tbuckley/cabot-search huggingface dataset:
Abstract 2972: Trabectedin exerts its potent and selective antitumor effects by irreversibly covalently bonding to duplex stem loops in G-quadruplexes
Authors: Alena Safarova, Marta Martínez Diez, Raquel M. Altares, Pablo M. Aviles, Marcelo Lima Ribeiro, Carmen Cuevas, Laurence H. Hurley
Journal: Cancer Research (2025)

Abstract Trabectedin, a marine-derived anti-tumor agent from the ecteinascidin family, shows effectiveness when treating cancers such as Ewing Sarcoma, small cell lung cancer (SCLC) and ovarian cancer. It features a unique carbinolamine group that forms reversible bonds with the N2 position of guanine, distinguishing it from typical DNA alkylating agents. Structurally, trabectedin also includes a C-subunit that widens the DNA minor groove, inducing transcriptional replication stress and genome instability. Given the sensitivity of Ewing Sarcoma to trabectedin and the role of G-quadruplexes (G4s) in binding EWSR1—especially those with longer stem loops—this study aims to redefine trabectedin’s molecular target by exploring its potential interaction with G4 structures. Building on these insights, we designed experiments using trabectedin in combination with wild-type (WT) and mutant MYCN G4s to assess whether trabectedin could irreversibly bond covalently to a consensus sequence within a duplex stem loop associated with a G4. Circular dichroism (CD) analysis confirmed that trabectedin stabilized a G4 containing a consensus covalent bonding site within the associated hairpin loop. Mass spectrometry (MS) demonstrated that a guanine in the trabectedin consensus binding site is essential for this irreversible covalent binding. Additionally, CD and MS showed that when trabectedin was bound covalently to the hairpin stem loop, it displaced GSA0932, a molecule that binds non-covalently to both the core structure and stem loop. Finally, we observed that trabectedin treatment significantly increased G4 frequency within cells. On a final note, trabectedin irreversibly binds to the N2 of guanine within a duplex stem loop of a G4, fully accounting for its downstream effects on transcription-dependent replication stress and genomic instability. While this data specifically pertains to trabectedin, other members of the ecteinascidins, which possess structurally distinct C-subunits, appear to exhibit varied downstream effects, such as on transcription. These differences may arise from variations in sequence selectivity at the stem-loop level, leading to the targeting of distinct G-quadruplex structures. Citation Format: Alena Safarova, Marta Martínez Diez, Raquel M. Altares, Pablo M. Aviles, Marcelo Lima Ribeiro, Carmen Cuevas, Laurence H. Hurley. Trabectedin exerts its potent and selective antitumor effects by irreversibly covalently bonding to duplex stem loops in G-quadruplexes [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 2972.
Abstract 6647: Targeting DCLK1-mediated glutamine addiction in chemoresistant ovarian cancer
Authors: Samrita Dogra, Cole Hladik, Sugantha Priya Elayapillai, Bethany Hannafon
Journal: Cancer Research (2025)

Ovarian cancer (OC) presents significant therapeutic challenges due to its frequent late-stage diagnosis accompanied by distant metastases and the development of chemoresistance. As existing FDA-approved targeted therapies for OC do not adequately address peritoneal metastases, there is an urgent need for innovative treatment strategies that specifically target the molecular and cellular pathways underlying metastasis and disease recurrence. Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase with a demonstrated role in cancer cell stemness, epithelial-mesenchymal transition (EMT), disease progression in gastrointestinal and pancreatic cancers and resistance in ovarian and lung cancer. The study objective is to evaluate the functional role of DCLK1 in the peritoneal metastasis of OC and investigate the associated benefits of antagonizing it as a novel strategy to mitigate OC metastasis. Our prior studies demonstrate DCLK1 inhibition reduces the number of visible metastases in an orthotopic OC model in mice. In this study, we used pharmacological inhibition (DCLK1-IN-1), and genetic manipulation (DCLK1 CRISPR-knockout (KO) and over-expression systems) to assess the role of DCLK1 in promoting OC metastasis. We observed that elevated DCLK1 expression enhanced OC cell adhesion to different extracellular matrices including collagen, fibronectin, and laminin. Furthermore, DCLK1 inhibition effectively reduced mesothelial cell clearance relative to control. Targeted gene expression profiling and pathway analysis revealed DCLK1 inhibition in cisplatin resistant (CPR) OC spheroids upregulated genes involved in glutamine metabolism. Using metabolic flux assays, we demonstrated increased oxygen consumption in DCLK1 KO CPR cells that was abrogated by BPTES (glutamine oxidation inhibitor). Furthermore, we show that combined treatment of OC CPR spheroids with DCLK1 inhibitor (DCLK1-IN-1) and glutamine antagonist (DRP-104) showed a synergistic cytotoxic effect. In addition, the novel combination strategy was significantly effective in reducing OC cell adhesion and mesothelial cell clearance relative to single agent alone. Collectively, our findings establish DCLK1 as a key regulator of metastasis and demonstrate that its inhibition induces glutamine dependency in chemoresistant tumor cells. Thus, the combined use of DCLK1 inhibitors (e.g., DCLK1-IN-1) with glutamine metabolism inhibitors (e.g., DRP-104) represents a rational therapeutic approach to mitigate peritoneal metastases in a chemoresistant setting. Citation Format: Samrita Dogra, Cole Hladik, Sugantha Priya Elayapillai, Bethany Hannafon. Targeting DCLK1-mediated glutamine addiction in chemoresistant ovarian 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 6647.
Abstract 4108: SMARCA4-driven oncogenic enhancer and transcriptional reprogramming in non-small cell lung cancer
Authors: Hye-Ju Yang, Eun-Ju Kim, Sang-Hyeon Song, Tae-You Kim
Journal: Cancer Research (2025)

Abstract SMARCA4, an ATPase subunit of the SWI/SNF complex, is frequently mutated in cancers and plays a crucial role in chromatin remodeling and gene regulation. However, the mechanisms by which SMARCA4 drives oncogenesis in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, we show that SMARCA4 restoration in SMARCA4-deficient NSCLC cells significantly enhances cell proliferation and migration. ATAC-seq and ChIP-seq analyses revealed that SMARCA4 restoration induces extensive epigenetic reprogramming, including altered chromatin accessibility, histone modifications, and activation of enhancers near genes linked to proliferation and migration. These changes were accompanied by increased expression of these genes, suggesting that SMARCA4-mediated enhancer reprogramming promotes oncogenic pathways. Motif analysis identified FOSL1 as a key transcription factor that collaborates with SMARCA4 by physically interacting with SWI/SNF subunits to activate enhancers. Enhanced FOSL1 binding correlated with the upregulation of proliferation- and migration-associated genes. Notably, FOSL1 knockout reduced the expression of these genes and suppressed cell growth, highlighting its critical role in SMARCA4-driven tumorigenesis. Furthermore, targeting SMARCA4 with small molecules such as BRM014 and ACBI1 selectively impaired cell viability in SMARCA4-restored cells, underscoring their potential as therapeutic agents for SMARCA4-dependent cancers. These findings reveal a central role for SMARCA4 in epigenetic regulation and enhancer activation, driven by the SMARCA4/FOSL1 axis, and offer insights into potential therapeutic strategies for NSCLC. Citation Format: Hye-Ju Yang, Eun-Ju Kim, Sang-Hyeon Song, Tae-You Kim. SMARCA4-driven oncogenic enhancer and transcriptional reprogramming in non-small cell lung 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 4108.
Abstract 6646: Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion
Authors: Jennifer E. Tuokkola, Lyndsay E. Reese, Ying Wang, Christine H. O'Connor, Annisa H. Rumahorbo, Kathryn L. Schwertfeger
Journal: Cancer Research (2025)

Abstract Signaling by fibroblast growth factor receptors (FGFRs) is active in up to 85% of breast cancers and results in enhanced proliferation, migration, and invasion of tumor cells. Here, we show that FGFR signaling regulates cholesterol metabolism in breast cancer. Specifically, we demonstrate that FGFR activation promotes cellular cholesterol storage by upregulating expression of the enzyme sterol O-acyltransferase 1 (SOAT1). Moreover, we demonstrate that inhibition of SOAT1 attenuates FGFR-driven colony formation and invasion in tumor cells. Finally, we identify a relationship between SOAT1 inhibition and decreased expression of matrix metalloproteinases by tumor cells. Taken together, these findings suggest a previously undiscovered metabolic role for FGFR signaling in breast cancer and present a therapeutic vulnerability that could be targeted in FGFR-driven cancers. Citation Format: Jennifer E. Tuokkola, Lyndsay E. Reese, Ying Wang, Christine H. O'Connor, Annisa H. Rumahorbo, Kathryn L. Schwertfeger. Fibroblast growth factor receptor signaling modulates cholesterol storage in a SOAT1-dependent manner to promote mammary tumor cell invasion [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 6646.
Abstract 4856: Chronic anti-CD3/CD28 stimulation during cell expansion generates exhausted T cells with a distinct metabolic and cytotoxic phenotype
Authors: Guoxiao Wang, Xiaoyu Zhang, Natalia Romero
Journal: Cancer Research (2025)

Abstract T cell exhaustion is one of the major causes of cancer immune evasion and contributes to the failure of immunotherapies targeted to solid tumors. Reversing T cell exhaustion is a promising strategy in cancer immunotherapy, as it can improve patients’ responses to immune checkpoint inhibitors and adoptive T cell therapies. Recent publications showed that impairment of mitochondria function plays a critical role in developing and maintaining T cell exhaustion. This prompted us to explore the possibility of using metabolic profiling of T cells to assess relative T cell exhaustion as a tool to optimize T cell therapy product development. In our study, we induced exhaustion in previously expanded T cells via chronic stimulation with anti-CD3/CD28 Dynabeads and used briefly stimulated (24-hour) counterparts as controls. Across all three donors tested, chronically stimulated T cells exhibited reduced net proliferation, increased percentage of PD1+Tim3+ population, and decreased IL-2 secretion upon restimulation, while TNFα and IFNγ secretion varied by donor. We performed Xcelligence RTCA impedance-based, acute killing assays using Epcam-BiTEs to engage T cells to the Epcam expressing T47D cells. Surprisingly, we found that in some donors, cells exposed to chronic anti-CD3/CD28 Dynabeads, despite secrete significantly less cytokines upon antigen restimulation, display similar acute cytotoxicity compared to its non-exhausted counterparts. Importantly, when assessed using Seahorse XF assays, these exhausted T cells displayed a very distinctive metabolic phenotype, including decreased maximal respiration and spare respiratory capacity (SRC), increased glycolytic activity, and reduced capacity to further increase glycolytic activity upon acute reactivation. These findings suggest that metabolic profiling can represent a valuable tool for identifying metabolically fit T cells and is a great addition to the current matrix of parameters for assessing T cell exhaustion. Citation Format: Guoxiao Wang, Xiaoyu Zhang, Natalia Romero. Chronic anti-CD3/CD28 stimulation during cell expansion generates exhausted T cells with a distinct metabolic and cytotoxic phenotype [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 4856.
Abstract 6432: Melanoma-driven alterations in lipid and iron metabolism in the bone marrow niche
Authors: Alexis Erasta Carey, Murilo Ramos Rocha, Cheyenne Palm, Vania Wang, Denys Balandin, Ethan Black, Kevin Zhang, Fan Huang, Ashani Weeraratna
Journal: Cancer Research (2025)

Abstract Melanoma is the deadliest form of skin cancer and age is a negative independent prognostic factor of overall survival for melanoma patients. Aging causes systemic changes, such as increased bone marrow (BM) adiposity and iron accumulation, which could impact the aged antitumor response. We hypothesize that elevated BM fat and iron due to aging promote immune dysfunction, weakening systemic antitumor defenses. We utilized flow cytometry to analyze melanoma- and age-related alterations to the BM and tumor immune cell composition. Our preliminary data suggest that mice challenged with melanoma systemically undergo myelopoiesis, resulting in an increase in myeloid cells in the BM; however, tumors of aged mice had increased myeloid cell infiltration. Conversely, the lymphoid compartment contracts in the BM of tumor-bearing mice, with reduced T and B lymphocytes and NK cells. Importantly, age- and tumor-related changes are not limited to immune cell population changes. Our data show significantly increased intracellular lipid accumulation in BM myeloid cells of tumor-bearing mice compared to control animals. However, analysis of overall lipid content in the BM from these mice shows a significant reduction of lipids in the BM niche, suggesting that myeloid cells in this niche might uptake the lipids from their environment. Increased lipid uptake and peroxidation has been linked with ferroptosis, an iron-dependent form of cell death. Utilizing a Prussian Blue stain, we show that intracellular iron increased in the BM of aged mice compared to young mice, suggesting the BM cells might be sequestering iron. Ultimately, there is an increased production of myeloid cells, an increase in intracellular lipids in myeloid cells as well as an increase in iron levels in the BM niche with aging and in the future, we would like to further explore ferroptosis in the BM niche. As a future direction, we would like to explore ferroptosis in the BM niche. These insights into lipid and iron metabolism in myeloid cells in the bone marrow niche will lead to a better understanding of the systemic response to melanoma and can inform future treatments for elderly patients with melanoma. Citation Format: Alexis Erasta Carey, Murilo Ramos Rocha, Cheyenne Palm, Vania Wang, Denys Balandin, Ethan Black, Kevin Zhang, Fan Huang, Ashani Weeraratna. Melanoma-driven alterations in lipid and iron metabolism in the bone marrow niche [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 6432.
Abstract 6448: Determinants of chemotherapeutic resistance in fusion-positive rhabdomyosarcoma
Authors: Taryn E. Shaw, Foram Shah, Jeffrey Toretsky, Aykut Üren
Journal: Cancer Research (2025)

Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, and is classified as fusion-positive (FP) or fusion-negative (FN) based on the presence of the PAX3::FOXO1 or PAX7::FOXO1 fusions. These chimeric proteins are formed by reciprocal chromosomal translocations and consist of an N-terminal portion of the PAX3 or PAX7 transcription factor fused to a C-terminal portion of the FOXO1 transcription factor. FP status is associated with worse event free survival for patients with RMS. Regardless of fusion status, most RMS patients receive a chemotherapy regimen consisting of some combination of vincristine, actinomycin D, and cyclophosphamide (VAC). Unfortunately, tumors may acquire resistance to these drugs over time, leading to relapse. Our work aimed to uncover genes that drive VAC resistance in FP-RMS using a two-pronged approach. To assess how FP-RMS cells gradually acquire resistance, we cultured FP-RMS cell lines (RH30, RH41, CW9019, U48484, U66788) in sublethal concentrations of vincristine, actinomycin D, or 4-hydroperoxy cyclophosphamide (4-HC, the active metabolite of cyclophosphamide) for multiple passages. We periodically assessed the IC50 of cells growing in drugs and increased drug doses as cells developed resistance. We generated four cell lines with a ∼5- to ∼20-fold increase in IC50. Using RNAseq, we identified differentially expressed genes between the parental and resistant cell lines that may act as drivers of chemotherapeutic resistance. To assess de novo resistance in FP-RMS, we used CRISPR inactivation and activation library screening. We generated FP-RMS cell lines (RH30, RH41, CW9019) stably expressing Cas9 or dCas9-VPR, an endonuclease-dead version of Cas9 fused to three transcriptional activators. We then transduced these cells with a CRISPR inactivation sgRNA library (18, 885 gene targets) or a CRISPR activation sgRNA library (19, 113 gene targets). Transduced cells were cultured in vincristine, actinomycin D, or 4-HC, and surviving cells were expanded and sequenced to determine which genes provided drug resistance when activated or deleted. We hope that the findings of these experiments will contribute to novel therapeutic targets for patients with VAC-resistant RMS tumors. Citation Format: Taryn E. Shaw, Foram Shah, Jeffrey Toretsky, Aykut Üren. Determinants of chemotherapeutic resistance in fusion-positive rhabdomyosarcoma [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 6448.
Abstract 3439: Study on the mechanism of sesamin inhibiting the malignant metastasis of prostate cancer
Authors: Yen Chen Chen, An-Chen Chang, Chih-Hsin Tang, Thomas I-Sheng Hwang
Journal: Cancer Research (2025)

Abstract Purpose: Prostate cancer (PCa), a malignant tumor of the urinary tract, is one of the most common cancers in men. PCa tends to metastasize to bones and lymph nodes, resulting in increased mortality. Sasamin is a plant compound extracted from sesame seeds. Some studies suggest that sesame lignans may have the potential for antioxidative, anti-inflammatory, and anti-tumor effects. Here, we aim to investigate the inhibitory effects of sesamin on the invasiveness of PCa cells in vitro and tumor progression in vivo. Materials and Methods: Human PCa cell lines DU145 and PC-3 were obtained from the Bioresource Collection and Research Center (BCRC). Cell survival was detected by Colony formation assay. Wound healing assay, Anoikis assay and Transwell migration/invasion assay were performed to analyze cell aggressiveness. The subcutaneous tumor model was performed to study the inhibition of tumor growth by sesamin treatment. The levels of ADAM9, PD-L1 and Ki67 protein expression in tumor tissues were detected by immunohistochemistry (IHC) staining. Results: Firstly, PCa cells were treated with different concentrations of sesamin, revealing a dose-dependent inhibition of both cell survival rate and proliferative ability. The co-administration of sesamin with a chemotherapeutic drug (docetaxel &amp; cabazitaxel) enhances chemosensitivity in PCa cells. Next, we found that sesamin inhibits cell motility, invasion, and anoikis resistance via ADAM9 down-regulation through the JNK and c-Jun signaling pathway in PCa cells. Interestingly, sesamin can reduce ADAM9-mediated cleavage of membrane-bound PD-L1 (mPD-L1) into its soluble form, thereby inhibiting immune escape in PCa. Moreover, subcutaneous injection of PCa cells in mice, followed by twice-weekly intraperitoneal injection of sesamin, resulted in tumor growth inhibition. IHC staining of mice tumor tissues revealed a decrease in the levels of ADAM9 and Ki67 expression, and an increase in mPD-L1 expression in the sesamin-treated group compared to the non-treated group. Conclusion: These results suggest that sesamin exhibits inhibitory effects on cell proliferation, migration, invasion, anoikis resistance, and immune escape in vitro, as well as tumor growth in vivo. The strategy of co-administration of sesamin can benefit clinical chemotherapy treatment, highlighting the potential of sesamin as an adjunctive treatment in PCa. Citation Format: Yen Chen Chen, An-Chen Chang, Chih-Hsin Tang, Thomas I-Sheng Hwang. Study on the mechanism of sesamin inhibiting the malignant metastasis of 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 3439.