tbuckley/cabot-search huggingface dataset:
Abstract 1342: Double knockdown of RAD51 and RAD54 overcame the radioresistance in bladder cancer
Authors: Hiroki Ide, Tetsushi Murakami, Eiji Kashiwagi, Sotaro Kitaoka, Takemi Shishido, Mayuko Yamaguchi, Masahiro Katsui, Shinsuke Funakoshi, Hiroshi Miyamoto, Mototsugu Oya
Journal: Cancer Research (2025)

Abstract Introduction and Objective: Radical cystectomy remains a main treatment for muscle-invasive bladder cancer (MIBC) because outcomes of radiotherapy (RT) have still been insufficient compared to surgery. Recent evidence indicated the involvement of DNA repair pathways with radio-resistance in MIBC. Previous study showed that RAD51 and RAD54 which promoted DNA repair cooperatively, were significantly associated with radio-sensitivity. More recently, our study demonstrated the significant association between estrogen receptor β signaling which was involved in radio-sensitivity in bladder cancer (BC), and their expression in it. However, there has been no study evaluating the relationship between RAD51/54 and radio-sensitivity in it. Therefore, we evaluated this association in BC cells. Methods: We compared the inhibitory effect of RT on BC cell viability between control and RAD51 and/or RAD54 knockdown BC cells (5637 and T24) cells. Moreover, we evaluated it on tumor growth in a mouse xenograft model between irradiated control and their knockdown cells. We also compared DNA double-strand breaks (DSB) via γ-H2AX foci formation, and DNA repair gene expressions in these cells after RT. Results: We then established radio-resistant cells and confirmed considerable elevation of the expressions of RAD51 and RAD54. In vitro experiments showed that RT reduced the viability in RAD51 or RAD54 knockdown cells more significantly than control cells. Moreover, double knockdown cells significantly reduced the cell viability more than each knockdown cell after irradiation in vitro and in vivo. Double knockdown of RAD51 and RAD54 resulted in a delay in DSB repair after RT. Conclusions: These results suggest that inhibition of both RAD51 and RAD54 has a potential of enhancing the cytotoxic effects of radiation in BC cells. Citation Format: Hiroki Ide, Tetsushi Murakami, Eiji Kashiwagi, Sotaro Kitaoka, Takemi Shishido, Mayuko Yamaguchi, Masahiro Katsui, Shinsuke Funakoshi, Hiroshi Miyamoto, Mototsugu Oya. Double knockdown of RAD51 and RAD54 overcame the radioresistance in bladder 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 1342.
Abstract 3070: Cytomegalovirus infection enhances spheroid formation and drives aggressive phenotype in glioblastoma via upregulation of SOX2 pRB pAKT and STAT3/IL-6 signaling
Authors: Vida Tajiknia, Noe Mercado, Jacquelin Real, Eain Murphy, Sean Lawler
Journal: Cancer Research (2025)

Abstract Background: Cytomegalovirus (CMV) infection has been implicated in glioblastoma (GBM) progression, with effects on stemness, immune evasion, and angiogenesis. Our work investigates the impact of CMV infection on spheroid formation, oncogenic pathways including SOX2, retinoblastoma protein (pRB), phospho-AKT (pAKT), and STAT3/IL-6 signaling, as well as cytokine modulation. Additionally, we evaluate the therapeutic potential of ganciclovir in reversing CMV-induced effects. Methods: GBM cell lines LN229, U251, U87, U138, and T98G were infected with the GFP-expressing CMV TB40 strain at a multiplicity of infection (MOI) of 0.5. Infection was confirmed via fluorescence microscopy and Western blotting for CMV pp65 protein. The stable cell line with infection was confirmed after multiple passage and presence of CMV protein. Spheroid formation assays assessed morphological changes and aggressiveness in vitro. Western blotting analyzed the expression of SOX2, pRB, pAKT, and phospho-STAT3 (pSTAT3), while cytokine profiles, including PD-L1, VEGF, angiopoietin-2, and IL-6, were measured in non-infected, infected, and ganciclovir-treated cells using Luminex panel. Results: CMV infection was confirmed in all GBM cell lines, with infection rates ranging from 60% to 90%. CMV-infected cells exhibited accelerated and more aggressive spheroid formation compared to non-infected cells. Infection led to upregulation of SOX2, pRB, pAKT, and pSTAT3, accompanied by elevated IL-6, indicating enhanced stemness, proliferation, and pro-inflammatory signaling. Cytokine profiling revealed significant increases in PD-L1and angiopoietin-2 with decrease in soluble VEGF levels following infection and treatment with Gancylovir, reflecting immune suppression and angiogenesis. Ganciclovir treatment modulate pro-tumorigenic cytokines, creating a more favorable tumor microenvironment. Conclusions: CMV infection accelerates spheroid formation and enhances the aggressive phenotype in GBM via upregulation of SOX2, pRB, pAKT, and STAT3/IL-6 signaling, alongside immune evasion and angiogenic cytokine shifts. Our data suggest the therapeutic potential of targeting CMV and its downstream pathways in GBM. These findings highlight the critical role of CMV in GBM pathogenesis and its promise as a therapeutic target. Citation Format: Vida Tajiknia, Noe Mercado, Jacquelin Real, Eain Murphy, Sean Lawler. Cytomegalovirus infection enhances spheroid formation and drives aggressive phenotype in glioblastoma via upregulation of SOX2 pRB pAKT and STAT3/IL-6 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 3070.
Abstract 986: <i>SMARCB1</i> missense mutants destabilize SWI/SNF complex stability and remodeling activity
Authors: Garrett W. Cooper, Benjamin Lee, Won Kim, Eliseo Salas, Yongdong Su, Victor Chen, Xiaoping Yang, Robert Lintner, Frederica Piccioni, Andrew Giacomelli, Thomas Howard, Karen Conneely, David Root, William Hahn, David Gorkin, Bo Liang, Jaclyn Biegel, Susan Chi, Andrew Hong
Journal: Cancer Research (2025)

SMARCB1-deficient cancers are aggressive and highly lethal pediatric malignancies. Loss of SMARCB1 protein expression, a subunit within the SWI/SNF chromatin remodeling complex, remains the key diagnostic feature of these cancers. This can occur through large deletions, balanced translocations, frameshift mutations, or truncating nonsense mutations. Here, we sought to understand the effect of missense mutations on the tumor suppressor function of SMARCB1 through deep mutational scanning (DMS). Specifically, we developed and introduced a library containing &amp;gt;99% of all possible SMARCB1 amino acid substitutions, including frameshift and nonsense mutants, into three pediatric SMARCB1-deficient cell lines (G401 - malignant rhabdoid tumor of the kidney, BT16 - atypical teratoid/rhabdoid tumor, and CCLF_PEDS9001_T1 - renal medullary carcinoma) and assessed cell fitness after 8-14 days. We observed broad mutational intolerance in three SMARCB1 domains: the winged-helix domain, intrinsically disordered region, and the RPT2 domain. Following our high-throughput study, we then focused on two highly enriched residues predicted to closely interact within the RPT2 domain of SMARCB1. We validated that specific missense mutations in these two residues mimic loss of function while retaining protein expression. Mechanistic studies revealed that these mutations destabilize the SWI/SNF complex, notably resulting in decreased affinity for SWI/SNF subunits known to be associated with cancer pathogenesis. This complex instability leads to diminished nucleosome remodeling and subsequent transcriptional deregulation. These findings challenge our current understanding of what a loss-of-function mutation means in the context of SMARCB1, suggesting that the absence of SMARCB1 protein expression may not be the sole indicator of SMARCB1 deficiency. Furthermore, this dataset provides a valuable resource for researchers to investigate key residues of SMARCB1 that may drive critical intermolecular interactions necessary for proper SWI/SNF complex assembly and function. Citation Format: Garrett W. Cooper, Benjamin Lee, Won Kim, Eliseo Salas, Yongdong Su, Victor Chen, Xiaoping Yang, Robert Lintner, Frederica Piccioni, Andrew Giacomelli, Thomas Howard, Karen Conneely, David Root, William Hahn, David Gorkin, Bo Liang, Jaclyn Biegel, Susan Chi, Andrew Hong. SMARCB1 missense mutants destabilize SWI/SNF complex stability and remodeling activity [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 986.
Abstract 3454: Charting single-cell metabolism co-evolution during metastasis
Authors: Yingcheng Charles Wu
Journal: Cancer Research (2025)

Metastasis, the leading cause of cancer death, exhibits a highly heterogeneous and suppressive cancer microenvironment. Here, we sequenced 97 matched samples by using single-cell RNA sequencing and spatial transcriptomics of colorectal cancer liver metastasis. Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as MRC1+ CCL18+ M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced amino acid metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. In parallel, metastatic cancer cells displayed the metabolic switch from OXPHOS to glycolysis, which is dependent on the metabolic master regulator LY6E. Our work described the metabolism co-evolution of both immune and cancer cells during metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy. Citation Format: Yingcheng Charles Wu. Charting single-cell metabolism co-evolution during 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 3454.
Abstract 385: Discovery of OST08267, an orally available PDE3A-SLFN12 molecular glue for the treatment of gastrointestinal stromal tumors with tyrosine kinase inhibitors (TKIs) resistance
Authors: Fangrui Wu, Lisheng Deng, Zhixiong Ma, Zhenyao Lu, Gabriel Deng
Journal: Cancer Research (2025)

Abstract Gastrointestinal stromal tumor (GIST) is the critically mesenchymal malignancy inhabiting the GI tract, which crucially induced by receptor tyrosine kinase (KIT) gene mutation. Although the tyrosine kinase inhibitors (TKIs), such as imatinib has prolonged survival significantly, the intrinsic and acquired resistance still disturbed more than 20% patients. Therefore, significant unmet medical remains needed. phosphodiesterase 3A (PDE3A)- Schlafen family member 12 (SLFN12) molecular glue is a novel anti-tumor targeted drug, mainly by mediating the formation of a complex between PDE3A and SLFN12, ultimately leading to the tumor apoptosis. In this study, we present OST08267, an orally available PDE3A-SLFN12 molecular glue tailored from the FDA-approved PDE3A inhibitor. Our transcriptional profiling of over 2, 000 patient samples revealed high expression levels of PDE3A and SLFN12 in GIST tumors, suggesting that GIST is a promising indication for this treatment with a high responsive rate of up to 60%. In vitro, OST08267 demonstrated significant anti-tumor activity, irrespective of KIT mutation status by testing against multiple GIST patient-derived organoids. In vivo, OST08267 causes dose-dependent regression of tumor volume in the GIST patient-derived xenograft (PDX) model with imatinib resistance, with 4 mg/kg/day dose resulting in deeper and durable tumor regressions that were maintained for at least a month even after the dosing had discontinued.Moreover, OST08267 exhibited favorable pharmacokinetic and toxicity properties. These promising preclinical results strongly support the potential of OST08267 to address unmet needs in GIST treatment, justifying its further clinical development. Citation Format: Fangrui Wu, Lisheng Deng, Zhixiong Ma, Zhenyao Lu, Gabriel Deng. Discovery of OST08267, an orally available PDE3A-SLFN12 molecular glue for the treatment of gastrointestinal stromal tumors with tyrosine kinase inhibitors (TKIs) resistance [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 385.
Abstract 896: Unleashing the power within: enhancing cancer treatment with invariant natural killer T cells
Authors: Daniah Alkassab, Carolina de Amat Herbozo, Thierry Mallevaey
Journal: Cancer Research (2025)

Invariant natural killer T (iNKT) cells are a promising target for adoptive cell therapy (ACT) due to their unique ability to recognize glycolipid antigens presented by the non-polymorphic MHC class I-like CD1d molecule, enabling heterologous application without the risk of alloreactivity. Activated, iNKT cells exhibit potent antitumor activity through cytokine secretion, chemokine release, and cytolysis, making them ideal candidates for off-the-shelf cancer therapies. However, limited knowledge of iNKT cell biology, particularly their functional heterogeneity, has hindered their therapeutic optimization. This study aimed to (a) investigate the functional heterogeneity of iNKT cells, (b) expand iNKT cells from human peripheral blood mononuclear cells (PBMCs), and (c) optimize the generation of cytotoxic iNKT cells by evaluating their phenotypic and functional profiles in response to various cytokine stimulations. PBMCs from 14 healthy donors (7 males and 7 females) were analyzed using spectral flow cytometry to assess the expression of key iNKT cytotoxic markers, along with markers associated with natural killer cells and CD8+ T cells. Phenograph clustering revealed distinct iNKT subpopulations, including one characterized by high expression of cytotoxic markers such as CD57, granzyme B, and granulysin, and another enriched for CD62L, a marker linked to central memory-like phenotypes with the potential to differentiate into cytotoxic subsets with enhanced antitumor activity. To optimize iNKT cell expansion, PBMCs were co-cultured with artificial antigen-presenting cells loaded with the iNKT ligand α-galactosylceramide in the presence of IL-2. iNKT cells were sorted two weeks post-initial stimulation and restimulated every 2-3 weeks using anti-CD3, resulting in the generation of millions of cells. To further enhance cytotoxic potential, iNKT cells were treated with cytokines such as IL-7, IL-15, IL-12, and IL-21. Preliminary findings demonstrated that cytokine stimulation influences the phenotypic profiles of iNKT cells. These findings provide a robust foundation for generating large quantities of cytotoxic iNKT subsets optimized for in vitro and in vivo assays. This work not only enhances the understanding of iNKT cell biology but also represents a significant step toward leveraging iNKT cells as versatile and powerful tools in ACTs. Citation Format: Daniah Alkassab, Carolina de Amat Herbozo, Thierry Mallevaey. Unleashing the power within: enhancing cancer treatment with invariant natural killer T 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 896.
Abstract 892: Development of iPSC-derived feeder cells to enhance NK cell expansion and cytotoxicity for cancer therapy
Authors: Zhi-Qian Lin, Meng-Ting Hsu, Yang Lin, Li-Fung Chen, Bing-Hong Chen, Yi-Chen Sun, Kai-Feng Hung
Journal: Cancer Research (2025)

Natural killer (NK) cells have been considered a promising candidate for cell therapy in cancer treatment. However, since NK cells constitute a minor fraction of peripheral blood mononuclear cells (PBMCs), recent efforts have concentrated on enhancing the efficiency of in vitro expansion. Among various approaches, the genetically engineered K562 cell line has shown promising potential in NK cell expansion. Nonetheless, as K562 cells are a cell line derived from human leukemia cells, the use of K562 as feeder cells raises significant safety concerns. To address this issue, we developed a novel feeder cell system by engineering hematopoietic progenitor cells (HPCs), derived from induced pluripotent stem cells (iPSCs), to express co-stimulatory molecules and cytokines on their surface via viral transduction. We showed that iPSC-derived HPCs efficiently prolong the lifespan of primary NK cells beyond two weeks, surpassing the typical half-life of NK cells in regular culture conditions. To further enhance the stimulatory effect of membrane-bound interleukin on the surface of feeder cells, we engineered a bispecific antibody comprising a recombinant cytokine and a single-chain variable fragment (scFv) with binding specificity to feeder cells. Interestingly, we found that the combination of HPC feeder cells and recombinant cytokines significantly enhance NK cell expansion and cytotoxicity. We also found that iPSC-derived feeder cells efficiently sustain the cytotoxicity activity of iPSC-derived NK cells, showing that iPSC-derived cells can serve as a powerful platform for cancer therapy. In conclusion, our novel feeder cell system shows great potential to enhance NK cell proliferation and activation. While further optimization is required, this non-cancerous source of feeder cells offers an appealing alternative to K562 cells, facilitating the development of NK cell-based cancer therapy. Citation Format: Zhi-Qian Lin, Meng-Ting Hsu, Yang Lin, Li-Fung Chen, Bing-Hong Chen, Yi-Chen Sun, Kai-Feng Hung. Development of iPSC-derived feeder cells to enhance NK cell expansion and cytotoxicity for 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 892.
Abstract 3048: <i>In vitro</i> and <i>in vivo</i> anti-cancer properties of novel synthetic inhibitor targeting human NAD(P) dependent steroid dehydrogenase-like
Authors: Hoe Suk Kim, So-Hyun Yoon Yoon, Sangeun Lee, Seungyeon Ryu, Han-Byoel Lee, Bong-Jin Lee, Wonshik Han
Journal: Cancer Research (2025)

Background: NAD(P)-Dependent Steroid Dehydrogenase-Like (NSDHL), which is involved in cholesterol synthesis, has been found to play a role in breast cancer stemness, growth, and metastasis. NSDHL is emerging as a potential new therapeutic target for breast cancer. This aim is to evaluate molecular mechanisms underlying the anti-cancer properties of a novel NSDHL inhibitor in breast cancer models in vitro and in vivo. Methods: A structure-based inhibitor of NSDHL (Compound 9) was developed by Dr. Lee Bong-Jin. Compound 9 (1-250 μM) was treated in diverse human breast cancer cell lines ( MCF-7, ZR75-1, BT474, BT-20, MDA-MB-231) for 2-7 days and administered by oral gavage (2.5 mg/kg/day) for 30 days in an orthotropic breast tumor model of BALB/c Nude mouse. Anti-cancer activities and molecular mechanisms of Compound 9 were evaluated by cell cycle analysis using DNA staining with PI, apoptosis analysis using annexin V/PI-labeling, cell proliferation analysis using crystal violet assay, cell migration analysis using transwell migration assay, western blot, immunohistochemistry, and TEM image. Result: Rhodamine B-conjugated Compound-9 was easily internalized into breast cancer cells within an hour. Compound 9 exerted anti-proliferative and anti-migratory activity, G0/G1 phase arrest, and apoptotic and autophagic death along with the downregulation of XIAP and BCL2, the upregulation of P62 and LC3II, and modulation of the Akt/mTOR/MAPK signaling pathway. A combination of Compound 9 and paclitaxel enhanced the anticancer activity of paclitaxel in cultured breast cancer cells. Compound-9, when given orally to mice, inhibited the breast tumor growth without affecting their body weight. Conclusions: We suggest that Compound 9 can be employed as a potential therapeutic drug to target NSDHL in cancer as well as cholesterol-related diseases. Citation Format: Hoe Suk Kim, So-Hyun Yoon Yoon, Sangeun Lee, Seungyeon Ryu, Han-Byoel Lee, Bong-Jin Lee, Wonshik Han. In vitro and in vivo anti-cancer properties of novel synthetic inhibitor targeting human NAD(P) dependent steroid dehydrogenase-like [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 3048.
Abstract 905: SMARCA4 mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy
Authors: Yonathan Lissanu, Yawen Wang, Ismail Meraz, Md Qudratullah, Sasi Kotagiri, Yanyan Han, Jack Roth
Journal: Cancer Research (2025)

Abstract SMARCA4 is a frequently mutated subunit of the SWI/SNF chromatin remodeling complex. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, we show that SMARCA4 loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show that SMARCA4 loss in tumor cells led to profound downregulation of STING, IL1β and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as STING, IL1β, type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated with STING and IL1β, indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response of SMARCA4-mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation. Citation Format: Yonathan Lissanu, Yawen Wang, Ismail Meraz, Md Qudratullah, Sasi Kotagiri, Yanyan Han, Jack Roth. SMARCA4 mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to 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 905.