tbuckley/cabot-search huggingface dataset:
Abstract 5: Noncanonical NF-kB and notch signaling activity supports ovarian cancer stem-like cells following chemotherapy
Authors: Gregory J. Jordan, Cecilia Gallo, Mikella Robinson, Omar Lujano-Olazaba, Carrie D. House
Journal: Cancer Research (2025)

Abstract In the United States, ovarian cancer is the most lethal gynecological malignancy and the fifth most lethal cancer for those at risk. Although patients typically respond well to initial chemotherapy treatments, approximately 80% of patients will relapse with chemotherapy-resistant disease. Studies suggest a subpopulation of ovarian cancer cells, termed cancer stem-like cells (CSCs), can resist chemotherapy and repopulate tumors following treatment. The mechanisms enabling these cells to survive chemotherapy and re-establish heterogeneous tumors are unclear but likely involve activation of multiple survival and developmental pathways. Our previous work shows that the noncanonical NF-κB transcription factor, RelB, supports ovarian CSCs, and our preliminary data suggests RelB regulates the expression of Notch pathway genes. Notably, Notch is upregulated in patient-matched tumors following chemotherapy relative to pre-treatment samples. We hypothesize that RelB-mediated upregulation of Notch signaling is required to maintain CSCs and facilitate tumor regrowth after chemotherapy. To test this hypothesis, we first used qRT-PCR and western blot to assess the expression of different Notch receptors and ligands under spheroid-forming 3D culture conditions relative to monolayer 2D conditions. We observed increased expression of most Notch genes in 3D conditions. Interestingly, in sorted CD117+ CSCs, Notch receptor expression (Notch 1 and Notch 3) was maintained, while expression of Notch ligands (DLL1 and DLL3) was reduced, and Jag2 expression was elevated relative to CD117- bulk tumor cells. Additionally, we observed a consistent increase in the Notch target gene CDKN1A in 3D growth conditions relative to 2D. To confirm and further assess Notch activity, we are currently using Notch reporter cells under various conditions, including spheroid culture, treatment with carboplatin and paclitaxel, RelB knockdown, and RelB activation. Our preliminary in vitro data suggests that RelB upregulates Notch signaling in CSCs to enhance stemness and tumor-initiation following chemotherapy treatment. These findings will be validated in an in vivo relapse model to assess the requirement for Notch signaling during relapse. This work highlights a novel collaboration between RelB and Notch activity in CSCs, which may guide the design of more effective therapeutic strategies to reduce relapse and improve survival outcomes for ovarian cancer patients. Citation Format: Gregory J. Jordan, Cecilia Gallo, Mikella Robinson, Omar Lujano-Olazaba, Carrie D. House. Noncanonical NF-kB and notch signaling activity supports ovarian cancer stem-like cells following chemotherapy [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 5.
Abstract 502: Exploring STEAP1 expression in prostate cancer cells in response to androgen deprivation and in small extracellular vesicles
Authors: Candice L. Bizzaro, Camilla A. Bach, Ricardo A. Santos, Cecilia E. Verrillo, Nicole M. Naranjo, Ishan Chaudhari, Waleed Iqbal, Alessandro Fatatis, Ada G. Blidner, Gabriel A. Rabinovic, William Kevin Kelly, Lucia R. Languino
Journal: Cancer Research (2025)

Abstract The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1 and 2) metalloreductases are therapeutic targets for advanced PCa, and their expression has been linked to androgen receptor (AR) signaling; however, the regulatory mechanism and function of STEAP in PCa progression remains elusive. In this study, we explore how in vitro androgen modulation influences STEAP family expression in cell lines with varying reliance on androgen signaling. Our data show that in response to androgen deprivation, STEAP1 and STEAP2 exhibit elevated transcript levels, while STEAP4 mirrors the expression profile of KLK3 (Kallikrein Related Peptidase 3), showing reduced expression. Further, we found that an AR splice variant, AR-V7, which emerges in aggressive PCa, correlates with lower STEAP1 expression under androgen deprivation compared to full hormone conditions. Given their role in the exocytic pathway, we evaluated STEAP1 and STEAP2 expression profiles in hormone refractory PCa cells and their derived circulating small extracellular vesicles (sEVs). STEAP1, but not STEAP2, is upregulated in sEVs from AR-negative cells with low STEAP1 levels (DU145 and PC3) and AR-positive cells with higher STEAP1 levels (C4-2B). These results indicate selective packaging of STEAP1 in PCa cell sEVs, irrespective of AR status and cellular STEAP1 expression levels. We have previously shown that β1 integrins in the prostate tumor epithelium are necessary for sEVs to support anchorage-independent growth. Here, ex vivo analysis of circulating sEVs from genetically engineered mice carrying PCa show that STEAP1 is found in the sEV cargo, independent of β1 integrins. Our findings underscore the nuanced interplay between androgen signaling and STEAP1 expression and highlight the potential use of STEAP1 in sEVs as a biomarker in PCa to inform diagnostic and therapeutic strategies. Citation Format: Candice L. Bizzaro, Camilla A. Bach, Ricardo A. Santos, Cecilia E. Verrillo, Nicole M. Naranjo, Ishan Chaudhari, Waleed Iqbal, Alessandro Fatatis, Ada G. Blidner, Gabriel A. Rabinovic, William Kevin Kelly, Lucia R. Languino. Exploring STEAP1 expression in prostate cancer cells in response to androgen deprivation and in small extracellular vesicles [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 502.
Abstract 865: Engineering a next-generation dual-knockout TIL product with AaCas12b nuclease editing
Authors: Jingwei Sun, Yao Sheng, Hongwei Zhang, Xi Zhu, Jingman Wang, Ke Liu, Shin-Shay Tian, Pin Wang, Xiaoping Zhao, Yarong Liu
Journal: Cancer Research (2025)

Advancing cellular therapies, particularly allogeneic and functionally enhanced treatments using gene editing technologies, necessitates rigorous safety and quality assessments to ensure clinical success. Among CRISPR nucleases, Cas12b—a type V CRISPR enzyme—stands out for its high editing fidelity, owing to its stringent mismatch intolerance between single guide RNA (sgRNA) and target DNA, surpassing SpCas9 in precision. An engineered variant of Cas12b from Alicyclobacillus acidiphilus, termed AaCas12bMax, has demonstrated exceptional on-target editing efficiency with minimal off-target activity, making it a promising tool for complex therapeutic gene editing. This study employed AaCas12bMax to develop GT300, a next-generation tumor-infiltrating lymphocyte (TIL) product incorporating a dual-gene knockout. Candidate sgRNAs for the target genes were identified through in silico analysis to minimize genome-wide mismatches. Top-performing guides, validated in HEK293 cells and human PBMC T cells, were further evaluated in TIL products and compared with SpCas9-mediated editing. The AaCas12bMax system achieved comparable knockout efficiency and target protein reduction to SpCas9, with functional evaluations showing similar cytotoxicity, cytokine secretion in vitro, and antitumor efficacy in a mouse PDX model using autologous TILs. Notably, TIL products edited with AaCas12bMax exhibited 3-5 times greater expansion and enhanced viability during large-scale production compared to those edited with SpCas9. These cells demonstrated improved stemness, reduced exhaustion, and apoptosis, alongside superior expansion post-infusion in vivo, suggesting reduced genetic stress during editing. Comprehensive off-target and chromosomal translocation analyses using SITE-seq, GUIDE-seq, and PEM-seq, validated by Amp-seq and hybrid capture assays, confirmed a superior safety profile for AaCas12bMax-edited GT300 compared to SpCas9. RNA-seq analyses at 6 and 24 hours post-electroporation revealed diminished activation of apoptosis and exhaustion pathways in AaCas12bMax-edited TILs. In conclusion, GT300 edited with AaCas12bMax demonstrated efficient gene editing, a superior safety profile, and significant improvements in cell expansion, viability, and fitness. A first-in-human clinical trial of GT300 is currently underway in China. Citation Format: Jingwei Sun, Yao Sheng, Hongwei Zhang, Xi Zhu, Jingman Wang, Ke Liu, Shin-Shay Tian, Pin Wang, Xiaoping Zhao, Yarong Liu. Engineering a next-generation dual-knockout TIL product with AaCas12b nuclease editing [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 865.
Abstract 1465: RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability
Authors: Beth Osia, Arianna Merkell, Felicia Wednesday Lopezcolorado, Xiaoli Ping, Jeremy M. Stark
Journal: Cancer Research (2025)

Abstract Human RAD52 plays essential roles in several homology-driven DNA repair pathways, including single strand annealing, transcription-coupled homologous recombination, and mitotic DNA synthesis (MiDAS). Although RAD52 is not essential, RAD52 loss with disruption of either the breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) genes is synthetic lethal. Thus, RAD52 is an intriguing potential target for treatment of BRCA-deficient cancers. However, the full breadth of pathways and factors that create a state of RAD52-dependence when compromised are not understood. To query RAD52 synthetic lethal relationships, we performed genome-wide CRISPR knock-out screens and identified hundreds of candidate synthetic lethal interactions. We then performed secondary screening and identified genes for which depletion causes reduced viability and elevated genome instability (increased 53BP1 nuclear foci) in RAD52-deficient cells. One such factor was ERCC6L, which marks DNA bridges during anaphase, and hence is important for genome stability in mitosis. Additionally, pan-cancer studies of altered ERCC6L expression have identified increased ERCC6L expression as a marker of poor prognosis in multiple types of cancer, making it a relevant target for cancer therapy. Thus, we investigated the functional interrelationship between RAD52 and ERCC6L. We found that RAD52 deficiency increases ERCC6L-coated anaphase ultrafine bridges, and that ERCC6L depletion causes elevated RAD52 foci in prometaphase and interphase cells. These effects were enhanced with replication stress (i.e. hydroxyurea) and topoisomerase IIα inhibition (ICRF-193), where post-treatment effect timings were consistent with defects in addressing stress in mitosis. Altogether, we suggest that RAD52 and ERCC6L co-compensate to protect genome stability in mitosis. Citation Format: Beth Osia, Arianna Merkell, Felicia Wednesday Lopezcolorado, Xiaoli Ping, Jeremy M. Stark. RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability [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 1465.
Abstract 393: Discovery of novel, potent and orally active GSPT1 molecular glue degraders
Authors: Chi-Chung Chan, Chun-Sing Li, Lihong Hu, Wenxi Li, Zhenzhen Zhu, Shuhui Chen
Journal: Cancer Research (2025)

Abstract Molecular glue degrader (MGD) is an emerging therapeutic strategy offering an exciting alternative to traditional small molecules exploring new target space. These small molecules interact with the ubiquitin-proteasome system (UPS) to promote degradation of protein of interest (POI), especially those considered to be challenging targets (e.g., GSPT1, VAV1, WIZ, BCL6, STAT6, IKZFs). In fact, clinical proof of concept has been obtained with immunomodulatory drugs such as thalidomide, lenalidomide and pomalidomide, which degrade IKZF1/IKZF3. GSPT1 (G1 to S phase transition protein 1) is a challenging POI engaged in regulation of cell cycle progression at the G1-S transition and in mRNA translation termination, playing a key role in cancer progression. Recently, encouraging results have been obtained with different modalities targeting GSPT1. GSPT1 degrader antibody conjugates are now in clinical trials for breast cancer (ORM-5029) and AML (BMS-986497/ORM-6151). Of interest, an orally active GSPT1 degrader (MRT-2359) is in Phase 2 trial for MYC-driven tumors including NSCLC and SCLC, with 2 PR, 1 SD in six biomarker positive patients (September 2024). Safety profile at this stage supports further clinical development. Preclinically, MRT-2359 is a potent GSPT1 degrader with nanomolar in vitro IC50 and oral bioavailability of ∼50%. It shows anti-tumor activity in NSCLC xenograft model starting at 1 mg/kg PO, QD. These encouraging results have prompted us to explore a series of GSPT1 MGDs.In the present study, we describe the discovery of a series of novel, potent and orally active GSPT1 MGD targeting tumors with high GSPT1 expression. In the BT-747 human breast cancer cell assay, IC50s for serval compounds are between 5 - 50 nM, in the same range as that of MRT-2359 and other comparators in the same assay. Significant GSPT1 protein degradation of these compounds is observed showing on-target mechanism of action, without affecting protein degradation in a panel of proteins. A representative compound in the series shows a promising pharmacokinetic profile (PO at 3 mg/kg; IV at 1 mg/kg) with an oral bioavailability of 55 %, Cmax of 0.78 µM, t1/2 of 2.3 hour and Vdss of 1.82 L/kg in mouse. This compound demonstrates in vivo efficacy in CDX model with a favorable profile comparable to that of MRT-2359. In summary, a series of orally active GSPT1 degraders have been discovered with preclinical profile suitable for further development to manage cancers with high GSPT1 expression. Citation Format: Chi-Chung Chan, Chun-Sing Li, Lihong Hu, Wenxi Li, Zhenzhen Zhu, Shuhui Chen. Discovery of novel, potent and orally active GSPT1 molecular glue degraders [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 393.
Abstract 2115: SIM0680, a potent antibody-drug conjugate for the treatment of solid tumors expressing ENPP3
Authors: Abdullah Emran, Yutian Zhang, Yi Yang, Liting Xue, Lu Gong, Amin Al-Shami, Yayuan Fu, Renhong Tang
Journal: Cancer Research (2025)

Abstract Introduction: The ATP- and cGAMP-hydrolysing ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) is an extracellular enzyme which has been implicated in checkpoint regulation of innate immune responses. Analysis of data in The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) indicates elevated expression of ENPP3 in multiple solid tumors compared to normal tissues. Moreover, immunohistochemistry studies suggest that the expression of ENPP3 on healthy epithelial lining is polarized toward the lumen of internal organs but becomes disorganized and non-apical after malignant transformation. This spatial distribution of expression could make ENPP3 an ideal target for antibody therapies, which may have access to CD203c exclusively on tumor cells and not on healthy tissues. Results: We have developed an antibody-drug conjugate, SIM0680, which is a fully humanized antibody that binds a membrane-proximal epitope on ENPP3 with high affinity and is coupled to a payload through a proprietary linker. Immunohistochemistry confirmed strong expression of ENPP3 in liver, renal, and colorectal carcinomas. SIM0680 had potent and specific cytotoxic activity against cell lines originating from these tissues and displaying various levels of ENPP3 expression. Consistent with the observed in vitro efficacy, SIM0680 demonstrated strong single-dose and dose-dependent anti-tumor activity in vivo against multiple cell line- and patient-derived renal cell and hepatocellular carcinoma xenografts in mice, without causing significant weight loss. Similar potent anti-tumor efficacy was observed in human myeloid and megakaryoblastic leukemia models. Conclusion: Our findings underscore the potential of targeting the apically restricted tumor antigen ENPP3 with antibody therapy and support clinical development of SIM0680 as a novel therapeutic modality for treatment of ENPP3-positive solid tumors. Citation Format: Abdullah Emran, Yutian Zhang, Yi Yang, Liting Xue, Lu Gong, Amin Al-Shami, Yayuan Fu, Renhong Tang. SIM0680, a potent antibody-drug conjugate for the treatment of solid tumors expressing ENPP3 [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 2115.
Abstract 165: Spatially resolved mechanostress effects on tumor microenvironments: Tumor cells and fibroblasts in focus
Authors: Wooseok Kim, Hyunseok Kim, Minki Kim, Zhangxian Lan, Hyung-Soon Park, Mi Ryung Roh, Joon Kim, Jong-Eun Park
Journal: Cancer Research (2025)

Abstract Tumorigenesis is influenced by various environmental factors, including growth-induced solid stress and fluid pressure, both of which are key drivers of tumor progression and resistance to therapy. While certain tumors arise in regions exposed to significant weight-pressure, how macroscopic mechanostress affects the tumor microenvironment remains largely unclear. In this study, we showed that macroscopic mechanostress disrupts nuclear envelope integrity. Single-cell RNA sequencing data demonstrated that the macroscopic pressure shows changes in gene expression within tumor microenvironment cells and reshaped fibroblast subtypes.In spatial transcriptomics, using a distance-based tumor border detection model, we can determine spatially resolved fine layers of tumor margin and peritumor regions. We found an increased proportion of fibroblasts, especially Lrrc15-positive myofibroblasts, located in peritumor region facing the tumor border. We also showed upregulated metastasis signature and immune inhibitory signature indicating that mechanostress-driven transcriptional changes promote metastasis and resistance to immunotherapy. Using a mouse plantar melanoma model, we found that exogenous mechanostress, mimicked by genetic disruption of the nuclear lamina, induces nuclear envelope rupture in melanoma cells and increases the number of Lrrc15-positive myofibroblasts. Interestingly, these myofibroblasts further contribute to nuclear envelope rupture in melanoma cells, creating a feedback loop. Together, our findings highlight a critical role for mechanostress in cancer progression, driven by nuclear envelope damage and shifts in tumor-stromal interactions. Citation Format: Wooseok Kim, Hyunseok Kim, Minki Kim, Zhangxian Lan, Hyung-Soon Park, Mi Ryung Roh, Joon Kim, Jong-Eun Park. Spatially resolved mechanostress effects on tumor microenvironments: Tumor cells and fibroblasts in focus [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 165.
Abstract 494: Identifying vulnerabilities in basal-like pancreatic adenocarcinoma (PDAC)
Authors: Sandra Zarmer, Ian McCabe, Jen Jen Yeh
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, with a 5-year survival of only 12.5%. There are two transcriptomic PDAC tumor subtypes: classical and basal-like. Basal-like PDAC is associated with worse patient outcomes and does not respond to the standard-of-care chemotherapeutic regimen FOLFIRINOX; new therapeutic strategies effective in basal-like PDAC are needed. To identify essential targets in basal-like PDAC, we designed a CRISPR library targeting 394 highly expressed basal-like exemplar genes and performed the screen basal-like cell lines derived from PDAC patient-derived xenograft (PDX) tumors. We found 46% of the library genes were essential (181/394, p&amp;lt;0.05), with the top Reactome pathways represented by essential genes being polo-like kinase mediated events, cell cycle checkpoints, formation of the cornified envelope, and Type I hemidesmosome assembly. Of 8 top lethal genes, 7 were validated. One of these validated targets was integrin subunit alpha 3 (ITGA3). Integrins are cell surface receptors that interact with extracellular matrix proteins, the cytoskeleton, as well as downstream effectors important in cancer signaling. ITGA3 was required for colony formation in basal-like PDX-derived cell lines. In basal-like organoids, shRNA knockdown of ITGA3 reduced growth compared to classical organoids. We report promising targets for basal-like PDAC that may play a role in subtype-specific biology and therapeutic response. Citation Format: Sandra Zarmer, Ian McCabe, Jen Jen Yeh. Identifying vulnerabilities in basal-like pancreatic adenocarcinoma (PDAC) [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 494.
Abstract 866: Next-generation neoantigen vaccines powered by AI-assisted discovery and APC-targeted delivery platforms
Authors: Jingwei Sun, Zhenjiang Liu, Ke Liu, Xi Zhu, Chenxi Hou, Hong Chen, Xu Wang, Jiahui Jin, Zhao Xu, Stephen Schoenberger, Pin Wang, Yarong Liu
Journal: Cancer Research (2025)

Abstract Neoantigen-based cancer vaccines have shown promising efficacy in recent clinical trials for treating solid tumors. However, traditional neoantigen prediction methods, which largely rely on HLA-peptide binding databases, often yield false-positive predictions, highlighting the need for more accurate strategies to identify truly immunogenic neoantigens. To address this, we developed NEOVigator, an advanced neoantigen discovery platform that combines an AI-driven algorithm with functional validation using tumor-specific T cells derived from autologous tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs). The NEOVigator platform mimics the complete antigen presentation and T-cell response cascade by isolating and expanding autologous antigen-presenting cells (APCs) to evaluate neoantigen expression, processing, MHC binding, and presentation. Patient-derived TILs and PBMC T cells are then used to assess TCR recognition and T-cell responses to APC-presented antigens. Trained on experimentally validated immunogenic neoantigens, the AI algorithm achieves over 40% predictive accuracy across diverse solid tumor types. To enhance neoantigen delivery and maximize antitumor T-cell responses, we developed an APC-targeted lipid nanoparticle (LNP) system. This innovative mRNA delivery platform enables efficient, APC-specific targeting across multiple organs while minimizing off-target expression in non-immune cells, such as hepatocytes. Preclinical toxicology studies in multiple species have demonstrated favorable tolerability for both the ionizable lipid L52715 and the APC-targeted LNP formulation. Our lead neoantigen vaccine candidate, GT601, has successfully entered an investigator-initiated clinical trial in China, marking a major milestone in translating the NEOVigator platform into next-generation cancer immunotherapies. Citation Format: Jingwei Sun, Zhenjiang Liu, Ke Liu, Xi Zhu, Chenxi Hou, Hong Chen, Xu Wang, Jiahui Jin, Zhao Xu, Stephen Schoenberger, Pin Wang, Yarong Liu. Next-generation neoantigen vaccines powered by AI-assisted discovery and APC-targeted delivery platforms. [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 866.