tbuckley/cabot-search huggingface dataset:
Abstract 1230: High throughput quantitative molecular characterization of cytotoxic antibody-drug conjugates in spheroid models for improved functional characterization, screening and candidate selection
Authors: Meghan Hogan, Andrea Hernández Rojas, Araba Sagoe-Wagner, Jodi Wong, Sarah Church, Brigitte Lovell, Sergio Hernandez, Lakshmi Chandramohan, Anna Juncker-Jensen, Kirsteen Maclean
Journal: Cancer Research (2025)

Abstract Background: Antibody-drug conjugates (ADCs) are a class of cancer therapeutics comprised of a linker-payload conjugated to a monoclonal antibody targeting a tumor-associated antigen (TAA), to enable the delivery of the cytotoxic payload to cancer cells. Presently, there is a need for improved in vitro models that better recapitulate in vivo tumor tissue complexity to aid in the screening and evaluation of novel ADCs during preclinical development. Specifically, we have developed in vitro 3D models from cancer cell lines yielding spheroids in a rapid, robust and uniform manner. Using these spheroid models, we have developed cell-based assays to functionally evaluate the cytotoxic activity of ADCs in vitro. For further comprehensive characterization of ADC activity in 3D cell line models, we utilized the nCounter® ADC Development Panel, a specialized gene expression tool for molecular characterization of biological function, with customizable gene content to address complex questions important for the success of ADCs throughout discovery, pre-clinical and clinical development. Methods: Spheroids were generated by seeding ovarian cancer cell lines into microtiter plates treated with ultra-low attachment coating, using automated liquid-handling robots, followed by incubation with ADCs under standard culturing conditions, prior to functional transcriptomic evaluation. The nCounter ADC Development Panel was analytically validated and included performance specification of accuracy, precision, analytical specificity, and RNA input range of the panel to directly profile 770 genes addressing essential biological questions relevant to ADC activity, including tumor targeting and antigen expression; ADC internalization; payload release; drug mechanisms of action; target cell death; immunogenic cell death; and mechanisms of resistance. Results: The combination of high-throughput spheroid assays and comprehensive transcriptomic analysis presented herein highlight an important and streamlined workflow to aid in the screening and selection of therapeutic cytotoxic ADC candidates for the treatment of solid tumors. Citation Format: Meghan Hogan, Andrea Hernández Rojas, Araba Sagoe-Wagner, Jodi Wong, Sarah Church, Brigitte Lovell, Sergio Hernandez, Lakshmi Chandramohan, Anna Juncker-Jensen, Kirsteen Maclean. High throughput quantitative molecular characterization of cytotoxic antibody-drug conjugates in spheroid models for improved functional characterization, screening and candidate selection [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 1230.
Abstract 3711: An RNA-binding phosphoprotein twist with BRCT domains in DNA damage repair: computational modeling of nucleolin
Authors: Nitu Farhin, Andriele S. Eichner, Anjana Saxena, Shaneen Singh
Journal: Cancer Research (2025)

Abstract Nucleolin (NCL), an RNA binding protein (RBP), and BRCA1, a tumor suppressor protein linked to breast and ovarian cancer susceptibility, colocalize at the sites of DNA damage and collaborate in homologous DNA repair pathways. Even so, the underlying mechanism where NCL and BRCA1 function together during DNA damage repair (DDR) remains unexplored. We utilized in silico approaches to unveil and characterize the shared interactome of BRCA1 and NCL. Our analysis revealed 49 common proteins interacting with BRCA1 and NCL, potentially influencing their functions. These proteins were systematically categorized into five distinct Gene Ontology (GO) annotation classes: DNA repair, RNA-binding, chromatin remodeling, DNA damage, and cell cycle regulation. Here, we predict interaction scenarios between full-length NCL and five BRCT-containing proteins crucial for DNA repair: BRCA1, MDC1, NBN, PARP1, and TP53BP1, to provide molecular insights into the interface. We strongly predict that the N-terminal acidic region of NCL which is also a site of several CK2 and CDK1 phosphorylation sites is involved in interaction with these five BRCT-containing proteins. Our computational models predict that RNA binding domains (RBDs) of NCL remain free to bind RNA or DNA, potentially facilitating its role in DDR. We further present the mutational landscape of the BRCT regions of these five proteins using the COSMIC database and identify the sites that might affect their interactions with NCL. Identifying the common interactome that associates with NCL and BRCA1 duo will facilitate our understanding of the intricate molecular interplay during the DDR. These protein-protein interactions potentially provide targetable interfaces, especially to combat aggressive triple-negative breast cancer where the DNA-repair pathway is predominantly deregulated. Citation Format: Nitu Farhin, Andriele S. Eichner, Anjana Saxena, Shaneen Singh. An RNA-binding phosphoprotein twist with BRCT domains in DNA damage repair: computational modeling of nucleolin [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 3711.
Abstract 3368: Hemophagocytic lymphohistiocytosis provisional prognostic score
Authors: Philip A. Haddad, Suma Chennapragada, Deepti Kantamani, S. Jashwanth Gaddam
Journal: Cancer Research (2025)

Abstract Background: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by the uncontrolled activation of lymphocytes and macrophages, leading to excessive cytokine production, hyperinflammation, and tissue damage. HLH presents in two forms: primary (familial) HLH, associated with autosomal recessive genetic mutations affecting cytotoxic function, and secondary (acquired) HLH, triggered by infections, malignancies, autoimmune diseases, or other underlying conditions. Given the variability in HLH outcomes, this study aimed to develop a provisional prognostic score (HLHPS) to stratify patient risk. Methods: We analyzed data from a real-world HLH database, comprising 255 cases. Data included demographic information (sex, age, race), blood counts, comorbidities, immunohistochemical and molecular disease phenotypes, treatment types, and survival outcomes. Of these, 219 cases with complete survival data were selected for analysis. A Cox proportional-hazards model and Log-rank tests were applied to identify clinicopathologic factors significantly affecting overall survival (OS), which were then incorporated into a provisional prognostic score based on the impact of hazard ratios. Results: The median OS for the cohort was 24 months. The key prognostic factors identified were: age &amp;gt;50 (9 vs. 60 months; p=0.003), underlying malignancy (2 vs. 60 months; p=0.0004), splenomegaly (22 vs. NR months; p=0.02), LDH &amp;gt;1000 U/L (24 vs. NR months; p=0.003), and sIL2R &amp;gt;5000 U/ml (6 vs. NR months; p=0.03). A prognostic model was created using these variables, with each variable assigned 1 point when present, for a total score ranging from 0 to 5. Risk categories were defined as low (0-1 points), intermediate (2 points), and high (3-5 points). This prognostic score system led to our cohort's most optimal risk discriminatory model, with low, intermediate, and high risk groups having a median OS of NR, 22, and 1.8 months, respectively (p&amp;lt;0.0001). Conclusion: The HLHPS is a promising tool for risk stratification in HLH patients, offering a new approach to predict outcomes. However, further prospective validation is necessary to confirm its utility. Citation Format: Philip A. Haddad, Suma Chennapragada, Deepti Kantamani, S. Jashwanth Gaddam. Hemophagocytic lymphohistiocytosis provisional prognostic score [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 3368.
Abstract 2854: The role of NONO in genome stability: Implications for RNA-DNA hybrid accumulation, genomic instability, and inflammatory signaling
Authors: Vikas Gaur, Sara Knowles, Weihang Chai
Journal: Cancer Research (2025)

Genomic instability, often resulting from replication stress and defects in DNA damage repair pathways, is a hallmark of cancer. The NONO protein, a multifunctional RNA-binding factor, plays a key role in DNA damage repair, transcriptional regulation and genome stability. Emerging evidence has linked NONO to cancer progression, though its mechanistic roles in maintaining genomic stability remain unclear. In our study, we demonstrate that NONO localizes at replication forks, as revealed by iPOND and SIRF assays, and interacts with replication polymerases. Loss of NONO in knockout (KO) cells leads to increased replication speed, significant RNA-DNA hybrid (R-loop) accumulation, and heightened genomic instability. These cells exhibit elevated micronuclei formation, abnormal chromosome segregation during metaphase, and increased 53BP1 foci, a marker of DNA double-strand breaks. NONO KO cells also show higher RPA loading under replication stress, highlighting their vulnerability to DNA damage. Additionally, the loss of NONO activates inflammatory response genes, including phospho-NFκB, p-IKKα, cGAS, and IRF3, suggesting that DNA-RNA hybrid accumulation and DNA damage may drive inflammatory signaling pathways. These findings position NONO as a critical regulator of genome stability, replication dynamics, and inflammation suppression. Our study highlights the essential role of NONO in maintaining genome integrity, interacting with replication machinery, and resolving R-loops. We will present ongoing work to further elucidate the mechanisms by which NONO contributes to genome stability and inflammatory responses in cancer cells. Citation Format: Vikas Gaur, Sara Knowles, Weihang Chai. The role of NONO in genome stability: Implications for RNA-DNA hybrid accumulation, genomic instability, and inflammatory signaling [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 2854.
Abstract 2041: Microsatellite instability as a biomarker for predicting chemoradiotherapy response in rectal cancer: insights from pathological and radiomic analyses
Authors: Euna Jeong, Hyowon Hong, Jaemin Jo, Shin Kim, SangJun Byun, Incheol Seo, Woon Kyung Jeong, Seong Kyu Baek, Hye Won Lee
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is one of the common causes of cancer-related deaths around the world. Rectal cancer accounts for approximately 30% of all colon cancers, half of which are diagnosed as locally advanced rectal cancer. Microsatellite instability (MSI) is a key biomarker in colorectal cancer (CRC), impacting immunotherapy outcomes and potentially influencing chemoradiotherapy (CRT) responses. In this study, we investigate the correlation between treatment response to CCRT according to MSI status. Methods: Tissue specimens were obtained by preoperative biopsy from 87 patients with rectal adenocarcinoma who underwent CRT. Patients received fluorouracil-based long-course neoadjuvant therapy. MSI analysis was performed on DNA extracted from tumors and matched normal tissue. The extracted DNA was tested by PCR targeting five microsatellite loci: BAT25, BAT26, D5S346, D2S123, and D17S250. Clinical and pathological parameters, including lymphovascular invasion and T/N stage, were compared between CRT responders and non-responders. In vitro, 3 MSI-H and 6 MSS colorectal cancer cell lines underwent gradient radiation exposure. Radiosensitivity was evaluated through XTT cell viability assays and apoptotic rates quantified via flow cytometry (FACS). Results: Preoperative MSI status was observed divided into MSI (MSI-H+MSI-L) and MSS. In the responder group (n=27), there were 5 people (18.52%) with MSI and 22 people (81.48%) with MSS, and in the non-responder group (n=60), 0 (0.0%) MSI and 60 (100%) MSS were observed (P = &amp;lt;0.005). Additionally, there were significant differences in ypT stage (P&amp;lt;0.001), ypN stage (P=0.003), lymphovascular (P=0.043) and perineural invasion (P=0.035). MSI-H cell lines demonstrated greater radiosensitivity, with significantly reduced viability in XTT assays and higher apoptosis rates in FACS analysis compared to MSS cell lines. Conclusion: Our findings suggest that MSI status is a significant predictor of response to CCRT, with patients exhibiting MSI tumors showing a higher likelihood of treatment response compared to those with MSS tumors. Enhanced radiosensitivity in MSI-H cell lines further supports the predictive value of MSI testing. Future studies should confirm these findings in larger cohorts. Citation Format: Euna Jeong, Hyowon Hong, Jaemin Jo, Shin Kim, SangJun Byun, Incheol Seo, Woon Kyung Jeong, Seong Kyu Baek, Hye Won Lee. Microsatellite instability as a biomarker for predicting chemoradiotherapy response in rectal cancer: insights from pathological and radiomic analyses [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 2041.
Abstract 3648: AI-enabled 3D multimodal integration platform reveals subcellular architecture of tumor immune microenvironment for therapeutic target and biomarker discovery and patient selection
Authors: Inyeop Jang, Yoonho Choi, Minji Kim, Jeonghwan Park, Jiyeon Sung, Byungsoo Ann, Clemenceau R. Jean, TaeHyun Hwang
Journal: Cancer Research (2025)

Background: Tumor immune microenvironment (TIME) organization fundamentally shapes cancer progression and immunotherapy outcomes. Traditional 2D spatial molecular approaches inadequately capture the complex three-dimensional architecture and cellular interactions within TIME. We developed an AI-driven platform integrating multiple spatial molecular datasets, enabling comprehensive 3D visualization for therapeutic discovery and patient selection. Methods: Our platform combines holotomography imaging, providing 3D refractive index maps, with diverse spatial molecular data: in situ molecular imaging, spatial proteomics, multiplex immunohistochemistry, and spatial transcriptomics. AI algorithms align datasets within a unified 3D coordinate system, while Poisson implicit surface reconstruction generates subcellular-resolution models. Platform validation used clinical samples from immunotherapy-treated patients. Results: The platform integrated multimodal spatial data into high-resolution 3D TIME representations, revealing novel relationships between protein expression, transcriptional patterns, and cellular architecture. 3D surface protein analysis with subcellular morphology identified patients with target protein expression outside tight junctions, indicating higher risk for adverse effects from antibody-drug conjugates and cellular therapies. This insight, unavailable through 2D analysis, enabled precise patient selection. Conclusions: This platform provides detailed subcellular-resolution TIME architecture analysis, offering actionable insights for therapeutic targeting, biomarker discovery, and patient selection. AI-driven 3D spatial multimodal TIME analysis advances precision medicine across multiple therapeutic approaches, including immunotherapy, targeted therapy, and drug delivery optimization. AI Disclosure: Original abstract content was written by the authors. Claude was used for editorial assistance and formatting without altering the scientific content or context of the work. Citation Format: Inyeop Jang, Yoonho Choi, Minji Kim, Jeonghwan Park, Jiyeon Sung, Byungsoo Ann, Clemenceau R. Jean, TaeHyun Hwang. AI-enabled 3D multimodal integration platform reveals subcellular architecture of tumor immune microenvironment for therapeutic target and biomarker discovery and patient selection [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 3648.
Abstract 893: A novel approach to treating HER2-low breast cancer: surface-engineered NK/tz cells targeted immunotherapy
Authors: Maria Jose Godoy Calderon, Eric Gauchat, VK Gadi
Journal: Cancer Research (2025)

Abstract Background: The majority (60-70%) of metastatic breast cancers (MBC) are HER2-low expressing, and in distinction to HER2+ disease, is not addicted for growth to this oncogene. Trastuzumab-based treatments have failed to improve the outcomes of patients with HER2-low breast cancer. Despite promising results with trastuzumab-deruxtecan (T-DXd), significant systemic toxicity and disease progression were observed highlighting the need to develop safer and more effective, and accessible therapies. This study evaluates the therapeutic potential of surface-engineered NK cells (SE-NK) modified with trastuzumab (Tz) for targeting HER2-low breast cancer cells. Methods: To establish a preclinical model, the triple-negative murine breast cancer cell line 4T1 was transduced with a lentiviral vector encoding human HER2, generating clones with HER2 expression comparable to HER2-low human breast cancer cells (MDA-MB-175). HER2 expression was validated using flow cytometry, confocal microscopy, and Western blot analysis. SE-NK/Tz cells were generated by embedding 25 ug Tz onto the NK cell surface using a hydrophobic linker. These cells were tested in vitro for HER2-specific cytotoxicity against the engineered 4T1-HER2-low cells. Results: Transduced 4T1-HER2-low cells exhibited HER2 expression levels consistent with HER2-low human breast cancer cells. In vitro, SE-NK/Tz cells demonstrated significantly enhanced cytotoxicity against 4T1-HER2-low cells (24%, p &amp;lt;0.05) compared to NK cells alone (0%) when an effector to target ratio of 1.25:1 was used. Conclusions: This study establishes the feasibility of using SE-NK/Tz cells as a novel immunotherapeutic approach for HER2-low breast cancer. We created for the firsttime to our knowledge a murine cell line with human HER2-low status comparable to expression values reported in patients. The preclinical findings support the potential of this strategy to overcome the limitations of current therapies by offering an effective and accessible treatment option. Future studies will explore mechanisms of immune activation and therapeutic efficacy in diverse in vivo HER2-low models. Citation Format: Maria Jose Godoy Calderon, Eric Gauchat, VK Gadi. A novel approach to treating HER2-low breast cancer: surface-engineered NK/tz cells targeted immunotherapy [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 893.
Abstract 2937: Animal models for evaluating the efficacy of anti-human HER2 ADC alone or in combination with IO therapy
Authors: Jean Huang, Chong Li, Ruili Lv, Qinjun Wang, Qingqing Xu, Heling Shen, Xiaofei Zhou
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) combine the targeting ability of antibodies with the killing power of cytotoxins, allowing for the release of highly toxic payloads within tumor cells, thereby enhancing therapeutic efficacy while reducing systemic toxicity. ADCs have demonstrated significant efficacy as monotherapy in the treatment of various tumors. However, like many cytotoxic agents, the issue of drug resistance limits the sustained efficacy they can achieve as standalone treatments. To overcome this challenge, the combined application of ADCs with other therapies is becoming a new focus of research. Among these, the combination of immuno-oncology inhibitors (IO) with ADCs has shown strong therapeutic potential in clinical settings. An appropriate preclinical evaluation model can effectively assess the therapeutic potential of ADCs. Biocytogen developed a HER2-expressing MC38 cell line called B-hHER2 MC38 plus. The HER2 expression level of B-hHER2 MC38 plus is similar to that of the human cell line NCI-N87, and it can form tumors normally in B-hHER2 mice. In a syngeneic transplantation model of B-hHER2 mice with MC38 plus cells, the anti-HER2 antibody-drug conjugate (ADC) analogous to trastuzumab, MMAE, exhibited a dose-dependent tumor suppression effect. When combined with the anti-mPD-1 antibody, it demonstrated a higher tumor suppression rate. In another syngeneic transplantation model where B-hHER2 MC38 plus cells were inoculated into B-h4-1BB/hHER2 mice, the commercial product DS8201 showed significant tumor growth inhibition. In the xenograft models using a diverse array of human tumor tissues - including breast cancer tumor tissues (BP0818 and BP1056), colorectal cancer tumor tissues (BP0170 and BP0847), lung cancer tumor tissues (BP0508 and BP0638), as well as breast cancer cell lines (BT-474 and MDA-MB-231), and the gastric cancer cell line (NCI-N87) - the commercial product DS8201 demonstrated significant tumor growth inhibition. Citation Format: Jean Huang, Chong Li, Ruili Lv, Qinjun Wang, Qingqing Xu, Heling Shen, Xiaofei Zhou. Animal models for evaluating the efficacy of anti-human HER2 ADC alone or in combination with IO 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 2937.