonstrating a robust, reproducible, and highly accurate targeted sequencing method for variant detection in oncology patients. Citation Format: Nripesh Prasad, Supriya Singh, Rebecca Beatty, Rachel Rock, Melanie Robinson, Annamaria Szanto, Sara Hildebrand, Boris Umylny, Thomas Halsey. Optimization of DNA and RNA extraction from tumor FFFPE samples and end-to-end automation and analytical validation of the TSO 500 HT v1 library preparation [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 6597.