tbuckley/cabot-search huggingface dataset:
Abstract LB430: QTX3544, a potent and selective G12V-preferring KRAS inhibitor, synergizes with EGFR inhibitors for enhanced anti-tumor activity
Authors: Yang J. Zhang, Jillian M. Silva, Yang W. Zhang, Elizabeth D. Vo, John M. Micozzi, Arghyotri Sinha, Ben Reid, Brook McDonough, Boyang Zhao, Gregory M. Lee, Christopher C. Pan, Rajsi Thaker, Jennifer Barry, Cameron Pitt, Hong Lin
Journal: Cancer Research (2025)

Abstract The KRAS G12V variant mutation is the second most prevalent oncogenic alteration in KRAS-driven cancers that leads to aberrant activation of the mitogen-activated protein kinase (MAPK) pathway and promotes tumorigenesis and metastasis. Although recent advancements in KRAS-targeted therapies have led to the approval of KRASG12C inhibitors and the clinical investigation of KRASG12D-selective and multi-KRAS inhibitors, there are no current strategies specifically targeting KRAS G12V-driven cancers. QTX3544 is a potent, selective, non-covalent, and orally bioavailable KRASG12V-preferring multi-KRAS inhibitor. QTX3544 inhibited both the “ON-state” (active) and “OFF-state” (inactive) KRAS activity in both biochemical and cellular assays with the most potent activity against KRASG12V and high selectivity over NRAS and HRAS. We examined the potential synergy between QTX3544 and EGFR inhibitors (afatinib and cetuximab) in KRAS G12V-driven cancer cell lines and tumor models. Cell viability assays showed that QTX3544 synergized with EGFR inhibitors and potently inhibited KRAS G12V-mutant cell proliferation. Combined treatment of QTX3544 with afatinib led to a deeper suppression of MAPK signaling and enhanced inhibition of colony formation in KRAS G12V-driven cancer cells compared to single-agent treatment. Co-administration of QTX3544 and cetuximab significantly enhanced anti-tumor efficacy and elicited greater tumor regressions in the Capan-2 pancreatic and SW-403 colorectal KRAS G12V-mutant cell line-derived xenograft models (CDX), as well as in a patient-derived colorectal tumor xenograft model (PDX), compared to monotherapy. Taken together, these preclinical data support the clinical strategy to combine QTX3544 and cetuximab to enhance the depth and breadth of therapeutic activity against KRAS G12V-driven cancers. Citation Format: Yang J. Zhang, Jillian M. Silva, Yang W. Zhang, Elizabeth D. Vo, John M. Micozzi, Arghyotri Sinha, Ben Reid, Brook McDonough, Boyang Zhao, Gregory M. Lee, Christopher C. Pan, Rajsi Thaker, Jennifer Barry, Cameron Pitt, Hong Lin. QTX3544, a potent and selective G12V-preferring KRAS inhibitor, synergizes with EGFR inhibitors for enhanced anti-tumor activity [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 LB430.
Abstract LB318: MYC primes a paralog synthetic lethality involving the mitochondrial transporters TIMM17A and TIMM17B and N-acetylaspartate
Authors: Sydney M. Moyer, Nina Ilic, Sydney Gang, Jasmine Stavridi, Gaia Taig, Joseph D. DeAngelo, Andrea Jiang, Brian H. Shim, Jonathan P. Rennhack, Melis A. Akinci, Jonathan So, Helen Wang, Federica Piccioni, Jessica A. Talamas, David E. Root, William C. Hahn
Journal: Cancer Research (2025)

Abstract To identify genes and pathways required for the survival of MYC-amplified cancers, we engineered and screened at genome scale an isogenic cell system where transformation is driven by oncogenic MYC. We found that the mitochondrial membrane transporter, TIMM17A, was uniquely essential for survival of MYC-transformed cells. This dependency arises due to MYC-driven suppression of TIMM17B, the paralog of TIMM17A. TIMM17A/B is an essential component of the mitochondrial TIM23 transporter complex, and MYC-induced suppression of TIMM17B creates a strong dependency on TIMM17A. N-acetylaspartate supplementation rescues TIMM17A dependency in MYC-amplified cell lines, highlighting the unique and crucial role of this metabolite in the viability of MYC-amplified cancers. These observations identify a paralog dependency required for the survival of a subset of MYC-driven cancers. Citation Format: Sydney M. Moyer, Nina Ilic, Sydney Gang, Jasmine Stavridi, Gaia Taig, Joseph D. DeAngelo, Andrea Jiang, Brian H. Shim, Jonathan P. Rennhack, Melis A. Akinci, Jonathan So, Helen Wang, Federica Piccioni, Jessica A. Talamas, David E. Root, William C. Hahn. MYC primes a paralog synthetic lethality involving the mitochondrial transporters TIMM17A and TIMM17B and N-acetylaspartate [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 LB318.
Abstract LB307: Epigenetic age in normal breast tissues and its association with breast cancer risk factors
Authors: Amarnath Singh, Joseph P. McElroy, Daniel Y. Weng, Sarah A. Reisinger, Cheryl Thompson, Freudenheim L. Jo, Peter G. Shields, Min-Ae Song
Journal: Cancer Research (2025)

Abstract Background: Chronological age is the most well-established risk factor for breast cancer; 80% of women diagnosed with breast cancer are aged 45 or older. This strong association is likely the result of age-related alteration in biological processes, including cellular senescence, telomere attrition, and epigenetic alteration, including DNA methylation. DNA-methylation-based age (mAge) estimates reflect biological age, and mAge provides insights into cumulative exposure to cancer risk factors, but there is limited understanding of how epigenetic age in normal breast tissue is related to breast cancer risk factors, including biological and epidemiological risk factors. Methods: We evaluated well-established DNA methylation age (mAge) estimates in the breast tissue of 91 cancer-free women, focusing on the first-generation mAge (Hannum and Horvath), mortality-related mAge (Grim and Pheno), and methylation-based-telomere-lengths (DNAmTL). Biomarkers that are potentially related to breast cancer risks were measured in breast tissue and blood, along with self-reported risk factors, including lifestyle, reproductive history, and family cancer history. Regression models, adjusted for chronological age, race, and body mass index (BMI), were used to estimate associations with a false discovery rate (FDR) at 0.05. Results: Higher BMI is significantly associated with older Hannum-mAge, Horvath-mAge, Grim-mAge, and longer DNAmTL. Grim-mAge and DNAmTL were positively associated with obesity biomarkers (adiponectin, IGF1, and IGFBP3 in breast tissue and blood), and reproductive-related markers (age at menarche and age at first use of oral contraceptives, age at first birth, and age at last birth). Additionally, Horvath-mAge was significantly associated with tissue Ki67, IGF1, and age at first use of oral contraceptives. A family history of breast cancer was significantly associated with shorter DNAmTL. Conclusion: We found associations between epigenetic age and various biological and epidemiological factors of breast cancer risk. Our findings support further studies to examine whether mAge, particularly Grim-mAge and DNAmTL, in normal breast tissue can predict the incidence of breast cancer and potentially can serve as a biomarker for personalized intervention, given that DNA methylation can be modified through lifestyle changes. Citation Format: Amarnath Singh, Joseph P. McElroy, Daniel Y. Weng, Sarah A. Reisinger, Cheryl Thompson, Freudenheim L. Jo, Peter G. Shields, Min-Ae Song. Epigenetic age in normal breast tissues and its association with breast cancer risk factors [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 LB307.
Abstract LB345: NANOME: A Nextflow pipeline for haplotype-aware allele-specific consensus DNA methylation detection by nanopore long-read sequencing
Authors: Yang Liu, Ziwei Pan, Christina Chatzipantsiou, Emma Wade, Thatcher Slocum, Lasya Karuturi, Yue Zhao, Shilpita Karmakar, Sheng Li
Journal: Cancer Research (2025)

Abstract Nanopore long-read sequencing has expanded the capacity of long-range, single-base, and single-molecule DNA-methylation (DNAme) detection and haplotype-aware allele-specific epigenetic phasing. Previously, we benchmarked and ranked the robustness of seven computational tools for DNAme detection using nanopore sequencing. Overall, the top performers were Megalodon, Nanopolish, DeepSignal and Guppy. However, these algorithms exhibit lower performance at regions with discordant non-singleton DNAme patterns, intergenic regions, low CG density regions, and repetitive regions compared to genome-wide region. Furthermore, long-read sequencing analysis of mammalian genomes requires higher computational resources than next-generation sequencing. To address these issues, we developed NANOME, the first cloud-compatible, Nextflow-based container environment for consensus DNAme detection. We designed a consensus DNAme predictive model using XGBoost, which integrates the output of Megalodon, Nanopolish, and Deepsignal for analyzing data obtained using Oxford Nanopore Technologies (ONT). The consensus model enhanced DNAme detection at single-base resolution by 12% (mean square error) and improved accuracy at single-molecule resolution by 3% (F1-score accuracy) for human B-lymphocyte cell lines (NA12878 and NA19240). The consensus model also detected ∼200,000 more CpGs than Nanopolish. Combing variant calling and long-read phasing, NANOME can detect haplotype-aware allele-specific DNAme in known imprinting controls. We conducted haplotype-aware methylation detection on the T2T genome for dataset NA12878, revealing significant variations in DMR density between gap and non-gap regions, with notable higher densities in gap regions of chromosomes 2, 10, and 20. Overall, NANOME represents a significant step forward in DNAme detection and long-range epigenetic phasing, offering a robust and accessible tool for researchers studying the epigenome. Citation Format: Yang Liu, Ziwei Pan, Christina Chatzipantsiou, Emma Wade, Thatcher Slocum, Lasya Karuturi, Yue Zhao, Shilpita Karmakar, Sheng Li. NANOME: A Nextflow pipeline for haplotype-aware allele-specific consensus DNA methylation detection by nanopore long-read sequencing [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 LB345.
Abstract LB451: Leukemia associated RhoGEF (LARG/ARHGEF12) phosphorylation at S1288 induces LARG plasma membrane localization and its ability to bind RhoA
Authors: Steven D. Scahill, Won Seok Yang, Joe Ramos
Journal: Cancer Research (2025)

Abstract Leukemia-associated RhoGEF (LARG) is a guanine nucleotide exchange factor (GEF) known for its specificity towards RhoA. LARG plays a crucial regulatory role in various cellular processes such as migration, proliferation, invasion, and metastasis by facilitating the exchange of GDP to GTP on RhoA. Activation of LARG at S1288 through phosphorylation by active RSK2 is key to triggering RhoA activation. However, the precise mechanism through which this phosphorylation event influences LARG and enhances the activation of the LARG-RhoA complex at S1288 remains unclear. Herein, we present findings demonstrating the essential role of S1288 phosphorylation in facilitating LARG-mediated invasiveness in response to Epidermal Growth Factor (EGF). Upon EGF stimulation, phosphorylation of LARG at S1288 is triggered by the activation of RSK2, thereby promoting the membrane translocation of LARG. Furthermore, phosphorylation of LARG at S1288 markedly enhances the assembly of the LARG-RhoA complex and RhoA activity. Analysis of patient-derived Glioblastoma Multiforme (GBM) cell lines and GBM tissue samples revealed a significant correlation between RSK activity, LARG S1288 phosphorylation and RhoA-GTPase activity. Elucidating the regulatory mechanisms governing this process is crucial for the development of targeted therapeutic interventions. Citation Format: Steven D. Scahill, Won Seok Yang, Joe Ramos. Leukemia associated RhoGEF (LARG/ARHGEF12) phosphorylation at S1288 induces LARG plasma membrane localization and its ability to bind RhoA [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 LB451.
Abstract SY21-01: Reprogramming the tumor microenvironment with a single punch- our journey from bench to bedside
Authors: Ping-Chih Ho
Journal: Cancer Research (2025)

Abstract Tumor cells develop various strategies to evade immune surveillance, one of which is the modulation of the metabolic state of the tumor microenvironment (TME). In response to metabolic stress in the TME, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired anti-tumor immunity, as intratumoral regulatory T cells (Tregs) exhibit increased survival and suppressive activity, while CD8+ T cells become more susceptible to ferroptosis and exhaustion. Here, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkey. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust anti-tumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCCs). Notably, PLT012 also reprograms immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 effectively reprograms anti-tumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Citation Format: Ping-Chih Ho. Reprogramming the tumor microenvironment with a single punch- our journey from bench to bedside [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 SY21-01.
Abstract SY14-02: Mapping synthetic lethal interactions at scale: A functional genomics approach to cancer therapeutic discovery
Authors: Francisca Vazquez
Journal: Cancer Research (2025)

Abstract The Cancer Dependency Map (DepMap) is an ongoing initiative to identify and explore synthetic lethal targets, by systematically linking tumor molecular alterations to gene dependencies and drug sensitivities. The resource used by scientists worldwide has significantly contributed to both basic and translational cancer research and has provided the community with a landscape view of synthetic lethal targets. Numerous targets identified through DepMap are actively under investigation, with several already advancing into clinical trials, highlighting their clinical relevance and potential. For instance, we recently discovered a synthetic lethal interaction involving the PELO-HBS1L and SKI complex, both involved in mRNA quality control. PELO is a promising synthetic lethal target in cancers with SKI complex deficiencies, such as those with FOCAD deletions or high microsatellite instability. Despite the progress, much work remains to fully exploit cancer dependencies. We have integrated next-generation patient-derived models, including organoids and neurospheres grown in 3D to better represent various cancer subtypes. Additionally, we used di-genic screening libraries to uncover synthetic lethal dependencies previously masked due to paralog redundancy. We are also actively expanding multi-omics datasets and building computational features that will enable the identification of novel molecular links to synthetic lethal dependencies. DepMap continues to grow with the ultimate goal of creating a comprehensive and detailed landscape of cancer vulnerabilities to accelerate precision cancer medicine. Citation Format: Francisca Vazquez. Mapping synthetic lethal interactions at scale: A functional genomics approach to cancer therapeutic discovery [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 SY14-02.
Abstract LB331: Enhanced polygenic risk score for pancreatic cancer
Authors: Samuel O. Antwi, Brandon J. Coombes, Nicholas B. Larson, Erin E. Carlson, Kari G. Rabe, Hunter J. Atkinson, Shounak Majumder, Jun Zhong, David McKean, Brian M. Wolpin, Rachael Z. Stolzenberg-Solomon, Alison P. Klein, Laufey T. Amundadottir, Ann L. Oberg
Journal: Cancer Research (2025)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. mainly because of late-stage diagnosis. Heritable genetic information can improve risk stratification for individuals with moderate to high-risk of PDAC for targeted screening and early detection. We aimed to develop an enhanced polygenic risk score (PRS) for PDAC using a Bayesian approach, LDpred2, that reweights risk estimates attributed to millions of polymorphisms (SNPs) estimated from genome-wide association studies (GWASs). We then compared the performance of LDpred2 with the commonly used genetic risk score (GRS) approach that is based only on genome-wide significant SNPs. Methods: GWAS summary statistics were obtained from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case Control Consortium for 9040 cases and 12496 controls and were used to compute weights for a GRS (17 SNPs) using a p-value threshold of 5e-8 and weights for an enhanced PRS (1.3 million SNPs) using LDpred2. These weights were then used to compute risk scores in an independent validation sample of 2616 cases and 45407 controls from the Mayo Clinic. We used logistic regression to test for associations of the GRS and PRS with PDAC risk, adjusting for age, sex, and the first 10 principal components of ancestry. Results: The validation sample was of mostly European ancestries (&amp;gt;95%). Cases were slightly older than controls (median age: 66 yrs. vs. 63 yrs.) and had a higher frequency of men than controls (57% vs. 42%). Comparisons between the GRS and the PRS are shown in Table 1. DeLong’s test comparing the AUCs between the two genetic scores showed the PRS significantly outperformed the GRS (AUC = 0.68 vs. 0.67; p = 7.6e-7). Conclusions: The LDpred2 PRS model that used a larger set of SNPs significantly improved prediction of PDAC. Comparing the top percentile of the PRS versus the rest showed that the PRS is a clinically significant risk score (OR &amp;gt; 3) for PDAC and could inform clinical decision making and genetic counseling of individuals identified as having a high risk of PDAC. Citation Format: Samuel O. Antwi, Brandon J. Coombes, Nicholas B. Larson, Erin E. Carlson, Kari G. Rabe, Hunter J. Atkinson, Shounak Majumder, Jun Zhong, David McKean, Pancreatic Cancer Cohort &amp; Case Control Consortia (PanScan and PanC4), Brian M. Wolpin, Rachael Z. Stolzenberg-Solomon, Alison P. Klein, Laufey T. Amundadottir, Ann L. Oberg. Enhanced polygenic risk score for pancreatic cancer [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 LB331.
Abstract LB239: Overcoming resistance to camptothecin-based topoisomerase I inhibitors through a novel core scaffold design strategy
Authors: Xiaodan Fu, Yaozong Li, Qilin Wang, Hui Liu, Dongmei Hu, Qun Dang
Journal: Cancer Research (2025)

Abstract Camptothecin (CPT) derivatives as DNA topoisomerase I (TOPO-1) are widely used to treat various cancers. However, their clinical efficacy was significantly undermined by both inherent resistance and the rapid development of emerging resistance. Although resistance mechanisms are complicated, some key factors are identified such as TOPO-1 mutations and drug efflux. Unfortunately, all clinical stage CPT-derived TOPO-1 inhibitors shared the original CPT core structure, thus little chance to address resistance via structural diversity. In this study, we aimed to discover a novel class of non-CPT core TOPO-1 inhibitors that specifically address the key enzyme mutations thus overcoming resistance to current TOPO-1 drugs in the clinic. Using a Computer-Assisted Drug Design (CADD) approach, a non-CPT core scaffold was designed to specifically improve binding to the clinically relevant R364H mutant. Molecules from the novel scaffold performed very well in our computational model showing significantly improved hydrogen bonding and polar interactions with both wild type and R364H mutated TOPO-1. Cellular assay proved that molecules with predicted enhancements led to a 30-fold improvement in inhibitory potency compared to topotecan in the R364H-mutant cell line. Furthermore, the novel compounds exhibited markedly reduced efflux in the BCRP-overexpressing cell lines, maintaining higher intracellular concentrations and thereby enhancing their anticancer activities. More importantly, compared to irinotecan these molecules demonstrated 50 to 1000-fold higher potency in patient-derived, irinotecan-resistant tumor organoid models, thus successfully addressed tumor resistance to current TOPO-1 inhibitors. In vivo antitumor activity was also validated in various PD animal models. A PCC molecule was identified and moved into IND-enabling development, which shows significant promise as next-generation therapies for cancers overcoming resistant to traditional TOPO-1 inhibitors. Recent breakthrough discoveries of ADCs attracted more attention to TOPO-1 inhibitors, however most if not all payloads targeting TOPO-1 still utilized the original CPT core (e.g. DXD, SN-38). Therefore, it is anticipated that ADC treatment will lead to new resistance, and our novel molecules with a non-CPT core could address future resistance via structure diversity. Citation Format: Xiaodan Fu, Yaozong Li, Qilin Wang, Hui Liu, Dongmei Hu, Qun Dang. Overcoming resistance to camptothecin-based topoisomerase I inhibitors through a novel core scaffold design strategy [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 LB239.