tbuckley/cabot-search huggingface dataset:
Abstract 3948: Enhancing immune checkpoint delivery to diffuse midline glioma (DMG) using focused ultrasound
Authors: Amelia Claxton, Paul Cressey, David Thurston, Esther Hulleman, Antonios Pouliopoulos, Darren Hargrave, Maya Thanou
Journal: Cancer Research (2025)

Brain tumors, such as diffuse midline glioma (DMG), remain the leading cause of cancer-related death in pediatric oncology due to their universal fatality and limited treatment options. Treatment of DMG is hindered by the blood-brain barrier (BBB) presenting a roadblock in the clinical translation of therapies, particularly for larger therapeutic agents such as antibodies (e.g., immune checkpoint inhibitors). Focused ultrasound (FUS) and cavitating microbubbles provide a solution to this by transiently disrupting the BBB in a controlled and safe manner, allowing significantly enhanced drug delivery to a brain tumor whilst avoiding healthy tissue. In this study, we investigated the use of immune checkpoint inhibitors in in vitro and in vivo (orthotopic murine) DMG models. An in vitro transwell model in combination with FUS was used to determine if immune checkpoint inhibitors can pass through an endothelial layer (BENd3) following FUS blood-brain barrier opening (BBBO) at therapeutic concentrations, using fluorescence imaging and flow cytometry. We further tested our immune checkpoint inhibitors in an in vivo orthotopic murine DMG model (mDMG-3.3). Uptake enhancement following FUS was determined using fluorescence imaging. The results demonstrated a significant increase in the delivery of antibodies across the BBB following FUS in vitro. We also showed that FUS BBBO had no significant effect on endothelial cell viability. FUS-induced BBBO was performed in tumor-bearing mice using systemically administered SonoVue microbubbles (2 mL/kg), and FUS (peak-negative pressure = 320 kPa, cycle number = 500, pulse repetition frequency (Hz) = 5, number of pulses = 600). T1-weighted MRI was used immediately after FUS-induced BBB opening to confirm that the BBB had opened. Real-time passive cavitation detection was also used to record the harmonic signals of the cavitating microbubbles to control BBB opening, and for post-experiment analysis of microbubble behavior. Immediately following BBBO, mice were dosed with fluorescently labelled antibody (10 mg/kg) i.v., and then FUS BBBO was shown to cause a significant enhancement in uptake of the labelled antibody into the sonicated region. These results suggest that FUS-BBBO is a suitable technology to safely enhance the uptake of immune checkpoint inhibitors into DMG tumors. Future work will include evaluation of the survival benefits of immune checkpoint inhibitors in our mouse DMG models. Citation Format: Amelia Claxton, Paul Cressey, David Thurston, Esther Hulleman, Antonios Pouliopoulos, Darren Hargrave, Maya Thanou. Enhancing immune checkpoint delivery to diffuse midline glioma (DMG) using focused ultrasound [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 3948.
Abstract 130: Matrix remodeling promotes macrophage recruitment in breast cancer
Authors: Ioannis K. Zervantonakis, Youngbin Cho
Journal: Cancer Research (2025)

Abstract A high number of tumor-associated macrophages (TAM) in breast tumors is associated with poor patient outcomes. Furthermore, activation of myosin II, a key cytoskeletal regulator, has been identified as a predictor of distant metastasis in triple negative breast cancer (TNBC). However, the relationship between myosin II activation in TNBC cancer cells and macrophage motility remains poorly understood. Here we employed a novel 3D microfluidic model of tumor-macrophage co-culture to study macrophage infiltration toward cancer cells with high spatiotemporal resolution and evaluation of extracellular matrix remodeling. Using a panel of TNBC cell lines we found that cancer cells with higher macrophage recruitment potential in a 3D matrix exhibited higher levels of myosin II activity. We found that macrophage infiltration was higher in decellurized extracellular matrices seeded with the high-macrophage recruiting cancer cell line EMT6 compared to the low-macrophage recruiting cancer cells E0771. Functional contractility analysis using traction microscopy revealed that EMT6 exerted higher matrix displacements compared to E0771 that could be suppressed by pharmacologically blocking myosin II in cancer cells or genetic silencing of the myosin regulatory light polypeptide 9. Consistent with these suppressive effects of targeting actomyosin contractility on matrix remodeling we also found that macrophage recruitment was reduced. These studies reveal the critical role of cancer cell-driven matrix remodeling in promoting macrophage infiltration that can be therapeutically targeted to revere the establishment of a macrophage-rich pro-tumorigenic tumor microenvironment. Citation Format: Ioannis K. Zervantonakis, Youngbin Cho. Matrix remodeling promotes macrophage recruitment in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 130.
Abstract 6809: IFITM3/MET axis drives osimertinib resistance through Akt pathway activation in <i>EGFR</i>-mutant lung cancer
Authors: Ritsu Ibusuki, Eiji Iwama, Atsushi Shimauchi, Hiroyuki Inoue, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Isamu Okamoto
Journal: Cancer Research (2025)

Abstract EGFR-mutant non-small-cell lung cancer (NSCLC) patients often experience significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). However, resistance to these therapies inevitably emerges over time through various mechanisms, limiting the long-term effectiveness of the treatment. The mechanisms of resistance and the duration required for resistance to emerge are highly variable and difficult to predict, highlighting the need for new therapeutic strategies to suppress resistance. In this study, we elucidated the mechanism by which IFITM3, a membrane protein whose expression is upregulated by cytokine stimulation, contributes to reduced sensitivity to the EGFR-TKI osimertinib and promotes the development of resistance through Akt pathway activation. Additionally, we demonstrated that IFITM3 levels are elevated in pre-treatment clinical specimens from EGFR-mutant NSCLC patients who developed early resistance to osimertinib, supporting its role in resistance development. Furthermore, Combined treatment with osimertinib and MET inhibitor results in synergistic growth inhibition in NSCLC xenograft mouse models with high IFITM3 expression. These findings provide a rationale for clinical trials investigating the co-administration of MET and EGFR inhibitors in patients with elevated IFITM3 levels to address the heterogeneity of EGFR-TKI resistance mechanisms. Citation Format: Ritsu Ibusuki, Eiji Iwama, Atsushi Shimauchi, Hiroyuki Inoue, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Isamu Okamoto. IFITM3/MET axis drives osimertinib resistance through Akt pathway activation in EGFR-mutant 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 6809.
Abstract 6804: Sanguinarine overcomes osimertinib resistance by inducing HMOX1-related ferroptosis in osimertinib resistant cells lines and tumors
Authors: Rongzhong Xu, Liubing Lin
Journal: Cancer Research (2025)

Abstract Epidermal Growth Factor Receptor (EGFR) gene, as a crucial oncogenic driver, plays a significant role in the occurrence and progression of non-small cell lung cancer (NSCLC). Osimertinib, as the latest generation of EGFR tyrosine kinase inhibitors (TKIs), has shown remarkable efficacy not only in patients with EGFR-sensitive mutations but also in those with rare EGFR mutations. However, similar to patients treated with first- or second-generation EGFR-TKIs, those treated with osimertinib eventually develop resistance Therefore, it is crucial to investigate the mechanisms of resistance and identify novel, rational strategies and drugs to overcome acquired resistance. Here we demonstrated that Sanguinarine, a natural benzophenanthridine alkaloid derived from rhizomes of the plant species Sanguinaria canadensis, which induces ferroptosis in osimertinib-resistance cells, leading to cell death. In this study, we found that sanguinarine induced more cell death in osimertinib-resistant cell lines, compared to osimertinib-sensitive EGFR-mutant cell lines. RNA-seq showed that sanguinarine increased higher expression level of HMOX1 in osimertinib-resistant cell lines than osimertinib-sensitive EGFR-mutant cell lines. Moreover, compared to osimertinib-sensitive cell lines, sanguinarine induces more ROS production, increases Fe2+ concentration, and promotes more ferroptosis in osimertinib-resistant cell lines. Interestingly, we found that HMOX1 levels are elevated in tissues from patients with EGFRm NSCLC who relapsed from EGFR-TKI treatment. Also, Osimertinib and other EGFR-TKIs up-regulate HMOX1 expression in EGFRm NSCLSC cells and tumors. Enforced expression of an ectopic HMOX1 gene in Osimertinib-sensitive EGFRm NSCLC cells increased the sensitivity of cells to sanguinarine by inducing more ferroptosis, whereas knockdown of HMOX1 in Osimertinib-resistant cell lines conferred resistance to sanguinarine. Importantly, sanguinarine inhibited more effective in osimertinib resistant EGFRm NSCLC xenograft in vivo than in osimertinib sensitive models. Together, compared to osimertinib-sensitive cell lines, sanguinarine induces more ROS production and increases Fe2+ concentration results in more ferroptosis in osimertinib-resistant cell lines. This difference may be due to the overexpression of HMOX1 in Osimertinib-resistant cells, making them more susceptible to the effects of sanguinarine. Citation Format: Rongzhong Xu, Liubing Lin. Sanguinarine overcomes osimertinib resistance by inducing HMOX1-related ferroptosis in osimertinib resistant cells lines and tumors [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 6804.
Abstract 4319: Loss of Golga7 suppresses oncogenic Nras-driven leukemogenesis without detectable toxicity in adult mice
Authors: Bo Jiao, Lei Yan, Rui Zhang, Wei Huang, Xinru Wang, Ping Liu, Ruibao Ren
Journal: Cancer Research (2025)

Abstract NRAS mutations are prevalent in human hematological malignancies and are also common in certain solid tumors, including melanoma and colon cancer. Despite their crucial role in oncogenesis, no effective therapies targeting NRAS have been developed. Inhibiting NRAS localization to the plasma membrane (PM) represents a promising strategy for cancer therapy, as its oncogenic signaling relies on PM localization. Knocking out Golgin subfamily A member 7 (Golga7), an accessory protein of RAS palmitoyltransferases, through a conditional gene editing approach drastically suppresses the development of myeloid leukemia induced by the activation of NrasG12D/G12D knock-in alleles in mice. The loss of Golga7 disrupts NRASG12D PM localization in bone marrow cells without altering the level of NRASG12D palmitoylation. Notably, Golga7 is dispensable for normal hematopoiesis in adult mice. While constitutive Golga7 knockout leads to embryonic lethality, the ubiquitous knockout of Golga7 induced in adult mice does not manifest any measurable toxic effects. These findings indicate that GOLGA7 is an effective and safe therapeutic target for NRAS-driven leukemias. Citation Format: Bo Jiao, Lei Yan, Rui Zhang, Wei Huang, Xinru Wang, Ping Liu, Ruibao Ren. Loss of Golga7 suppresses oncogenic Nras-driven leukemogenesis without detectable toxicity in adult mice [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 4319.
Abstract 4179: ADCK1 expression modulates pro-cancerous characteristics of hepatocellular carcinoma
Authors: Noel A. Jacquet, Yunfeng Zhao
Journal: Cancer Research (2025)

The incidence of hepatocellular carcinoma (HCC) has steadily increased over the past few decades, with minimal progress in developing effective therapeutic agents. As the most common form of primary liver cancer, HCC is currently the third leading cause of cancer-related deaths. HCC originates from hepatocytes, the primary liver cell type responsible for vital metabolic functions, including the processing of amino acids, lipids, carbohydrates, and xenobiotics. Dysregulation of cellular metabolism can drive malignancies and lead to tumorigenesis. AarF Domain Containing Kinase 1 (ADCK1), a putative kinase, is implicated in regulating mitochondrial functions, which are essential for cellular metabolism. Defects in mitochondrial function are known to contribute to tumorigenesis. Although ADCK1 remains poorly studied in humans, early research suggests its involvement in the tumorigenesis of parathyroid, colon, and osteosarcoma cancers. Our lab aims to elucidate the role of ADCK1 in cellular metabolism and the behavior of HCC cells. Bioinformatics analysis conducted by our group revealed that high ADCK1 expression correlates with worse overall survival rates in HCC patients compared to those with low ADCK1 expression. To investigate the impact of ADCK1 loss, we generated ADCK1 knockout (KO) clones in HCC cells. Our findings indicate that the loss of ADCK1 modulates several malignant characteristics associated with HCC tumorigenesis, including alterations in cellular proliferation, cell cycle regulation, programmed cell death, colony formation, and mitochondrial respiration. Future studies will explore the mechanisms underlying these processes, to establish ADCK1 as a promising therapeutic target for HCC treatment. This abstract has been proofread and enhanced for clarity through the assistance of Grammarly and ChatGPT AI. Citation Format: Noel A. Jacquet, Yunfeng Zhao. ADCK1 expression modulates pro-cancerous characteristics of hepatocellular carcinoma [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 4179.
Abstract 7021: Discovery of a highly potent and orally bioavailable ER PROTAC degrader for the treatment of breast cancer
Authors: Guan Zhou, Yuanli Wang, Wei Xue, Yongzheng Ding, Jing Cheng, Kanghua Wang, Weiwei Yu, Wenmin Chen, Fuming Xu
Journal: Cancer Research (2025)

Abstract Breast cancer is the most prevalent invasive cancer among women globally and approximately 70-80% of newly diagnosed breast cancer cases are ER-positive (ER+). Estrogen receptor α (ERα) is a prime target for the treatment of ER+ breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. A promising therapeutic strategy to overcome endocrine resistance in ER+ breast cancer is the development of ER degraders using the proteolysis targeting chimera (PROTAC) technology. Facilitated by our new cereblon ligand library, we have discovered a potent and orally bioavailable ER PROTAC degrader GLR203801, with its binding affinity to cereblon increased by 20-fold than that of ARV-471. GLR203801 exhibited robust protein degradation in both ER wild-type cell lines (DC50 &amp;lt; 1 nM, Dmax&amp;gt; 90%) and mutant cell lines harboring Y537S or D538G mutation (DC50 2-10 nM, Dmax &amp;gt; 80%). Profound inhibition of the expression of ER-regulated genes GREB1 and PR was observed with GLR203801 in all the tested cell lines. GLR203801 shows more potent cell growth inhibition activity and maximum inhibition is 20%-30% higher than that of ARV-471 in all the tested ER wild-type and mutant cell lines. GLR203801 was characterized with favorable PK profile in vivo, with longer T1/2 and higher plasma exposure than ARV-471. GLR203801 displayed significantly enhanced antitumor efficacy than ARV-471 in five ER+ xenograft models (MCF-7, T-47D, ZR-75-1, MCF-7Y537S, and T-47DD538G), with tumor regression observed in wild-type xenograft models. PK/PD studies demonstrated that the tumor exposure of GLR203801 was 10 to 20-fold higher than that of ARV-471, and GLR203801 degraded &amp;gt;95% of ER in MCF-7WT and T-47DD538G tumor tissue. In addition, GLR203801 in combination with CDK4/6 inhibitors showed synergistic anti-tumor efficacy in T-47D xenograft model. GLR203801 also effectively inhibited the viability of breast-cancer patient derived ER+ organoids. The good tolerance of GLR203801 in toxicity study both in SD rats and beagle dogs supports it as a promising preclinical candidate for further clinical development. Citation Format: Guan Zhou, Yuanli Wang, Wei Xue, Yongzheng Ding, Jing Cheng, Kanghua Wang, Weiwei Yu, Wenmin Chen, Fuming Xu. Discovery of a highly potent and orally bioavailable ER PROTAC degrader for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7021.
Abstract 4462: Covalent inhibition of eIF4E: A computational approach
Authors: Xingchuan Ma
Journal: Cancer Research (2025)

Abstract Covalent docking has emerged as a promising strategy for targeting challenging protein residues. Specifically, lysine residues, which are often overlooked due to their lower nucleophilicity compared to cysteines, have shown potential in the development of covalent inhibitors for eukaryotic translation initiation factor 4E (eIF4E), a critical regulator of protein synthesis implicated in breast cancers. Leveraging aryl sulfonyl fluorides, recent studies had successfully docked to K162 within eIF4E and shown reduced protein activity, but the molecules had faced significant specificity and instability. In this study, I improved the molecules in the following aspects: specificity and stability. Regarding specificity, I found additional lysine residues, such as K106 and K108, as promising targets for covalent inhibition through structural analyses of eIF4E. I also designed bivalent molecules that covalently bind to both lysine residues simultaneously. This bivalent binding increases the specificity as there are only two regions of two lysine residues in three amino acids, whereas there are a total of 15 lysine residues. The differences in binding affinity and docking score between the bivalent and control groups were insignificant, suggesting that the potency of the bivalent molecule didn’t drop. Finally, through molecular dynamic simulations, I verified that there is conformational changes at the cap-binding site after covalent inhibition, demonstrating the biological efficacy of the drug molecules. Citation Format: Xingchuan Ma. Covalent inhibition of eIF4E: A computational approach [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 4462.
Abstract 7015: Intelligent molecular glue discovery by identifying glueable ligase-target pairs at scale
Authors: Phil Burke, Arpita Sen, David Noble, Abhishek Dogra, Ruchi Bansal, Dasha Krayushkina, Natasha Seelam Murakowska, Kerry McGowan, Charles Lin, Yeweon Lee, Randolph Lopez
Journal: Cancer Research (2025)

Abstract Targeted protein degradation can be induced by monovalent small molecules, called molecular glues. These molecules modify the substrate-binding interface of E3 ubiquitin ligases and reroute their binding to novel targets, opening the possibility of therapeutically inhibiting proteins previously considered “undruggable”. However, for a molecular glue to sufficiently stabilize a ligase-target interaction and induce degradation, the two proteins must exhibit proper shape complementarity and contain productive amino acid contacts - two proteins selected at random are unlikely to be glued by any small molecule. Identifying novel “glueable” ligase-target pairs requires the discovery and characterization of weak interactions (likely in the micromolar affinity range) between thousands or more potential pairs of human E3 ligases and therapeutically relevant target proteins. The need to evaluate vast numbers of potential protein interactions while maintaining exquisite sensitivity for weak interactions presents a major technical roadblock. To address this challenge, we apply AlphaSeq, a high-throughput and highly sensitive experimental platform for measuring protein-protein interactions, to discover and structurally characterize weak interactions between ligases and target proteins. We validate our approach by characterizing known ligase-target interactions, such as between the E3 ligase MDM2 and the tumor suppressor protein p53. We then leverage AlphaSeq for the discovery of molecular glues for novel ligase-target pairs and orthogonally validate these interactions with surface plasmon resonance (SPR). Finally, we use AlphaSeq mutational data to structurally characterize the interaction interface and inform the intelligent discovery of molecular glues. Citation Format: Phil Burke, Arpita Sen, David Noble, Abhishek Dogra, Ruchi Bansal, Dasha Krayushkina, Natasha Seelam Murakowska, Kerry McGowan, Charles Lin, Yeweon Lee, Randolph Lopez. Intelligent molecular glue discovery by identifying glueable ligase-target pairs at scale [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 7015.