tbuckley/cabot-search huggingface dataset:
Abstract 6768: Targeting the Her2 and ERα receptors has a significant impact on therapy-resistant ER-positive breast cancer
Authors: DeZha Robinson, Hogyoung Kim, Alexandra Caroline Dunn, Clark Jules Perkins, Sihyoung Kim, Sichan kim, Emily Lauren Schenk-Smith, Simak Ali, Matthew Burow, Emma Elkins, Christopher Williams
Journal: Cancer Research (2025)

Background: Resistance to endocrine therapy remains a significant clinical hurdle to the management of breast cancer. Mutations in the ESR1 gene (most frequently Y537S) are associated with metastatic disease recurrence in patients previously treated with endocrine therapy. We have shown that silmitasertib, a clinical phase CK2 inhibitor, can inhibit the proliferation of tamoxifen-sensitive and tamoxifen-resistant breast cancer cells in part by disrupting ERα/ERα variant expression. As such, we investigated the antiproliferative and antimigratory efficacy of silmitasertib in CRISPR-edited MCF-7 cells expressing ERαY5237S. Our findings suggest that pharmacological targeting of CK2 may represent an effective strategy in treating ERα-mutated, endocrine therapy-resistant BCa. Methods: Using parental MCF-7 and MCF-7 ERαY537S cells, we assessed cell proliferation in the monolayer cultures, as well as 3D spheroid growth and wound healing activity using live cell imaging in the presence of silmitasertib. We measured the impact of CK2 inhibition on established mitogenic pathways by RT-PCR and/or immunoblot analysis (Her2, Cyclin D1, S6/pS6, S27, ERK/pERK). Subsequently, we assessed the efficacy of combined exposure to the HER2/EGFR inhibitor lapatinib with or without silmitasertib in both MCF-7 and MCF-7 Y537S cells. Results: Our studies show that MCF-7 Y537S cells exhibit enhanced sensitivity to both antiproliferative and anti-migratory effects of silmitasertib compared to parental MCF-7 cells. HER2 was also overexpressed in MCF-7 Y537S, and the combination of lapatinib and silmitasertib, revealed an additive effect on cell proliferation. Conclusion: Our studies suggest that the development of ERαY537S mutations in BCa results in enhanced sensitivity to growth inhibition elicited by CK2 blockade. Our studies provide a convincing rationale for the therapeutic targeting of CK2 in the context of ERα-mutated, endocrine-resistant breast cancer. Citation Format: DeZha Robinson, Hogyoung Kim, Alexandra Caroline Dunn, Clark Jules Perkins, Sihyoung Kim, Sichan kim, Emily Lauren Schenk-Smith, Simak Ali, Matthew Burow, Emma Elkins, Christopher Williams. Targeting the Her2 and ERα receptors has a significant impact on therapy-resistant ER-positive 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 6768.
Abstract 3968: Developing T cell and organoid co-cultures derived from breast cancer patients of African descent for drug screening
Authors: Batoul Farran, Moses Kamita, Sylvester Antwi, Valerie Ofori Abohah, Harriet Larrious-Lartey, Jessica Bensenhaver, Haythem Ali, Eleonor Walker, Foster Amponsah, Josephine Nsaful, Rose Dampson, Patrick Kafui Akakpo, Evelyn Jiagge
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer. It is highly prevalent in women of West Sub-Saharan African ancestry (WSSA) and African American (AA) women, resulting in poorer survival outcomes compared to European American (EA) women. Studies have shown that immune cells in the tumor microenvironment (TME) contribute to the progression of TNBC by immune suppression, the reprogramming of macrophages into pro-tumorigenic subtypes and the release of inflammatory cytokines. A previous study by our laboratory revealed that the immune processes and markers associated with TNBC are different in TNBC patients of African ancestry compared to EA patients. We have established platforms consisting of T cells co-cultured with organoids derived from patients of diverse ancestries to investigate the interactions between immune cells and TNBC cells. Organoids from Ghanaian (GH), EA and AA patients were successfully established from PDXs and primary tumors. T cells were isolated from patient PBMCs (matched tumor and T-cell), activated and tested in co-cultures with organoids, derived from TNBC tumors. Flow cytometry was performed to assess the efficacy of T cell killing. The activated T cells successfully eradicated TNBC cells at conditions that replicate in vivo T cell infiltration in TNBC, as evidenced by decreased percentages of EpCAM+ cells. Concomitantly, we observed a reduction in the percentages of CD3+ CD137+ activated T cells, suggesting that the tumor cells in the co-culture also impacted T cells. Based on our initial results, we are evaluating the effects of co-culture on distinct populations of cytotoxic T cells as well as on markers of activation and exhaustion to determine potential differences between TNBC patients of diverse ethnicities. Characterizing the differences in tumor-immune cell interactions within the TNBC tumor microenvironment between EA and AA TNBC patients will hopefully inform the development of novel therapeutic strategies for women of African descent. Citation Format: Batoul Farran, Moses Kamita, Sylvester Antwi, Valerie Ofori Abohah, Harriet Larrious-Lartey, Jessica Bensenhaver, Haythem Ali, Eleonor Walker, Foster Amponsah, Josephine Nsaful, Rose Dampson, Patrick Kafui Akakpo, Evelyn Jiagge. Developing T cell and organoid co-cultures derived from breast cancer patients of African descent for drug screening [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 3968.
Abstract 6744: Why the analytical development of agonistic antibodies is challenging? A comprehensive strategy to unlock their characterization for immunotherapy and autoimmunity
Authors: Gaurav Agrawal, Venkatesh Chari, Luhan Yang, Jennifer Lin-Jones, Alpana Prasad, Jane Lamerdin
Journal: Cancer Research (2025)

Abstract Checkpoint blockade antibodies, or checkpoint inhibitors, are established as effective cancer therapeutics. A contrasting class of therapeutics, agonistic checkpoint antibodies, has recently emerged for attenuating inflammation in autoimmune diseases. Despite showing clinical promise, their development remains challenging due to limitations in conventional checkpoint assay designs that often fail to replicate physiologically relevant conditions in vitro and are sometimes confined to assessing only inhibitory responses. Here, we introduce a novel checkpoint assay design in a co-culture format involving Fcγ receptor-expressing cells, directly measuring the stimulatory activity of agonistic antibodies. Through testing various classes of Fcγ receptors and diverse cell backgrounds, we have established a specific and robust assay design for several key checkpoint receptors such as CD40, CD137, PD-1, and BTLA. Notably, we have identified previously unrecognized agonistic activity in a clinically approved blockade antibody, underscoring the importance of exploring similar activity in other therapeutics of this nature. The assay is optimized as a thaw-and-use format, exhibiting high reproducibility with ease of execution, and qualified for potency and stability studies as needed for commercial release testing in a quality-controlled environment. Citation Format: Gaurav Agrawal, Venkatesh Chari, Luhan Yang, Jennifer Lin-Jones, Alpana Prasad, Jane Lamerdin. Why the analytical development of agonistic antibodies is challenging? A comprehensive strategy to unlock their characterization for immunotherapy and autoimmunity [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 6744.
Abstract 6765: Antitumor activity of Selenopsammaplin A analog by targeting histone methyltransferase DOT1L in prostate cancer cells
Authors: Jaeho Han, Sehun Yang, Woong Sub Byun, Sung Chul Jang, Eun Seo Bae, Chae Won Ock, Hyen Joo Park, Hyeung-geun Park, Sang Kook Lee
Journal: Cancer Research (2025)

Abstract The overexpression of the disruptor of telomeric silencing 1-like (DOT1L), which is a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), has been related to poor outcomes in patients with Castrate-resistant prostate cancer (CRPC). Therefore, targeting DOT1L is considered a potential therapeutic approach to overcome the significant medical challenges of CRPC. In our previous study, we designed selenopsammaplin A (SPA) analogs as non-nucleoside DOT1L inhibitors to suppress human breast cancer cell proliferation and metastasis. However, the antitumor activity and the precise underlying mechanism of SPA analogs in prostate cancer cells remain unclear. Herein, we administered SPA-10091-HCl, a DOT1L-targeting degrader, to effectively hinder the growth and DOT1L-mediated H3K79 methylation in CRPC (PC3 and DU145) cells. Mechanistically, SPA-10091-HCl selectively degrades DOT1L protein through the nuclear ubiquitin-proteasome pathway, thereby suppressing H3K79 methylation in CRPC cells. SPA-10091-HCl inhibits CRPC cell proliferation, migration, and invasion, with the E-cadherin expression upregulation and N-cadherin and vimentin expression downregulation. Additionally, prolonged SPA-10091-HCl treatment induced apoptosis by regulating apoptosis-associated protein expressions. Moreover, SPA-10091-HCl effectively inhibited tumor growth in the PC3 cells-implanted xenograft mouse model without any overt toxicity. These results indicate SPA-10091-HCl as a potential candidate for further development as a chemotherapeutic agent against CRPC. Citation Format: Jaeho Han, Sehun Yang, Woong Sub Byun, Sung Chul Jang, Eun Seo Bae, Chae Won Ock, Hyen Joo Park, Hyeung-geun Park, Sang Kook Lee. Antitumor activity of Selenopsammaplin A analog by targeting histone methyltransferase DOT1L in prostate 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 6765.
Abstract 6763: A cellular platform for systematic comparison of RAS inhibitors using PRISM multiplexed screening
Authors: Matthew G. Rees, Mustafa Kocak, Matthew J. Emmett, Colleen T. Harrington, Anthony Fazio, Alvin Kalathungal, Ursula Widocki, Claudine Mapa, Dennie T. Frederick, Jillian N. Eskra, Laura Doherty, Blanche C. Ip, Melissa M. Ronan, William R. Sellers, Jennifer A. Roth
Journal: Cancer Research (2025)

Abstract The discovery and development of direct inhibitors of KRAS is transforming therapeutic options across diverse cancer types. Here, we use the PRISM collection of nearly 900 cancer cell lines, including more than 150 KRAS-mutant cell lines, to characterize 19 KRAS-targeting inhibitors or degraders, including G12C-, G12D-, and pan-KRAS inhibitors. Agents were tested at 8 doses (threefold dilution) for 5 days across a median of 883 cell lines. For each agent, we assessed its selectivity and correlation with KRAS mutation status and genetic dependency. For each cell line, we categorized its sensitivity to each individual agent and in aggregate by comparing across RAS modulators. For example, all 10 KRAS G12C inhibitors or degraders tested showed significant selectivity for cell lines harboring the G12C mutation, with RMC-6291, adagrasib, divarasib, and sotorasib showing the greatest enrichment. Among G12C-mutant cell lines, all 10 G12C-targeting agents were preferentially active against NCIH358 cells (rank 1-3, median 1.5) while OV56 cells showed much more variability in response (rank 5-623, median 92). Similar trends were observed for pan-KRAS inhibitors (NCIH358: median rank 7; OV56: median rank 655). Further, we characterized a panel of downstream (MEK, ERK) or upstream (SHP2, SOS1, RTK) RAS/MAP kinase pathway modulators in the PRISM assay to understand similarities and differences between direct and indirect RAS pathway suppression. Finally, we also explored orthogonal assay formats, including ultra-low adherent and extended-duration (10-day) screening, to investigate kinetic and environmental factors associated with inhibitor response. Collectively, our work provides a comprehensive profile of the cellular effects of current RAS-targeting therapeutics, and provides a foundation for the characterization of newly-emerging agents. Citation Format: Matthew G. Rees, Mustafa Kocak, Matthew J. Emmett, Colleen T. Harrington, Anthony Fazio, Alvin Kalathungal, Ursula Widocki, Claudine Mapa, Dennie T. Frederick, Jillian N. Eskra, Laura Doherty, Blanche C. Ip, Melissa M. Ronan, William R. Sellers, Jennifer A. Roth. A cellular platform for systematic comparison of RAS inhibitors using PRISM multiplexed screening [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 6763.
Abstract 6738: Towards developing a novel therapy for pain: A monoclonal antibody that specifically inhibits voltage-gated sodium channels Nav1.7
Authors: Debin Li, Na Lu, Rui Song, Meimei Liu, Gavin Zhang, Huihui Xu, Yuting Xue, Liyan Su, Huaxing Zhu
Journal: Cancer Research (2025)

Abstract Background: Pain is caused by the transmission of action potentials through nerve fibers to the dorsal root ganglia, ultimately reaching the higher nervous system. Voltage-gated sodium channels (VGSCs) member Nav1.7, encoded by SCN9A and primarily localized to the dorsal root ganglion neurons, has been explored as a prominent target for pain management. The Nav1.7 protein is structurally complex. Composed of about 2000 amino acids, this protein possesses four homologous domains, each containing six transmembrane alpha helices. In addition, the Nav family has nine members that share high sequence homology. This structural complexity makes it particularly challenging to develop antibodies that bind to epitopes that cause inhibitory effects on the target. And it’s high sequence homologymakes it particularly challenging to develop antibodies with high specificity. Leveraging on our NovoiSMART® technology, we successfully developed NP067, a highly specific and functional monoclonal antibody against Nav1.7. Methods: It was previously shown that IL-1β upregulates the expression of ADAMTS1, and this upregulation is disrupted by the inhibition of Nav1.7. Therefore we measured the expression of ADAMTS1 under IL-1β induced upregulation, with or without our new antibody NP067. We also compared several known Nav1.7 antagonists and NP067 for their effects to influence the expression of ADAMTS1. The specificity of NP067 against Nav1.7 was confirmed by flow cytometry experiments on two cell lines. MCF-7 cells were used for negative confirmation as this cell line expresses SCN5A/SCN7A/SCN8A antigens but not SCN9A. And A549 cells were used for positive confirmation and this cell line expresses SCN5A/SCN7A/SCN8A as well as SCN9A. Results: NP067 inhibited IL-1β-induced ADAMTS1 gene expression, and the effects were stronger than other reference molecules. Flow cytometry data showed that NP067 was highly specific to Nav1.7, and the affinity were higher than other reference molecules. Conclusions: NP067 is a functional and specific Nav1.7 antibody that have great potential in pain treatment. NP067 also shows great potential both as a monotherapy or coupling with other drugs. Citation Format: Debin Li, Na Lu, Rui Song, Meimei Liu, Gavin Zhang, Huihui Xu, Yuting Xue, Liyan Su, Huaxing Zhu. Towards developing a novel therapy for pain: A monoclonal antibody that specifically inhibits voltage-gated sodium channels Nav1.7 [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 6738.
Abstract 7160: The distribution of tertiary lymphoid structures serves as a hallmark of hot tumors and is associated with long-term survival and the efficacy of immune checkpoint inhibitors in patients with small cell lung cancer: A retrospective and prospective analysis
Authors: Chaoqi Zhang, Peng Wu, Le Wang, Dexin Shang, Junhan Zhou, Jingjing Liu, Chunqi Lin, Nan Sun, Jie He
Journal: Cancer Research (2025)

Abstract Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs capable of predicting the outcome and therapeutic response in various tumors. Nevertheless, the distribution and clinical significance of TLSs in small cell lung cancer (SCLC) have never been explored. Here, we enrolled over 1500 cases from 6 centers in this retrospective and prospective analysis to elucidate the immune landscape and predictive value of TLSs in SCLC. By employing immunohistochemistry (CD3, CD20, CD21, and CD23) and RNA-seq analysis, we discovered that a high abundance of TLSs was associated with a lower recurrence rate and long-term survival in patients with resected SCLCs. Univariate and multivariate analyses indicated that the status of TLSs was significantly correlated with a lower risk of relapse and cancer-specific death (P&amp;lt;0.01), independent of clinicopathological and molecular classifications (ASCL1, NEUROD1, POU2F3, and YAP1). Through the analysis of single-cell RNA sequencing data from 6 patients and whole slide digital pathology analysis of immunohistochemistry (CD45RO, CD4, CD8, CD14, CD68, CD163, CD57, CD66b, Foxp3, and PD-L1) from more than 600 patients, we found that tumors with a high abundance of TLSs were characterized by a high proportion of effector T cells and a high infiltration of anti-tumor immune cells. More importantly, we demonstrated that the status of TLSs was associated with an improved objective response rate, progression-free survival, and overall survival independently of CD8+ T-cell density in SCLCs with immune checkpoint inhibitors from 2 independent retrospective cohorts and a prospective cohort. In summary, our findings highlight that TLSs is a hallmark of hot tumors in SCLC and represents a promising biomarker for long-term survival and immunotherapy. Citation Format: Chaoqi Zhang, Peng Wu, Le Wang, Dexin Shang, Junhan Zhou, Jingjing Liu, Chunqi Lin, Nan Sun, Jie He. The distribution of tertiary lymphoid structures serves as a hallmark of hot tumors and is associated with long-term survival and the efficacy of immune checkpoint inhibitors in patients with small cell lung cancer: A retrospective and prospective analysis [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 7160.
Abstract 6491: Advancing precision oncology: Integrating AVI-PDX and patient-derived organoid technologies for enhanced preclinical modeling in immuno-oncology
Authors: Clélia Costechareyre, Romain Teinturier, Jürgen Loskutov, Mayrone Mongellaz, Madeleine Nadolny, Marjorie Lacourrège, Loraine Jarrosson, Céline Delloye-Bourgeois, Lena Wedeken, Valérie Castellani
Journal: Cancer Research (2025)

Abstract The AVI-PDX platform enables the creation of miniature, patient-specific tumor models within living organisms, specifically avian embryos. We have developed next-generation, humanized models that incorporate immune cells, expanding the utility of AVI-PDX for investigating immune cell-based therapies and checkpoint inhibitors, both as monotherapies and in combination with standard treatments. Recently, patient-derived organoids have become valuable models for oncology research, offering diverse molecularly characterized resources. However, traditional organoids often lack key components of the stroma and immune microenvironment, limiting their application for studying immune-modulating therapies. To overcome these challenges, we combined AVI-PDX with patient-derived organoid technologies to create an avian patient-derived organoid model, termed AVI-PDO. Here, we describe the generation of a colorectal cancer (CRC) AVI-PDO model.Colorectal tumor organoids from a patient sample were cultured, dissociated, and micro-implanted into avian embryos at established sites within the AVI-PDX model. We conducted a time-course analysis, harvesting embryos 3 to 6 days post-implantation and visualizing them using light-sheet microscopy. Notably, we observed that initially dispersed tumor cells aggregated and reformed 3D organoid-like structures within the embryo. To further characterize these structures, we performed immunolabeling on tissue cryosections, revealing tumor cells organized into spherical formations with central lumens, expressing polarity markers. Additionally, a significant number of Ki67-positive cells were present, indicating active proliferation within these structures. This study demonstrates that our combined AVI-PDX and organoid approach allows the re-creation of organoid-like structures within avian embryo tissues, providing a novel humanized model. This model paves the way for studying immune-based therapies within a whole organism context, offering a comprehensive system that includes systemic signaling and the tissue microenvironment. Citation Format: Clélia Costechareyre, Romain Teinturier, Jürgen Loskutov, Mayrone Mongellaz, Madeleine Nadolny, Marjorie Lacourrège, Loraine Jarrosson, Céline Delloye-Bourgeois, Lena Wedeken, Valérie Castellani. Advancing precision oncology: Integrating AVI-PDX and patient-derived organoid technologies for enhanced preclinical modeling in immuno-oncology [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 6491.
Abstract 6754: A payload screening and ADC evaluation platform for STING agonist antibody drug conjugates
Authors: Ying Meng, Li Li, Min Kang, Xiao Li, Haiting Dai, Tj (Tiejun) Bing
Journal: Cancer Research (2025)

Abstract Antibody drug conjugates (ADCs) are a class of rapidly developing targeted biotherapeutic drugs, which consist of three elements: antibody, linker, and payload. ADCs combine the high specificity of antibodies with the potency of payloads, delivering the highly efficient small molecule within the target tumor cells. As one of the new payload types, stimulator of interferon genes (STING) agonist can initiate the innate immune response, enhancing the attack on tumor cells. STING agonist ADCs, allowing tumor-localized activation of STING, may achieve greater anti-tumor activity and better tolerability. By combining the STING binding assay, different THP-1 reporter assay, we can support for STING agonist activities screening. RT-qPCR assay and WB assay can be applied for demonstrating the molecular mechanisms of candidates. For specific screening and evaluation of HER2 STING agonist ADCs, HER2 overexpression reporter assay, co-culture assays of tumor cell lines or STING knockout tumor cell lines with THP-1, hPBMC, as well as whole blood can be utilized at different project stages. Citation Format: Ying Meng, Li Li, Min Kang, Xiao Li, Haiting Dai, Tj (Tiejun) Bing. A payload screening and ADC evaluation platform for STING agonist antibody drug conjugates [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 6754.