tbuckley/cabot-search huggingface dataset:
Abstract LB232: Deciphering novel MRTF-A inhibitors and combination strategies for HCC therapy
Authors: Miriam Jasmin Franz, Laura Rupprecht, Pia Wenisch, Petra Wohlleben, Vladimir Chubanov, Thomas Gudermann, Salla Kyheröinen, Achim Aigner, Maria Kristina Vartiainen, Markus Heinrich, Susanne Mühlich
Journal: Cancer Research (2025)

Abstract Myocardin-related transcription factor A (MRTF-A) is a coactivator of the transcription factor serum response factor (SRF) that promotes the expression of genes involved in cell proliferation, migration and differentiation and triggers HCC progression. Therapeutic knockdown of MRTF-A induces senescence and quiescence in HCC xenografts and may be harnessed as a novel molecularly targeted strategy for the treatment of HCCs and recurrent disease. We recently demonstrated that the negative gating modulator NS8593 of the transient receptor potential cation channel TRPM7 inhibits MRTF-A by promoting its nuclear export. We generated derivatives of NS8593, which are more potent in inhibiting SRF transcriptional activity, as determined by reporter gene assays. Remarkably, we assessed MRTF-A nuclear localization by Fluorescence Loss in Photobleaching (FLIP) to define responsiveness to the novel MRTF inhibitors. Upon administration of the improved NS8593 analogs, nuclear export of MRTF-A was increased and the expression of the MRTF/SRF target genes such as transforming growth factor β1 (TGF-β1) and tetraspanin 5 (TSPAN5) was significantly reduced, resulting in senescence induction and proliferation arrest in HCC cells. Our novel MRTF inhibitors highlight the therapeutic potential of targeting this pathway, also in combination therapies with receptor tyrosine kinase inhibitors. Thus, our studies illuminate for the first time the potential of combining MRTF-A inhibitors with established therapies to combat HCC growth and drug resistance. Citation Format: Miriam Jasmin Franz, Laura Rupprecht, Pia Wenisch, Petra Wohlleben, Vladimir Chubanov, Thomas Gudermann, Salla Kyheröinen, Achim Aigner, Maria Kristina Vartiainen, Markus Heinrich, Susanne Mühlich. Deciphering novel MRTF-A inhibitors and combination strategies for HCC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB232.
Abstract LB179: <i>TCF7</i> deletion accelerates intestinal adenoma development by unleashing the proliferation of slow-cycling tumor stem cells
Authors: Marika Jenna Lassila, Cinzia Bessone, Fatemeh Seyednasrollah, Johanna Aspholm, Tatiana V. Petrova, Tuomas Kaprio, Caj Haglund, Pauliina Kallio, Kari Alitalo
Journal: Cancer Research (2025)

Abstract Somatic loss of function of APC tumor suppressor gene and aberrant activation of WNT signaling are key initiation events in colorectal cancers (CRCs). TCF/LEF transcription factors are mediators of the Wnt signaling pathway. Although their collective role in CRC is well established, the contribution of individual TCF/LEF factors and their isoforms to CRC tumorigenesis is not completely understood. Here, we discovered that in the ApcMin/+ mouse model of CRC development, 90% of Tcf7+ cells were slow-cycling tumor stem/progenitor cells, which also co-expressed the tumor stem/progenitor cell marker Prox1. Furthermore, TCF7+ cells in CRC patient samples also express CRC stem cell markers. The Tcf7/Lef1 double-positive tumor stem/progenitor cells from Apc mutant mice expressed lower levels of Myc targets, cell cycle regulator E2F, and overall G2M signaling than double-negative cells. Both constitutive deletion of the long isoforms of Tcf7 and conditional inactivation of Tcf7 in Lgr5+ or Prox1+ tumor stem/progenitor cells in Apcfl/fl or ApcMin/+ mice increased Myc expression and cell proliferation, leading to a robust increase in intestinal tumorigenesis. Deletion of either Tcf7 or Lef1 in Apcfl/fl mice increased the expression of inhibitors of differentiation 1-3 (Id1-3) and Fosl1, a downstream target of both Tcf7 and Id1, that is mitotic machinery controller and driver of CRC metastasis, and decreased the proportion of tumor enterocytes. These findings revealed that Tcf7 and Lef1 act to restrain the proliferation of slow-cycling tumor stem/progenitor cells. Our findings could lead to the discovery of additional therapeutic vulnerabilities during CRC development. Citation Format: Marika Jenna Lassila, Cinzia Bessone, Fatemeh Seyednasrollah, Johanna Aspholm, Tatiana V. Petrova, Tuomas Kaprio, Caj Haglund, Pauliina Kallio, Kari Alitalo. TCF7 deletion accelerates intestinal adenoma development by unleashing the proliferation of slow-cycling tumor stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB179.
Abstract LB141: <i>In vivo</i> co-produced BTEs targeting FSHR and Her2 overcome ovarian cancer therapeutic resistance in mice
Authors: Pratik Sanjivkumar Bhojnagarwala, Devivasha Bordoloi, Joshua Jose, David B. Weiner
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OC) is a deadly disease in need of newer therapies. Several immunotherapy approaches including checkpoint inhibitors, cancer vaccines and CART cells have been explored for OC, with limited clinical success. Bispecific T cell engagers (BTEs) allow direct engagement of adaptive immunity, potentially making them important for OC. First-generation BTEs suffer from short half-lives, resulting in poor pharmacokinetics which reduces their effectiveness. BTEs also have complex manufacturing processes and stringent storage requirements, resulting in increased costs and potentially reducing accessibility and limiting patient uptake. Heterogeneity in expression of tumor associated antigens (TAAs) further complicates treatment with a single BTE, as OC can evade the immune impact of targeting a single antigen. Targeting multiple TAAs could enhance anti-tumor efficacy. We describe a novel approach by adapting Knob-into-hole technology into a DNA format designed for in vivo assembly and secretion of bivalent BTEs (dKBTEs). This unique approach allows for simplified multi-TAA targeting to overcome tumor heterogeneity. Two dKBTEs targeting FSHR (dK_FSHRxCD3) and Her2 (dK_Her2xCD3) were designed and tested. in vitro, both dKBTEs expressed at expected sizes, bound to their respective TAA and T cells and induced T cell effector functions. These dKBTEs demonstrated potent and specific cytotoxicity of several OC cell lines which are derived from tumors with different driver mutations and resistance to several approved therapies for OC. In mice, they showed superior pharmacokinetics and tumor control compared to first-generation BTEs. Combination therapy with both dKBTEs further improved tumor control over single dKBTE therapy. DNA delivery allows for in vivo production, assembly and secretion of BTEs without compromising expression or activity when codelivering two dKBTEs. This study demonstrates that in vivo codelivery of dKBTEs targeting multiple TAAs can better impact antigen heterogeneity and evasion, presenting a promising strategy for OC treatment. Citation Format: Pratik Sanjivkumar Bhojnagarwala, Devivasha Bordoloi, Joshua Jose, David B. Weiner. In vivo co-produced BTEs targeting FSHR and Her2 overcome ovarian cancer therapeutic resistance in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB141.
Abstract LB049: Novel and user-friendly hybridization capture workflow for low quality samples on small gene panels
Authors: Ekaterina Star, Daniel Saatman, Jinglie Zhou, Alexandra Wang
Journal: Cancer Research (2025)

Abstract Hybridization capture targeted sequencing is a valuable and cost-effective method for in-depth sequencing of specific areas of interest to detect desired low allele frequency variants. While this approach has many advantages over WGS, commercially available workflows are notoriously complex and tend to have a long hands-on time and challenging hot liquid washes. Integrated DNA Technologies (IDT) novel xGen™ Hyb and Wash v3 (xGen v3) workflow overcomes the laboratory challenges of hybridization capture. xGen v3 has no pre-heating, no hot-liquid handling, and no temperature-sensitive urgency. This workflow reduces significantly the amount of time users must spend at their lab bench while executing the protocol. The simple and user-friendly workflow increases throughput, decreases hands-on time and easily adaptable for automation.In this study we demonstrate xGen v3 workflow performance with non-GIAB Formalin-Fixed Paraffin-Embedded (FFPE) input samples using panels of varying sizes from 11Mb target bed size to custom panel smaller than 200Kb with different probe design strategies. Libraries were constructed from Horizon Discovery FFPE standard, formalin compromised standards and NA12878 using IDT’s xGen cfDNA &amp; FFPE DNA Library Prep Kit. This was followed by 1-plex hybridization capture using xGen v3 kit workflow with library total input into capture from 500ng to 100ng and sequenced on Illumina’s NextSeq2000 sequencer. xGen v3 workflow performance remains high regardless of input type, quality or input amount into capture. We also demonstrate consistently high performance across all panels tested regardless of probe design strategy. IDT’s unique hybridization and capture technology eliminates hot liquid handling while demonstrating excellent performance with input and hybridization time flexibility. The simple and user-friendly workflow increases throughput and decreases hands-on time. This workflow supports large gene panels and more focused specific gene monitoring, which could be leveraged for a variety of NGS oncology research applications. Citation Format: Ekaterina Star, Daniel Saatman, Jinglie Zhou, Alexandra Wang. Novel and user-friendly hybridization capture workflow for low quality samples on small gene panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB049.
Abstract LB032: Preclinical evaluation of GPC3 targeting antibody-TCR T cells in HCC models with tumor rechallenging
Authors: Guangyan Xiong, Hongbing Zhang, Cheng Liu
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Glypican-3 (GPC3), highly expressed in HCC but minimally in normal tissues, is a promising target for cell therapy. ECT204, a GPC3-targeting T cell product developed using the ARTEMIS Cell Receptor Platform, incorporates an Antibody T-Cell Receptor (AbTCR) combining an antibody-derived targeting domain with a human γδ T-cell receptor effector domain and a Costimulatory Receptor (CSR)1. Previous studies have demonstrated superior anti-tumor activity, safety, and reduced exhaustion of ARTEMIS T cells compared to CAR-T cells in hematologic cancer models2. To address challenges of T-cell therapy against solid tumors, including poor tumor infiltration, T cell exhaustion, short T cell persistence and high tumor burden with limited T cell dosing potential, we evaluated ECT204 in rigorous HCC models. In the HepG2 xenograft model, ECT204 T cell exhibited abundant infiltration by immunohistochemistry staining, significantly higher than GPC3-targeting CAR-T. Notably, circulating ECT204 T cells were drastically lower PD-1 expression compared with its CAR-T counterpart. When tested for T cell persistence in HepG2 re-challenge model, ECT204 suppressed re-inoculated tumor 75 days after the initial T-cell dosing. Expansion of ECT204 T cells were detected in peripheral blood after re-challenge, indicating the presence of memory cells that can sustain response. While preclinical studies with high T cell doses are useful for proof-of-concept purposes, they may not reflect clinically feasible doses. Remarkably, ECT204 effectively killed HepG2 cells in vitro at effector:target ratios as low as 1:16 and eliminated tumors in xenografts at a low dose of 0.5 x 106 cells. Overall, these stringent preclinical evaluations support the clinical translation of ECT204. ECT204 is currently in the ARYA-3 Phase 1/2 trial for adults with advanced HCC and is actively enrolling patients in the expansion phase. 1. He, P., et al. “A novel antibody-TCR (AbTCR) T-cell therapy is safe and effective against CD19-positive relapsed/refractory B-cell lymphoma.” Journal of Cancer Research and Clinical Oncology. 149, 7 (2023). 2. Xu, Y., et al. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discovery. 4, 62 (2018). Citation Format: Guangyan Xiong, Hongbing Zhang, Cheng Liu. Preclinical evaluation of GPC3 targeting antibody-TCR T cells in HCC models with tumor rechallenging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB032.
Abstract LB154: <i>Peptostreptococcus anaerobius</i> induces colorectal cancer stemness and chemoresistance via its surface protein NIpC/P60 interacting with Annexin A2 to activate YAP/Hippo signaling pathway
Authors: Liu Yali, Chi Chun Wong, Yating Zhang, Kai Yuan, Chuanfa Liu, Weixin Liu, Mingxu Xie, Jun Yu
Journal: Cancer Research (2025)

Abstract Chemoresistance is a common challenge in colorectal cancer (CRC) and contributes significantly to treatment failure and relapse. Here, we investigate the role of the CRC intratumoral pathogen Peptostreptococcus anaerobius in promoting colorectal cancer stem cell (CSC) stemness and chemoresistance, elucidating its molecular mechanisms. We found that intratumoral P. anaerobius is positively correlated with stemness-related genes, such as CD133 and LGR5, in CRC patients (n=73). Gavage with P. anaerobius enhanced CRC formation and increased the populations of Cd133+ and Lgr5+ cells within CRC tissues from ApcMin/+ and AOM/DSS models, indicating that P. anaerobius promotes CSC characteristics in CRC. Furthermore, co-culture with P. anaerobius significantly increased the self-renewal capacity and sphere-forming ability of human colorectal CSCs, alongside elevated expression levels of CD133 and LGR5. Notably, P. anaerobius also conferred resistance to oxaliplatin and 5-fluorouracil treatment in both human CSCs in vitro and in AOM/DSS-induced CRC models. Mechanistically, we discovered that the outer membrane protein NlpC/P60 from P. anaerobius interacts with the Annexin A2 receptor on colorectal CSCs. Co-immunoprecipitation, SPR assays, and crosslinking MS revealed that NlpC/P60 competed with Yes-associated protein 1 (YAP) for binding to Annexin A2 (ANXA2). This interaction disrupted the intracellular binding between ANXA2 and YAP, leading to the release of YAP from the cell membrane, promoting YAP translocation into nucleus to activate Hippo signaling pathway. Importantly, neutralizing antibodies against ANXA2 blocked the interaction between P. anaerobius and colorectal CSCs, thereby abrogating the effects of P. anaerobius on stemness and chemoresistance. Consistent with these pre-clinical findings, higher levels of P. anaerobius were observed in chemotherapy non-responders compared to responders among CRC patients. In summary, P. anaerobius drives CRC stemness and chemoresistance through the NlpC/P60-Annexin A2 interaction, leading to YAP1-mediated activation of the Hippo signaling pathway. Targeting this interaction may offer a promising strategy to overcome P. anaerobius-mediated chemoresistance in CRC. Citation Format: Liu Yali, Chi Chun Wong, Yating Zhang, Kai Yuan, Chuanfa Liu, Weixin Liu, Mingxu Xie, Jun Yu. Peptostreptococcus anaerobius induces colorectal cancer stemness and chemoresistance via its surface protein NIpC/P60 interacting with Annexin A2 to activate YAP/Hippo signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB154.
Abstract LB024: CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency
Authors: Josef Leibold, Philip Bucher, Judith Feucht, Nadine Brückner, Jule Kortendieck, Melanie Grimm, Karlotta Bartels, Steffen Hardy, Hannah Wurzer, Meike Thiemann, Celina May, Julia Quach, Nayan Jain, Letizia Quintanilla de Fend, Yu-Jui Ho, Francisco J. Sanchez-Rivera, Jie Sun, Bettina Weigelin, Martina Rausch, Mara Mitstorfer, Irene Gonzalez-Menendez, Michel Sadelain
Journal: Cancer Research (2025)

Abstract Chimeric antigen receptor (CAR) T cell therapy has demonstrated promising outcomes in patients with certain refractory hematological malignancies. However, insufficient functional T cell persistence impedes therapeutic success of CAR therapies in a significant number of patients. Here, we performed a CAR-adapted screen of base-edited PIK3CD alleles to optimally calibrate PI3K/AKT signaling in T cells given its critical role in T cell function, metabolism, and fate. Our screen comprised both, prototypic 4-1BBz and CD28z CAR T cells to account for the distinct effector and memory functions imparted to T cells through incorporation of different costimulatory domains in CARs. We identified individual point mutations that induce beneficial CAR T cell profiles through precise balancing of endogenous PI3Kδ signaling strength in 4-1BBz and CD28z CAR T cells, respectively. Remarkably, point mutations with differing effects on PI3Kδ signaling activity were advantageous within the distinct CAR contexts: While 28z CAR T cells profited from attenuated signaling, the PI3Kδ-activating mutation E81K enhanced proliferative capacity, metabolic fitness and effector function in 4-1BBz but not in 28z CAR T cells. E81K-modified BBz CARs ameliorated long-term functional T cell persistence and enhanced therapeutic efficacy in established in vivo models of hematological and solid tumors without evidence of malignant transformation. Together, these data illustrate the importance of tailoring intrinsic T cell signaling capacities to the specific requirements of different CAR designs and demonstrate the potential of base editing to precisely optimize T cell function for bespoke cellular therapies. Citation Format: Josef Leibold, Philip Bucher, Judith Feucht, Nadine Brückner, Jule Kortendieck, Melanie Grimm, Karlotta Bartels, Steffen Hardy, Hannah Wurzer, Meike Thiemann, Celina May, Julia Quach, Nayan Jain, Letizia Quintanilla de Fend, Yu-Jui Ho, Francisco J. Sanchez-Rivera, Jie Sun, Bettina Weigelin, Martina Rausch, Mara Mitstorfer, Irene Gonzalez-Menendez, Michel Sadelain. CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB024.
Abstract LB034: Combination immunotherapy promotes integrated anti-tumor immunity in fibrolamellar carcinoma
Authors: Jason A. Carter, Lindsay K. Dickerson, Sara K. Daniel, Xiuyun Jiang, Heidi Kenerson, Raymond S. Yeung, Ian N. Crispe, Venu G. Pillarisetty
Journal: Cancer Research (2025)

Abstract Fibrolamellar carcinoma (FLC) is a rare liver cancer typically arising in adolescents or young adults without underlying liver disease. Characterized molecularly by a conserved DNAJB1-PRKACA fusion oncogene and histologically by dense intratumoral stromal bands, the unique FLC tumor immune microenvironment (TIME) results in limited intrinsic anti-tumor immunity and poor clinical responses to single-agent immune checkpoint blockade. We hypothesized that the lack of robust anti-tumor immune response in FLC is mediated through two distinct mechanisms that generate both T cell exclusion and intratumoral immunosuppression. Using single-nuclear RNA sequencing from more than 110,000 cells in the FLC TIME and adjacent non-tumor liver, we found increased expression of immune checkpoint molecules and inferred cell-cell communication between CXCL12+ myofibroblasts and CXCR4+ lymphocytes. Targeting these pathways with combination CXCR4 inhibition (AMD3100) and PD-1 blockade in a human tumor slice culture model system significantly increased tumor cell death relative to isotype control and both monotherapies. Live confocal microscopy and multiplex immunohistochemistry demonstrated increased T cell activation and migration towards tumor cells with combination therapy. Single-cell RNA sequencing of treated tumor slices and spatial multi-omics further revealed an integrated immune response following combination immunotherapy involving cytotoxic T cells, helper T cells, and dendritic cells. Together, our findings demonstrate that combination CXCR4 and PD-1 inhibition cooperatively overcome both immune exclusion and immunosuppression in the FLC TIME. Furthermore, these results provide pre-clinical evidence for rational selection of combination immunotherapy in a rare tumor type that currently has no effective systemic therapies. Citation Format: Jason A. Carter, Lindsay K. Dickerson, Sara K. Daniel, Xiuyun Jiang, Heidi Kenerson, Raymond S. Yeung, Ian N. Crispe, Venu G. Pillarisetty. Combination immunotherapy promotes integrated anti-tumor immunity in fibrolamellar carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB034.