tbuckley/cabot-search huggingface dataset:
Abstract 5400: SEPHS2 loss reprograms glucose metabolism to activate the pentose phosphate pathway by stabilizing PCK1 through NAD(+)
Authors: Yihuizhi Zhang, Qinhua Zhang, Weibo Zhang, Weijian Ding, Baotong Zhang, Siyuan Xia
Journal: Cancer Research (2025)

Abstract Selenium is an essential trace mineral that plays a crucial role in metabolism, primarily through its incorporation into selenoproteins. However, whether and how selenium modulates glucose metabolism in cancer cells remains unclear. This study focuses on SEPHS2, a key enzyme in synthesizing selenoproteins, which converts hydrogen selenide into selenophosphate. We found that SEPHS2 knockout inhibits both glycolysis and oxidative phosphorylation (OXPHOS), as indicated by an seahorse assay. Interestingly, SEPHS2 loss redirects more glucose to the pentose phosphate pathway. Mechanistically, SEPHS2 knockout elevates NAD+ levels, which are essential for SIRT2/3 enzymatic activity. The increase in the activity of SIRT2/3 leads to deacetylation of PCK1, a posttranslational modification required to prevent PCK1’s ubiquitination and subsequent degradation. Thus, SEPHS2 knockout stabilizes PCK1 by reducing its ubiquitination. Since PCK1 is a key regulator of gluconeogenesis, SEPHS2 knockout promotes gluconeogenesis while reducing cellular glucose uptake, suppressing glycolysis, down-regulating oxidative phosphorylation and enhancing the pentose phosphate pathway. Collectively, our findings define the selenium-metabolizing enzyme SEPHS2 as a key regulator of glucose metabolism, guiding cancer cells in choosing between glycolysis and the pentose phosphate pathway. This study offers valuable insight into the essential role of selenium metabolism in maintaining glucose homeostasis. Citation Format: Yihuizhi Zhang, Qinhua Zhang, Weibo Zhang, Weijian Ding, Baotong Zhang, Siyuan Xia. SEPHS2 loss reprograms glucose metabolism to activate the pentose phosphate pathway by stabilizing PCK1 through NAD(+) [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 5400.
Abstract 7055: An IL1RAP ADC is efficacious in distinct oncofusion-driven pediatric cancers
Authors: Haifeng Zhang, Wei Li, Xiaqiu Yang, Qingfeng Huang, Yue Zhou Huang, Alberto Delaidelli, Andrew Lytle, Melanie Rouleau, Christian Steidl, Dimiter Dimitrov, Poul Sorensen
Journal: Cancer Research (2025)

Abstract Our recent studies identified the cell surface protein IL-1 receptor accessory protein (IL1RAP) as a crucial regulator of redox homeostasis and a suppressor of ferroptosis (iron-mediated cell death) in Ewing sarcoma (EwS). IL1RAP directly binds to the CD98/xCT plasma membrane antiporter to enhance cystine uptake, thereby replenishing cysteine and glutathione (GSH) pools in EwS cells. Moreover, when extracellular cystine is limited, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration (TSS) pathway for de novo cysteine synthesis. IL1RAP depletion diminishes GSH pools and induces oxidative stress to trigger anoikis and ferroptosis, thereby inhibiting EwS metastatic capacity. Importantly, IL1RAP is minimally expressed in normal tissues, including blood and bone marrow, with placenta as the only normal tissue to express IL1RAP, nominating this protein as a promising immunotherapy target. Here, we uncover that distinct fusion oncoproteins activate IL1RAP expression in cancers of different lineages, including EWS-ETS fusions in Ewing sarcoma (EwS), the ETV6-NTRK3 fusion in diverse tumor types, and the NPM-ALK fusion in anaplastic large cell lymphoma (ALCL). To target IL1RAP in these cancers via immunotherapy, we identified a highly specific IL1RAP binder from phage-display biopanning, and engineered an IL1RAP-directed human IgG based antibody-drug conjugate (ADC; X12-IL1RAP-PBD) linked to the DNA damaging agent, pyrrolobenzodiazepine (PBD). In proof-of-concept studies, our proprietary X12-IL1RAP-PBD induced potent DNA damage, apoptosis, and bystander cell killing in in vitro. In preclinical mouse models, X12-IL1RAP-PBD induces dramatic and durable regression of tumor xenografts expressing of the oncofusions at dosing of only 0.2mg/kg. Moreover, essentially no signs of toxicity were noted, with stable body weights and no histological evidence of toxicity in vital organs such as liver, lung, kidney, and brain. Moreover, X12-IL1RAP-PBD fully blocked tail vein injected EwS cell-induced liver changes in vivo, again without any toxicity. Thus, this first-in-class IL1RAP-targeting ADC is highly efficacious in preclinical models of multiple oncofusion-driven cancers, warranting further clinical translation. Citation Format: Haifeng Zhang, Wei Li, Xiaqiu Yang, Qingfeng Huang, Yue Zhou Huang, Alberto Delaidelli, Andrew Lytle, Melanie Rouleau, Christian Steidl, Dimiter Dimitrov, Poul Sorensen. An IL1RAP ADC is efficacious in distinct oncofusion-driven pediatric cancers [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 7055.
Abstract 6974: Identification of a potent KRAS (ON) inhibitor with selectivity for mutant KRAS over HRAS and NRAS
Authors: Keith Koch, Kim Alley, Karyn Bouhana, Richard Brizendine, Paul Carlson, Mark Chicarelli, Michelle Crow, Brad Fell, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, John Fischer, Ravi Jalluri, Amber Johnson, Cori Malinky, Macedonio J. Mejia, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Mareli Rodriguez, Leah Salituro, Vinny Scarato, Aaron Smith, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wodd, Yeyun Zhou
Journal: Cancer Research (2025)

Abstract Oncogenic KRAS gene mutations are prevalent across human cancers, including: pancreatic, lung, and colorectal. In the US alone, it is estimated that over 165, 000 cancer patients are affected by KRAS mutations annually. Early successes in the discovery of mutation specific therapeutics for KRAS led to the development of marketed agents adagrasib and sotorasib, which selectively inhibit KRASG12C. While these precision medicines address a critical unmet medical need, they only treat ∼11% of patients with oncogenic KRAS mutations. Recent efforts to address this disparity have resulted in the identification of pan KRAS inhibitors that target all clinically relevant mutations. Herein, a novel preclinical pan KRAS (ON) inhibitor, demonstrating picomolar cellular activity across a panel of prevalent KRAS mutations is highlighted. This lead series exemplar has a differentiated mechanism of action compared to the tri complex multi RAS inhibitors currently in development, with selectivity over HRAS and NRAS. In vivo characterization to be presented includes pharmacokinetics, pharmacodynamics measuring inhibition of pERK, and efficacy in KRAS mutant tumor bearing mouse models. Citation Format: Keith Koch, Kim Alley, Karyn Bouhana, Richard Brizendine, Paul Carlson, Mark Chicarelli, Michelle Crow, Brad Fell, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, John Fischer, Ravi Jalluri, Amber Johnson, Cori Malinky, Macedonio J. Mejia, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Mareli Rodriguez, Leah Salituro, Vinny Scarato, Aaron Smith, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wodd, Yeyun Zhou. Identification of a potent KRAS (ON) inhibitor with selectivity for mutant KRAS over HRAS and NRAS [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 6974.
Abstract 5044: Whole-genome investigation of transcription factors that promote UV damage and mutation
Authors: Bo Chi, Raluca Gordan
Journal: Cancer Research (2025)

Abstract Understanding the spatial distribution of ultraviolet light (UV)-induced damage and mutation across the genome is an important question due to their oncogenic role in melanoma and other cancers. Previous research suggests UV-induced Cyclobutane Pyrimidine Dimer (CPD) damage lesions and mutations are enriched at transcription factor (TF) binding sites, genomic locations where TFs bind to regulate gene expression. However, current studies of the links between observed enrichment and TF activity revolve around individual qualitative studies with a control sample (often naked DNA) representing sequence effects. With many TFs, damaged sites, and other contributory factors, we seek to quantitatively assess the genome-wide relationship between TF activity, damage formation, and mutagenesis. To accomplish this, we designed a distribution-free simulation pipeline to model the baseline effects of the underlying nucleotide sequence on damage and mutation accumulation by connecting TF binding sites, ATAC-seq chromatin accessibility, CPD lesions in cellular and naked DNA, and mutations from melanoma patients. This analysis reveals that CPDs exhibit varying patterns at the binding sites of TFs relative to what would be expected based on sequence context alone. While some TFs show no additional association with CPD damage, others demonstrate either an enrichment or a reduction in CPDs at their binding sites. Specifically, the top TF clusters associated with UV damage enrichment at a position are ETS, NFY, SPI, and MBD2. ETS, in particular, is consistent with previous studies as a suggested damage driver. In contrast, the top TF clusters associated with reduced damage are AP1, CCAAT_CEBP, NR (including NR1H3 and NR1I2), NFY, and IRF. Using a similar simulation approach, we identified that the most damaged positions in most of the top TF clusters had corresponding mutational enrichment. However, NFY, with damage enrichment at a non-mutagenic TT dimer, showed no mutational enrichment. These clusters can serve as a preliminary list for experimental validation of the modulation of UV-induced damage and mutagenesis driven by TF binding. Our findings and further study will reveal novel insights into the role of TFs in DNA damage accumulation and mutagenesis, which may be vital in reducing cancer incidence. Citation Format: Bo Chi, Raluca Gordan. Whole-genome investigation of transcription factors that promote UV damage and mutation [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 5044.
Abstract 4780: Engineered ICAM-1 refractory trastuzumab improves its therapeutic activity against HER2-positive cancers in native and antibody-drug conjugate (ADC) format
Authors: J. Bradford Kline, Luigi Grasso, Nicholas C. Nicolaides
Journal: Cancer Research (2025)

Abstract The ICAM-1 protein has recently been found to bind the CH3 domain of IgG1-type antibodies and suppress their immune effector activity and internalization against ICAM-1 over-expressing cancer cells. Immune effector suppression involves reduced binding of IgG1 to CD16a Fc-γ-activating receptors on NK cells leading to reduced antibody dependent cellular cytotoxicity (ADCC), as well as binding of the complement initiating C1q protein leading to reduced complement dependent cytotoxicity (CDC) via allosteric alteration of the Fc domain. The effect of ICAM-1 on reduced antibody internalization, a requisite for ADC cytotoxicity, due to the physical interaction of the ADC antibody component with cell surface ICAM-1 has shown significant suppression of ADC activity against antigen-positive target cells. To overcome ICAM-1/IgG1 cytotoxic suppression, we identified a consensus motif within the IgG1 CH3 domain when modified leads to ICAM-1 refractory antibodies, thereby restoring maximal immune effector and ADC cytotoxicity of target cells. Here we present the development of an ICAM-1 refractory trastuzumab and its efficacy against HER2 cancer cells over-expressing ICAM-1 in native and ADC format. These data demonstrate the importance of how tumor-produced proteins may negatively impact the cytotoxic effects of tumor-targeting antibodies and offers a novel platform to improve upon the efficacy of antibody-based therapeutics in the presence of immunosuppressive proteins such as ICAM-1. Citation Format: J. Bradford Kline, Luigi Grasso, Nicholas C. Nicolaides. Engineered ICAM-1 refractory trastuzumab improves its therapeutic activity against HER2-positive cancers in native and antibody-drug conjugate (ADC) format [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 4780.
Abstract 5438: Exploring glioblastoma pharmacotherapy with an anti-epileptic drug: Multi-omic insights and tumor xenograft studies
Authors: Anjali Yadav, Shraddha P. Bhutkar, Vikas V. Dukhande
Journal: Cancer Research (2025)

Abstract Glioblastoma multiforme (GBM) remains one of the most aggressive brain tumors, with a 5-year survival rate of only 6%. GBM resistance to standard-of-care therapies underscores the need for novel treatment approaches. Metabolic reprogramming is a promising hallmark of cancer, indicating a therapeutic avenue. Lactate dehydrogenase (LDH) is upregulated in GBM and adversely affects the survival of GBM patients. In this study, we investigated the repurposing potential of a putative LDH inhibitor Stiripentol (STP), an FDA-approved anti-epileptic drug, to inhibit GBM progression. Using various in vitro biological assays and 3D spheroid assays, STP treatment demonstrated a reduction in GBM cell viability and growth. However, the precise mechanism of STP’s anticancer activity remains unclear. We aimed to elucidate STP's molecular mechanism and metabolic alterations underlying its anticancer activity in GBM. Additionally, we studied the efficacy of STP through in vivo tumor xenograft model. We adopted a multi-omics approach consisting of transcriptomics and metabolomics coupled with bioinformatic analyses. Our results from transcriptomics showed significant alterations in genes such as ALDH1A3, SERPINB2, AOX1, FGF1, TRIM22 and others involved in several biological processes such as oxidoreductase activity, extracellular membrane binding and response to DNA damage. Our metabolomic analysis demonstrated highly dysregulated metabolite enrichment in the Warburg effect, pentose phosphate pathway, glycolytic pathway, and homocysteine degradation upon STP treatment. Our metabolic and transcriptomic analysis bridges the mechanistic gap into the oxidoreductive stress and DNA damage response upon STP treatment. Our tumor xenograft studies showed significant efficacy of STP with decreased tumor volume and tumor weight. Our future studies will further elucidate the mechanistic basis of STP effects in GBM. Taken together, our findings suggest that STP has potential as a novel therapeutic lead for GBM that merits further validation and optimization to enhance its efficacy. This research was supported by an award from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R16GM145557 and by funds from the College of Pharmacy and Health Sciences, St. John’s University, NY Citation Format: Anjali Yadav, Shraddha P. Bhutkar, Vikas V. Dukhande. Exploring glioblastoma pharmacotherapy with an anti-epileptic drug: Multi-omic insights and tumor xenograft studies [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 5438.
Abstract 7129: PDL1 expression on immune cells from solid tumor patients: Implications for tumor immunity and immunotherapy
Authors: Angelina Bisconte, Rachel Owen, Jackie Benko, Jorge Pardo, Samantha Splitt, Deb Phippard
Journal: Cancer Research (2025)

Abstract Programmed death-ligand 1 (PD-L1) is a key immune checkpoint molecule that regulates immune responses by binding to PD-1 on T cells, contributing to immune tolerance and suppression. PD-L1 expression in solid tumors has become an important biomarker for evaluating the efficacy of immune checkpoint inhibitors in cancer therapy. Characterization of PD-L1 expression on immune cells, particularly CD8+ T cells, in patients with various solid tumors, including melanoma, non-small cell lung cancer (NSCLC), and breast cancer was performed using cryopreserved peripheral blood mononuclear samples using flow cytometry. In addition to PD-L1, co-expression of markers of T cell activation (e.g., CD69, CD86, Ki67) and exhaustion (e.g., PD-1, LAG3) was analyzed to gain a comprehensive understanding of immune cell status. PD-L1 expression was highly variable across patients within solid tumor indications, with elevated expression found on CD8+ T cells, suggesting an upregulation in response to persistent tumor antigenic stimulation. Furthermore, PD-L1+ CD8+ T cells often co-expressed markers of exhaustion, such as PD-1 and LAG-3, indicating a potential role for PD-L1 in T cell dysfunction and immune evasion. These findings underscore the complexity of PD-L1 expression by immune cells and its role in shaping immune responses in solid tumor patients. Through integrating PD-L1 profiling with other markers of immune activation and exhaustion, this highlights the potential of PD-L1 as a predictive biomarker for immunotherapy response and provides insights into the mechanisms of immune evasion in solid tumor cancers. Citation Format: Angelina Bisconte, Rachel Owen, Jackie Benko, Jorge Pardo, Samantha Splitt, Deb Phippard. PDL1 expression on immune cells from solid tumor patients: Implications for tumor immunity and immunotherapy [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 7129.
Abstract 7212: Preclinical analysis of ONC206 and ONC212 with lurbinectedin in pancreatic cancer
Authors: Tej Tummala, Ashley S. Uruchurtu, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry
Journal: Cancer Research (2025)

Abstract Pancreatic cancer is a devastating disease with a poor five-year survival rate of approximately 12%. Given the poor prognosis of the disease, it is vital to develop novel improved therapeutic regimens. Lurbinectedin is a chemotherapeutic that stalls and degrades RNA Polymerase II after binding to guanine-rich sequences in the minor groove of DNA, stalling transcription and inducing single- and double-stranded DNA breaks. Our group recently described lurbinectedin’s potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines. Our group also recently described a synergistic interaction between lurbinectedin and imipridone ONC201/Dordaviprone, an anticancer compound that induces the TRAIL apoptotic pathway, in small cell lung cancer cell lines. We now demonstrate that a combination of lurbinectedin and ONC212, a chemical derivative of ONC201, results in highly efficient and synergistic killing of pancreatic tumor cells in vitro. Under combinatorial conditions, cells seemingly exhibit an upregulation of DR5 and γH2AX and a downregulation of ClpX in the presence of ONC212. Future studies will analyze whether a combination of lurbinectedin and ONC212 or lurbinectedin and ONC206, another imipridone and chemical analogue of ONC201, proves more efficient at killing pancreatic tumor cells in vitro. Our results are developing insights into novel combinatorial therapeutic regimens while investigating the molecular mechanisms underlying synergism. Citation Format: Tej Tummala, Ashley S. Uruchurtu, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Preclinical analysis of ONC206 and ONC212 with lurbinectedin in 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 7212.
Abstract 5605: Development of a novel protein phosphatase 2A (PP2A) activator, PPA27, as a potential therapeutic for melanoma
Authors: Hannah Johnson, Amandeep Singh, Asif Raza, Satya Narayan, Arun K. Sharma
Journal: Cancer Research (2025)

Abstract Protein phosphatase 2A (PP2A) is a vital serine/threonine phosphatase acting as a tumor suppressor, often inactivated in melanoma and other cancers. This study builds upon our initial findings on the PP2A activators PPA24 and PPA27, focusing on extended in vitro and in vivo evaluations to assess PPA27's therapeutic potential against melanoma. In our previous work, both compounds demonstrated selective cytotoxicity in melanoma cell lines. Here, we further characterize PPA27’s efficacy across five melanoma cell lines (SK-MEL-2, SK-MEL-28, A375, Mel1241, and 451Lu), showing IC50 values ranging from 3.45-8.94 µM, with consistent effectiveness regardless of BRAFV600E mutation status. Mechanistic analyses revealed that PPA27 induced apoptosis in a dose-dependent manner as confirmed by increased caspase-3/7 activation and PARP cleavage. Notably, PPA27 treatment significantly downregulated phosphorylated ERK1/2, particularly in BRAFV600E-positive A375 cells, suggesting differential modulation of MAPK pathways in mutant and wild-type contexts. To validate these findings in vivo, the efficacy of PPA27 was assessed in xenograft melanoma mouse models. The compound significantly reduced tumor growth compared to control without any apparent systemic toxicity. Additionally, pharmacokinetic and ADMET analyses indicate that PPA27 possesses excellent bioavailability, stability, and metabolic properties, supporting its potential for clinical translation. Furthermore, combinatorial studies suggest that PPA27 enhances the efficacy of existing BRAF inhibitors, potentially addressing drug resistance issues in melanoma therapy. These findings highlight PPA27's robust therapeutic potential and provide new insights into its mechanism of action. In conclusion, our expanded investigation establishes PPA27 as a promising candidate for melanoma treatment, warranting further preclinical studies before consideration for clinical trials targeting both BRAF-mutant and wild-type melanoma subtypes. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Satya Narayan, Arun K. Sharma. Development of a novel protein phosphatase 2A (PP2A) activator, PPA27, as a potential therapeutic for melanoma [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 5605.