tbuckley/cabot-search huggingface dataset:
Abstract 4792: Highly specific GLUT-1 inhibiting antibodies for the treatment of pancreatic cancer
Authors: Siret Tahk, Paule Hermet, Kyumhyuk Kim, Takefumi Morizumi, Anu Ustav, Kai Virumäe, Robin Pau, Korneelia Anton, Alastair J. King, Francisca Neethling, Andres Männik, Joan Teyra, Oliver Ernst, Mart Ustav
Journal: Cancer Research (2025)

Abstract Background: Cancer cells often exhibit upregulated glucose metabolism to support their abnormal growth and division. Targeting the cancer-specific glucose transporter GLUT-1 offers a promising strategy to limit glucose uptake and disrupt tumor metabolism. Unlike small molecule inhibitors, monoclonal antibodies provide a unique opportunity to selectively target complex multi-pass membrane transporters. This study presents the development of highly specific antibodies that recognize GLUT-1 glycovariants, effectively blocking GLUT-1 function in cancer cells while preserving glucose transport across the blood-brain barrier. Methods: GLUT-1-specific monoclonal antibodies were generated using GLUT-1-displaying virus-like particles (VLPs) as immunogens. Chickens were chosen for immunization due to their ability to produce antibodies against highly conserved multi-transmembrane proteins. Antibody discovery was conducted using HybriFree B cell cloning technology and phage display. Functional screens included assays for 2-deoxyglucose uptake inhibition and cancer cell proliferation. Results: The identified antibodies bind GLUT-1 with nanomolar EC50 values and exhibit no cross-reactivity with other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and reprograms GLUT-1-dependent cancer cells to rely on oxidative phosphorylation (OXPHOS). This metabolic shift synergizes with OXPHOS inhibitors, resulting in significant cancer cell growth inhibition at doses subtherapeutic as monotherapies. In vivo, the combination of ICO-33 and an OXPHOS inhibitor was well-tolerated and led to substantial tumor growth suppression in colorectal and pancreatic cancer models. Importantly, ICO-33 preserves glucose uptake in the brain, minimizing systemic toxicities. Conclusions: This study highlights the discovery of GLUT-1-targeting monoclonal antibodies with high specificity and efficacy. The lead antibody, ICO-33, effectively restricts glucose uptake in cancer cells and enhances sensitivity to OXPHOS inhibitors, demonstrating its potential as a candidate for clinical development in cancer therapy. Citation Format: Siret Tahk, Paule Hermet, Kyumhyuk Kim, Takefumi Morizumi, Anu Ustav, Kai Virumäe, Robin Pau, Korneelia Anton, Alastair J. King, Francisca Neethling, Andres Männik, Joan Teyra, Oliver Ernst, Mart Ustav. Highly specific GLUT-1 inhibiting antibodies for the treatment of pancreatic 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 4792.
Abstract 4136: The causes and consequences of off-target activation of the GCN2-eIF2a-ATF4 axis in cancer therapy
Authors: C. Ryland, Nasreen Marikar, Vu Nguyen, Varuna Nangia, Alicia Darnell, Stacey Bagby, Kasey Couts, Matthew G. Vander Heiden, Philip Reigan, Sabrina L. Spencer
Journal: Cancer Research (2025)

Abstract Kinase inhibitors are notorious for their promiscuity and off-target effects. We discovered that multiple clinical inhibitors used in the treatment of cancer, including dabrafenib and encorafenib, activate the GCN2 kinase at patient-relevant concentrations in an off-target manner via direct interaction. GCN2 is an activating kinase of the integrated stress response (ISR) that leads to induction of the transcription factor ATF4. Cotreatment with a GCN2 inhibitor in BRAF-V600E melanoma cells significantly alters the rate of drug resistance and cell outgrowth. We thus propose that off-target activation of GCN2 affects development of drug-resistant and metastatic phenotypes. Finally, we perform an in silico inhibitor screen, identifying dozens of FDA-approved inhibitors used in the treatment of cancer that appear to share this off-target GCN2 interaction. Citation Format: C. Ryland Ill, Nasreen Marikar, Vu Nguyen, Varuna Nangia, Alicia Darnell, Stacey Bagby, Kasey Couts, Matthew G. Vander Heiden, Philip Reigan, Sabrina L. Spencer. The causes and consequences of off-target activation of the GCN2-eIF2a-ATF4 axis in 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 4136.
Abstract 4782: Inducing abscopal effect in colorectal cancer via antibody-conjugated photothermal nanoparticles in combination with immunocytokine
Authors: Myeung Ryun Seo, Jinwon Park, Hee Geon Park, Jae Choi, Sang Moo Lee, Sangin Lee, Sae Hyung Lee, Hobin Yang, Sungyoul Hong, Yu-Kyoung Oh, Young Kee Shin
Journal: Cancer Research (2025)

Abstract Colorectal cancer is characterized by high rates of recurrence and metastasis, making it particularly challenging to manage due to multidrug resistance after treatment and/or the difficulty of detecting metastatic lesions. Photothermal therapy (PTT) has emerged as a promising strategy to overcome the drug resistance, with ongoing studies investigating its potential to induce the abscopal effect—an immune-mediated response targeting metastatic cancer. However, current research indicates that PTT alone is insufficient to trigger a significant abscopal effect and requires combination with immune modulators, such as immune checkpoint inhibitors or immune stimulating cytokines. Interferon-β (IFN-β), a cytokine capable of directly inducing tumor cell death, also exhibits anticancer effects through immune cell modulation. We hypothesized that combining PTT with IFN-β could induce a synergistic response, enhancing the abscopal effect. In a previous study, we developed antibody-conjugated polydopamine (PDA) nanoparticles targeting Claudin-3 (CLDN3), a protein overexpressed in various cancers, including colorectal cancer, to serve as a material for PTT. In addition, we utilized a CLDN3-targeting antibody-IFN-β mutein fusion protein (ABN202, αCLDN3) to enhance the abscopal effect. The objective of this study was to evaluate whether combining PTT with ABN202 (αCLDN3-IFN-β) could synergistically enhance immune cell activation compared to each treatment alone. Moreover, in human interferon receptor 1/2 knock-in mice, the combination effectively inhibited tumor growth at distant sites. It also demonstrated that the efficacy in preventing recurrence when tumor was re-challenged after the treatment. Therefore, these findings suggest that PTT in combined with ABN202 (αCLDN3-IFN-β) is a promising a novel therapeutic strategy for preventing cancer metastasis and recurrence in colorectal cancer. Citation Format: Myeung Ryun Seo, Jinwon Park, Hee Geon Park, Jae Choi, Sang Moo Lee, Sangin Lee, Sae Hyung Lee, Hobin Yang, Sungyoul Hong, Yu-Kyoung Oh, Young Kee Shin. Inducing abscopal effect in colorectal cancer via antibody-conjugated photothermal nanoparticles in combination with immunocytokine [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 4782.
Abstract 3842: ZNF217 promotes breast tumor progression by facilitating angiogenesis
Authors: Ann Dharshika Shangaradas, Parinda Tennakoon, Margaret A. Schwarz, Laurie E. Littlepage
Journal: Cancer Research (2025)

Abstract The transcription factor ZNF217 is amplified in 20-30% of breast cancers and is identified as a putative oncogene. Its overexpression accelerates tumor progression, metastasis, and chemoresistance in vivo and correlates strongly with poor prognosis in patients. To identify growth factors that are released from mammary epithelial cells that overexpress ZNF217, we analyzed the conditioned media from MCF7 cells with or without knockdown of ZNF217 using a 71-Plex Discovery assay. Conditioned media from MCF7 cells deficient for ZNF217 showed a significant downregulation in the secretion of VEGF-A, PDGF-AA, and PDGF-AB/BB and was validated by ELISA in conditioned media from both MCF7 cells and in MDA-MB-231 cells that overexpress ZNF217. VEGF-A, PDGF-AA, and PDGF-AB/BB are key components in promoting angiogenesis, a key hallmark of cancer. RNA sequencing data and qRT-PCR revealed no significant difference in the transcriptional expression of VEGF-A and PDGF-AA/AB/BB after ZNF217 knockdown. To evaluate if the secretion of the identified angiogenic factors promotes endothelial cell sprouting, we co-cultured endothelial progenitor cells with the conditioned media from MCF7 cells ± siZNF217. Endothelial cells treated with media from MCF7 ± siZNF217 induced a sprouting phenotype in endothelial cells grown in conditioned media from ZNF217 expressing cells compared to knockdown cells. Together, these data suggests that ZNF217 is a promotor of VEGF-A secretion and promotion of angiogenic phenotypes in endothelial cells. We also evaluated the role of ZNF217 in the expression of the VEGFR-2 signaling. Knockdown of ZNF217 also decreased the expression of KDR (VEGFR-2 receptor for VEGF-A) in MCF7 cells, suggesting a potential autocrine signaling role for VEGF-A in the cancer cells. Single cell RNA sequencing data of mammary tumors derived from orthotopic injection of PyMT±Zfp217 revealed an increased population of endothelial cells in FVB mice injected with Zfp217 overexpressing cells compared to vector expressing control cells. These findings highlight a novel role for ZNF217 as a promoter of angiogenesis during breast cancer progression. Thus, unravelling the mechanisms of ZNF217-mediated angiogenesis will be an instrumental step in determining if anti-angiogenic therapies are an effective and novel strategy used to overcome metastatic growth in breast cancer patients with tumors that overexpress ZNF217. Citation Format: Ann Dharshika Shangaradas, Parinda Tennakoon, Margaret A. Schwarz, Laurie E. Littlepage. ZNF217 promotes breast tumor progression by facilitating angiogenesis [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 3842.
Abstract 3826: Awakened dormant cancer cells undergo highly mesenchymal to quasi-mesenchymal transition and acquire stemness
Authors: Jingwei Zhang, Robert Allan Weinberg
Journal: Cancer Research (2025)

Abstract The awakening of dormant disseminated cancer cells is likely responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, non-proliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, inflammation of the surrounding tissue microenvironment causes them to shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire stemness and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their stemness, doing so without ongoing heterotypic signaling from the lung microenvironment. EGFR ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse. Citation Format: Jingwei Zhang, Robert Allan Weinberg. Awakened dormant cancer cells undergo highly mesenchymal to quasi-mesenchymal transition and acquire stemness [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 3826.
Abstract 4230: Preclinical characterization of ATG-042, a novel MTAP null-selective PRMT5 inhibitor
Authors: Ya Kong, Ge Lin, Ming Zhang, Peng Chen, Jay Mei, Bing Hou
Journal: Cancer Research (2025)

Background: Targeting the PRMT5-MTA complex has become a promising strategy for treating MTAPnull cancer in a synthetically lethal manner, avoiding on-target-off-tumor hematological toxicity when using first-generation, non-selective PRMT5 inhibitors. The MTAP gene is deleted in around 10-15% of all human malignancies and the top3 human cancers with the highest frequency of MTAP deletion are GBM, pleural mesothelioma and bladder cancer with high unmet medical need (TCGA data). Herein, we report the preclinical feature of ATG-042, a novel MTAPnull-selective PRMT5 small molecule inhibitor with good brain penetration. Methods: The in vitro activity and MTAP selectivity of ATG-042 on cell proliferation were profiled using HCT116 MTAP wild type (wt) cells, HCT116 MTAP knock out (ko) cells and multiple endogenous MTAPnull cell lines. The in vivo efficacy was tested in cell derived xenograft (CDX) mouse models with HCT116 MTAP wt cells, HCT116 MTAP ko cells, LU99 cells (MTAPnull) and U87MG-luc (MTAPnull). The pharmacokinetic and toxicological properties were assessed with corresponding assay methods. Results: ATG-042 demonstrated potent and selectively inhibitory effect on HCT116 MTAP ko cells’ proliferation (IC50=52nM) and SDMA expression (IC50=0.06nM), but very weak effect on HCT116 MTAP wt cells. Consistently, ATG-042 showed excellent anti-proliferative activities on multiple endogenous MTAPnull cell lines with IC50 values between 10nM and 100nM. ATG-042 demonstrated high permeability (Caco2 assay, A to B, Papp =12.2 x10-6cm/s;ER=0.9), good metabolic stability, and low risk of drug-drug interaction. In vivo PK study shows that ATG-042 is well absorbed, with a dose-dependent increase in plasma distribution and high oral bioavailability in mice, SD rats and beagle dogs. Furthermore, ATG-042 is brain-penetrable (B/P ratio=51% in mice; KPuubrain=0.73 in rats). ATG-042 showed robust in vivo efficacy in both subcutaneous CDX models (HCT116 -MTAP ko, LU99) and orthotopic CDX model (U87MG-luc) as a single agent. In addition, ATG-042 also exhibited the potential in combination with other drugs for antitumor therapy. ATG-042 was well tolerated in both SD rats and beagle dogs after four weeks of continuous administration. Conclusions: In summary, ATG-042 is an oral MTAP null-selective PRMT5 inhibitor with potent efficacy against MTAPnull tumor. It also demonstrated good tolerability and brain penetrability. Citation Format: Ya Kong, Ge Lin, Ming Zhang, Peng Chen, Jay Mei, Bing Hou. Preclinical characterization of ATG-042, a novel MTAP null-selective PRMT5 inhibitor [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 4230.
Abstract 3609: The impact of household smoky coal and 5-methylchrysene exposures on oxidative damage
Authors: Wei Hu, Jason Yy Wong, Batel Blechter, Lützen Portengen, George S. Downward, Yongliang Zhang, Mohammad Rahman, Bryan Bassig, Jun Xu, Jihua Li, Dean H. Hosgood, Lauren Hurwitz, Nathaniel Rothman, Roel C. Vermeulen, Qing Lan
Journal: Cancer Research (2025)

Abstract Background: Household air pollution (HAP) is a significant global health burden. In Xuanwei, China, never-smoking women experience the highest lung cancer rates worldwide, primarily due to the domestic use of smoky (bituminous) coal for heating and cooking. Our previous studies in this region identified methylated polycyclic aromatic hydrocarbons (PAHs), particularly 5-methylchrysene (5-MC), as potential significant contributors to lung cancer risk. 8-oxoguanosine (8-oxoGsn), a product of oxidative damage to RNA, has been reported a marker of oxidative damage in the body. Here, we examined whether the exposure to smoky coal and 5-MC are related to 8-oxoGsn. Methods: We conducted our analyses in an exposure assessment study in Xuanwei, China, which included 160 never-smoking women, out of which 43 had a repeated measurement. Information on the history of fuel usage was collected using an administered questionnaire. The 5-MC exposures were predicted with validated exposure models. We quantified plasma 8-oxoGsn levels using the Cayman DNA/RNA Oxidative Damage ELISA Kit. Generalized estimating equations (GEE) models were used to analyze the association between coal or 5-MC exposures and 8-oxoGsn levels, accounting for repeated measurements. Models were adjusted for age, body mass index (BMI), and other potential confounders. Results: The current, ever, and lifetime use of smoky coal were associated with increased 8-oxoGsn levels (pg/ml) compared to non-smoky coal use [Mean(SD): 6562(1755) vs. 6106(1269), p=0.021; 6551(1677) vs. 5948(1174), p=0.0023; 6590(1784) vs. 6236(1437), p=0.0082, respectively). Exposure to 5-MC (ng/m3-year) in adulthood was significantly associated with higher 8-oxoGsn levels (pg/ml) [Mean(SD): 5784(970), 6412(1534), 6789(1826) in increasing tertiles of 5-MC, p for trend=0.037]. Conclusion: Our findings suggest that exposure to smoky coal and 5-MC may elevate levels of 8-oxoGsn, formed through oxidative stress, reactive oxygen species production, and nucleic acid damage, which are critical pathways in the pathogenesis of cancer. Citation Format: Wei Hu, Jason Yy Wong, Batel Blechter, Lützen Portengen, George S. Downward, Yongliang Zhang, Mohammad Rahman, Bryan Bassig, Jun Xu, Jihua Li, Dean H. Hosgood, Lauren Hurwitz, Nathaniel Rothman, Roel C. Vermeulen, Qing Lan. The impact of household smoky coal and 5-methylchrysene exposures on oxidative damage [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 3609.
Abstract 3626: Deoxycytidine kinase (dCK) gene expression patterns and racial disparities: Findings from the Multiethnic Cohort study
Authors: Saunjoo Yoon, Sherise Rogers, David Bogumil, Edward Agyare, Renee Reams, Mariana Stern, Seth Ablordeppey, Diana J. Wilke, Bo Han
Journal: Cancer Research (2025)

Abstract Background: Significant disparities exist in pancreatic cancer outcomes across different racial and ethnic groups, with African Americans experiencing disproportionately higher incidence and mortality rates than other ethnic groups. The genetic underpinnings of these disparities, particularly concerning drug metabolism and treatment response, remain poorly understood. Deoxycytidine Kinase (dCK) plays a crucial role in activating nucleoside analogs for pancreatic cancer treatment. Our study aim was to characterize dCK expression patterns across different racial/ethnic groups and evaluate the association between genetic variations in dCK and survival outcomes. Methods: Germline genetic variation was analyzed on a subset of 756 cases in the Multiethnic Cohort (MEC) study. Incident pancreatic cancer cases were identified using SEER state cancer registries. Samples were genotyped across various arrays and imputed to the 1000 genomes reference panel using the Minimac4 algorithm. Imputed data was filtered to SNPs and short indels within the dCK gene coding region. Genetically determined dCK gene expression was estimated using imputed data. Associations between genetic variation and mortality among cases were estimated using Cox proportional hazards regression. Results: Sample characteristics are shown in Table 1 Table 1. Sample Characteristics: (N =756) Race/Ethnicity African-American Japanese-American Latino Native Hawaiian White Cases (n) 129 266 152 76 133 Females (%) 60.5% 59.4% 45.4% 55.3% 47.4% Deaths 122 238 136 67 127 Pancreatic Cancer Deaths 101 207 112 59 111 Person-Months Total 1253 3778 1921 1201 2488 Mean Age at Dx (years) 79.4 79.0 78.4 75.8 77.0 Mean Survival (months) 9.7 14.2 12.6 15.8 18.7 Median Survival (months) 4.1 4.9 5.2 5.5 5.0 . Nine variants from the dCK gene with an imputation quality score of R2 &amp;gt; 0.8 across all samples were highly correlated within each self-reported ethnic group—the highest correlation was among African Americans. There was no association between any variants and pancreatic cancer survival nor interactions between dCK variants dosage and chemotherapy treatment on mortality rate. Conclusions: To further evaluate the potential influence of the variants on survival and mortality, we are testing the protein levels using Immunohistochemistry (IHC) staining and Western blot. Citation Format: Saunjoo Yoon, Sherise Rogers, David Bogumil, Edward Agyare, Renee Reams, Mariana Stern, Seth Ablordeppey, Diana J. Wilke, Bo Han. Deoxycytidine kinase (dCK) gene expression patterns and racial disparities: Findings from the Multiethnic Cohort study [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 3626.
Abstract 7025: Novel Insights into anti-tumor mechanisms of small-molecule ID antagonists
Authors: Sergey Yaklichkin, Yohannes Ambaw, Michelle Saoi, Justin Cross, Robert Benezra
Journal: Cancer Research (2025)

Abstract Inhibitors of Differentiation (ID) proteins (ID1-4), members of the helix-loop-helix (HLH) transcription regulator family, play critical roles in cancer progression and metastasis. Previously, we developed AGX51, a small-molecule ID antagonist, and its more potent derivative, AGX-A, which target ID proteins for degradation. Loss of ID proteins induces reactive oxygen species (ROS) accumulation and promotes lipid peroxidation, leading to non-ferroptotic cell death in breast cancer (BC) cells. This cell death can be rescued by the lipid scavenger alpha-tocopherol, implicating lipid ROS in the mechanism. To investigate changes in lipid composition, we performed non-targeted LC-MS lipidomic profiling of AGX-A-treated BC cells. This analysis revealed significant increases in specific lipid classes, including phosphatidylinositols (PI) (+47.06%), lysolipids (+23.53%), and phosphatidylcholine (PC) (+6.5%) correspondently, indicating a distinct lipidomic signature compared to classical ferroptotic inducers. Importantly, co-treatment with alpha-tocopherol restored lipid composition to basal levels, supporting the hypothesis that non-ferroptotic lipid peroxidation is a key mechanism underlying these changes. Furthermore, combining AGX-A with the general lipase inhibitor Orlistat significantly enhanced its cell-killing effects. Lipidomic profiling of this combination revealed notable increases in triacylglycerol species, which are likely susceptible to lipid peroxidation, amplifying AGX-A's cytotoxic activity. These findings highlight the therapeutic potential of ID antagonists in inducing a unique, non-ferroptotic cell death pathway. By altering lipid metabolism and exploiting lipid peroxidation, ID antagonists represent a promising strategy for targeting aggressive and drug-resistant tumors. Citation Format: Sergey Yaklichkin, Yohannes Ambaw, Michelle Saoi, Justin Cross, Robert Benezra. Novel Insights into anti-tumor mechanisms of small-molecule ID antagonists [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 7025.