tbuckley/cabot-search huggingface dataset:
Abstract 4237: Homogenous detection of O-Acetyl-ADP-ribose as a generic HTS assay method for SIRTs
Authors: Ha Pham, Mahbbat Ali, Anibal Ramos-Martinez, Robert Lowery
Journal: Cancer Research (2025)

Abstract Sirtuins (SIRTs) are deacetylases that catalyze removal of acetyl groups from histones and other proteins; they are important components of the epigenetic regulatory landscape and have been targeted for diverse indications, including cancer. SIRTs deacetylate in an NAD-dependent reaction that yields O-acetyl-ADP-ribose (OAADPr) and nicotinamide as products along with the deacetylated protein. Screening and hit-to-lead efforts targeting SIRTs has been hampered by a lack of robust HTS assays methods for detection of SIRT enzymatic activity, a situation that is exacerbated by the diversity of deacetylated protein products and the inherent instability of the OAADPr product. To address this unmet need, we developed a generic activity assay for SIRTs based on enzymatic conversion of OAADPr to AMP in real time, which is then detected using the Transcreener AMP/GMP assay with a fluorescence polarization (FP) or time resolved Förster resonance energy transfer (TR-FRET) readout. Using recombinant full length Sirt1 and Sirt2, we determined optimal NAD, acetylated peptide substrate, and enzyme concentration for initial velocity detection of deacetylase activity. For both enzymes, a robust signal was observed using concentrations in the nanomolar range, and there was good concordance in activity measured using FP and TR-FRET readouts. The assays were validated for HTS using a 1,280 collection of bioactive compounds. Selected hits were further profiled in dose-response assays. The assay Z’ value was above 0.7, supporting its robustness for screening and hit-to-lead/SAR for Sirt1 and Sirt2 antagonists. To our knowledge, the Transcreener OAADPr assay is the first SIRT activity assay that relies on detection of OAADPr rather than the deacetylated protein product. By enabling homogenous detection of SIRT activity with native acetylated substrates, it should simplify screening and profiling of inhibitors and facilitate drug discovery efforts targeting SIRTs. Citation Format: Ha Pham, Mahbbat Ali, Anibal Ramos-Martinez, Robert Lowery. Homogenous detection of O-Acetyl-ADP-ribose as a generic HTS assay method for SIRTs [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 4237.
Abstract 5083: Investigating the impact of T cell receptor repertoire diversity on cancer outcome
Authors: Naja Lange, Asbjørn Kjær, Randi Istrup Juul, Iver Nordentoft, Lars Dyrskjøt, Nicolai Juul Birkbak
Journal: Cancer Research (2025)

Abstract T cells are key effector cells in the adaptive immune system, playing a central role in the defense against pathogens. However, as we age, T cells undergo functional decline due to immunosenescence, the gradual decay of the immune system with age. This decline negatively affects the function and composition of immune cells, leading to an increased susceptibility to age-related diseases, such as cancer. We hypothesized that characterization of the peripheral blood T cell receptor (TCR) repertoire has the potential to provide insights into the current state of the immune system and serve as a biomarker for cancer progression. To investigate this, we analyzed the peripheral blood TCR repertoire in 5441 non-cancer patients and 450 cancer patients, utilizing sequencing data of the TCR-β chain from multiple cohorts obtained locally and from public sources. In both cancer and non-cancer patients, we observed a decline in the percentage of non-expanded clones, averaging approximately 4.6% (P = 2.15 × 10-8) and 3.5% (P &amp;lt; 2 × 10-16) for every 10-year increase in age, respectively. This decline was accompanied by a proportional increase in the expanded T cell clones with advancing age. Analyses of TCR-β diversity across age groups revealed that, among older individuals, males exhibited lower diversity than females in both non-cancer (P = 4.9 ×10-5) and cancer patients (P = 5.3 × 10-5). Additionally, investigating the relationship between tumor stage and TCR-β diversity showed that lower diversity correlates with more advanced tumor stages. Our results suggest that low TCR diversity represents reduced immune competency and a limited ability to prevent cancer progression. Citation Format: Naja Lange, Asbjørn Kjær, Randi Istrup Juul, Iver Nordentoft, Lars Dyrskjøt, Nicolai Juul Birkbak. Investigating the impact of T cell receptor repertoire diversity on cancer outcome [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 5083.
Abstract 4251: Drugging of ACOD1 is associated with tumor regression in syngeneic tumor models
Authors: Adonia E. Papathanassiu, Weixing Li, Yajie Zhong, Carmen Chak-Lui Wong
Journal: Cancer Research (2025)

Abstract Aconitase decarboxylase 1 (ACOD1, also known as Immune Response Gene or IRG1) is a mitochondrial enzyme responsible for the synthesis of the metabolite itaconate in the TCA cycle of pro-inflammatory macrophages. Utilizing Acod1-/- mice and Acod1 KO cells, recent studies have assigned a cancer-promoting role for ACOD1 and demonstrated its expression in immunosuppressive macrophages, found in the TME of syngeneic tumors (Chen et al, Sci. Adv 2023), and in anti-PD-1 (aPD1)-resistant prostate cells (Schofield et al., Cell Rep 2024). To explore the druggability of ACOD1, we synthesized a series of small MW inhibitors and selected two compounds (ERG344 and its derivative ERG350) for further study. Here, we report that, while both compounds suppress synthesis of itaconate in vitro, ERG350 exhibited a 1000-fold improvement in inhibiting ACOD1 enzymatic activity (IC50 of ∼200 nM) compared to ERG344. Furthermore, both molecules exhibited acceptable pharmacokinetic profiles with half-lives of 8h for ERG344 and 11h for ERG350. Administration of 3 mpk ERG344 as a monotherapy in mice bearing CT26 colon tumors led to complete tumor regression in ∼20% of the animals and partial tumor regression in ∼40% of the animals. Immunophenotyping of ERG344-treated CT26 tumors revealed an increase in the frequency of tumor infiltrating lymphocytes (TILs), especially those expressing the CX3C chemokine receptor 1 (CX3CR1), and an increase in the frequency of mature dendritic cells DC (CD3-CD11b+F4/80-MHCII+CD206-) suggesting that ACOD1 inhibition promotes initiation of an anti-tumor immune response. Increased probability of survival was also observed in the CT26 colon cancer model after daily administration of ERG350 in doses ranging from 0.25 to 3 mpk. The study further reports the effect of ACOD1 inhibition in additional syngeneic models including models of hepatocellular carcinomas Citation Format: Adonia E. Papathanassiu, Weixing Li, Yajie Zhong, Carmen Chak-Lui Wong. Drugging of ACOD1 is associated with tumor regression in syngeneic tumor models [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 4251.
Abstract 3634: Short-term outcomes of breast cancer surgery by race-ethnicity in the Military Health System
Authors: Yvonne Eaglehouse, Sarah Darmon, Matthew Nealeigh, Tracey Koehlmoos, Craig D. Shriver, Kangmin Zhu
Journal: Cancer Research (2025)

Abstract Background: Racial-ethnic differences in receiving breast cancer treatment in the U.S. are well documented and have been partly attributed to access to care. However, little is known about possible disparities in short-term outcomes following breast cancer surgery. This study aimed to compare racial-ethnic groups in experience of post-operative outcomes following breast cancer surgery in the equal access U.S Military Health System. Methods: We identified a cohort of women aged 18 and older diagnosed with stage I-III breast cancer between 2001 and 2014 who received mastectomy without reconstruction for their cancer in the MilCanEpi database. Information on 30-day complications, reoperation, and inpatient admission were captured. Multivariable logistic regression estimated the adjusted odds ratios (AORs) with 95% confidence intervals (CIs) in association with race-ethnicity for the outcomes. Results: Among 886 Asian or Pacific Islander (API), 1,246 non-Hispanic Black (NHB), 497 Hispanic, and 4,898 non-Hispanic White (NHW) women receiving mastectomy for stage I-III breast cancer, the odds of 30-day complications were lower for API (AOR=0.63, 95% CI=0.47, 0.86) and similar for NHB (AOR=0.79, 95% CI=0.62, 1.02) and Hispanic (AOR=0.97, 95% CI=0.70, 1.34) compared to NHW women. The likelihood of reoperation was similar between the racial-ethnic groups. Hispanic women had higher odds of 30-day inpatient admission (AOR=1.55, 95% CI=1.10, 2.17) and the likelihood was statistically similar for API and NHB compared to NHW women. Conclusions: In the equal access Military Health System, API women were less likely and NHB and Hispanic women as likely as NHW women to experience 30-day complications following primary surgical treatment without reconstruction for non-metastatic breast cancer. This highlights the importance of access to care in providing quality surgical care regardless of a patients’ racial or ethnic background. The reason for higher likelihood of 30-day inpatient admission despite similar likelihood of complications among Hispanic women warrants further research. Citation Format: Yvonne Eaglehouse, Sarah Darmon, Matthew Nealeigh, Tracey Koehlmoos, Craig D. Shriver, Kangmin Zhu. Short-term outcomes of breast cancer surgery by race-ethnicity in the Military Health System [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 3634.
Abstract 5898: Investigation of EGFR mutations in lung cancer patients through liquid biopsy analysis
Authors: Pin-fei Wei, Shang-Gin Wu
Journal: Cancer Research (2025)

Objective: Lung cancer is the leading cause of cancer-related mortality in Taiwan as of 2023. Early diagnosis and continuous monitoring are critical for improving patient prognosis. Studies indicate that approximately 50% of lung cancer patients in Asia have EGFR gene mutations. Among patients receiving first- and second-generation targeted therapies, over 50% develop resistance due to T790M gene mutations. The gold standard for lung cancer diagnosis involves pathological tissue examination, including cytological analysis, immunohistochemistry, and genetic testing. Recently, blood-based liquid biopsy for EGFR qPCR gene mutation analysis has emerged as a novel method due to its rapid turnaround time and reduced invasiveness. This study aims to compare EGFR gene qPCR mutation detection via liquid biopsy with tissue biopsy results and assess the clinical utility of liquid biopsy for EGFR qPCR testing. Methods: From March 2018 to April 2020, we collected 416 peripheral blood samples via venipuncture for EGFR liquid biopsy using the Cobas EGFR Mutation Test v2. Simultaneously, corresponding tissue biopsy samples were obtained for EGFR genetic analysis using Sanger or MASS sequencing. We compared results from both testing methods and statistically evaluated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and concordance rate. Results: Among the 416 samples, 280 were from females and 136 from males, aged 32 to 92 years (average age 65). The EGFR mutation test results included: negative (221 cases), deletion in exon 19 (Del 19) (65 cases), L858R (65 cases), Del 19+T790M (34 cases), Del 19+L858R (21 cases), T790M (2 cases), and other mutations (8 cases). Of the 416 cases, 230 lacked available pathological tissue reports for comparison. In the 186 cases with pathology reports, we noted various timing discrepancies between liquid and tissue biopsies. Among 94 patients with both liquid biopsy and tissue biopsy results, the overall concordance rate was 77.7%. Using tissue biopsy as the gold standard, sensitivity, specificity, PPV, NPV, and concordance rates for detecting Del 19, L858R, and T790M mutations were as follows: Del 19 (0.83/1/1/0.86/0.92), L858R (0.67/1/1/0.87/0.89), T790M (0.38/0.93/0.64/0.81/0.79). Conclusion: EGFR liquid biopsy qPCR can be effectively utilized at lung cancer diagnosis and for monitoring drug resistance during targeted therapy. Compared to tissue biopsy, liquid biopsy qPCR using peripheral blood is a less invasive procedure with improved efficacy and an overall concordance rate deemed clinically acceptable. Citation Format: Pin-fei Wei, Shang-Gin Wu. Investigation of EGFR mutations in lung cancer patients through liquid biopsy analysis [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 5898.
Abstract 2251: Non-depleting anti-OX40 antibodies boosts tumor-infiltrating T cells and impairs Tregs without effector T cell depletion
Authors: Cristobal Costoya, Mariela Navarrete, Aniruddh Tyagi, Dafne Franz Demane, Maria Vila de Mucha, Sergio A. Quezada
Journal: Cancer Research (2025)

Abstract While antagonistic antibodies targeting CTLA-4 and PD-1 have demonstrated significant success in cancer immunotherapy, agonistic antibodies such as anti-OX40 have shown limited efficacy. This disparity is potentially due to a lack of understanding of how antibody Fc regions interact with FcγRs on innate immune cells. Anti-OX40 antibodies currently in clinical trials are predominantly human IgG1, a strong FcγR engager. This design assumes differential surface OX40 expression will result in regulatory T cell (Treg) depletion and CD4+ effector T cell (Teff) activation, yet the therapeutic outcomes remain suboptimal. Using transplantable murine cancer models, we compared the efficacy of anti-OX40 isotypes with distinct FcγR-binding affinities. Weak FcγR-binding mouse IgG1 triggered robust pan-T cell activation and expansion within the tumor microenvironment while reducing Treg suppressive capacity and destabilizing their transcriptional program. Conversely, strong FcγR-binding mouse IgG2a resulted in the depletion of both Tregs and Teffs from tumors, compromising therapeutic efficacy. Notably, combining anti-OX40 mouse IgG1 with anti-PD-1 resulted in synergistic responses, achieving nearly 100% complete tumor rejection, while anti-OX40 mouse IgG2a failed to show such synergy. These findings indicate that anti-OX40 antibodies with strong FcγR-binding may hinder optimal anti-tumor activity. A more effective approach could involve using weak FcγR-binding isotypes, which preserve effector T cells while activating agonistic signaling and impairs Treg function, thereby enhancing therapeutic efficacy without off-target effects. Future studies will validate these results in patient-derived tumor models to inform the development of anti-OX40-based therapies. Citation Format: Cristobal Costoya, Mariela Navarrete, Aniruddh Tyagi, Dafne Franz Demane, Maria Vila de Mucha, Sergio A. Quezada. Non-depleting anti-OX40 antibodies boosts tumor-infiltrating T cells and impairs Tregs without effector T cell depletion [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 2251.
Abstract 5074: Estimation of homologous recombination deficiency map from spatial transcriptomics
Authors: Jeongbin Park, Yuchang Seong, Dongjoo Lee, Hongyoon Choi
Journal: Cancer Research (2025)

Background: Homologous recombination deficiency (HRD) is a predictive biomarker for various anti-cancer drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based chemotherapeutic agents. The HRD score has been estimated using genomic and molecular assays, even though due to cancer heterogeneity, HRD could vary in the tumor microenvironment. Here, we developed a model to predict HRD score by estimating copy numbers and calculating loss of heterogeneity (LOH), large-scale state transitions (LST), and telomeric-allelic imbalance (TAI) scores resulting in exhibiting both spatial coherence and heterogeneity, making them suitable for clinical biomarkers addressing tumor heterogeneity. To estimate these scores with counts from ST data, STARCH algorithm was utilized and the copy number for each gene across spots within cancer clones was obtained. HRD scores are determined by adding together LOH, TAI, and LST. We applied these analyses to Visium and VisiumHD data from breast cancer samples and visualized the spatial distribution of the HRD score within the cancer cell map in the tumor microenvironment. Result: This method was applied to both Visium and Visium HD data to show the heterogeneity in the HRD score. The HRD scores effectively reflected spatial patterns and demonstrated high heterogeneity, highlighting their potential as clinical biomarkers. Furthermore, when applied to direct Visium data (Visium FF), the HRD scores predicted using only gene expression data yielded similar conclusions to those calculated considering both gene expression and allele counts. Notably, the concordance between the two approaches was higher when normal spots were not separately input. Additionally, running the analyses separately or collectively produced comparable conclusions. Conclusion: By developing a model to predict HRD scores from ST data, it becomes possible to analyze the relationship between pathophysiological mechanisms and HRD across various cancer types. This approach not only enhances our understanding of tumor biology but also enables the prediction of HRD score maps while accounting for spatial heterogeneity in predictive biomarkers. Such advancements could improve personalized treatment strategies and clinical decision-making for patients. Citation Format: Jeongbin Park, Yuchang Seong, Dongjoo Lee, Hongyoon Choi. Estimation of homologous recombination deficiency map from spatial transcriptomics [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 5074.
Abstract 5980: Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in digestive cancer
Authors: Lélia Polit, Gizem Altay, Mia Cabantous, Anna-Rose Gryspeert, Jérome Cartry, Jacques RR. Mathieu, Sabrina Bedja, Alice Boileve, Michel Ducreux, Sophie Postel-Vinay, Fanny Jaulin, Gustave Ronteix
Journal: Cancer Research (2025)

Abstract Context: Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data, we explore the use of large PDOs collections to characterize ADC efficacy and affinity with the targeted cells through systematic mapping of the relationship between target antigen abundance and payload efficacy. Methods: We have assembled a matched collection of PDOs and transcriptomic data from 135 colorectal (CRC) and pancreatic (PDAC) cancer patients, generated from primary tumour samples and metastatic biopsies. Patients ranged from 31 to 89 years old and had experienced an average of 2.6 lines of treatment prior to the PDO-generating tissue sampling. We used gene expression levels of well-known target antigens such as CEACAM5, HER2, and TROP2 as proxies for protein expression. This data is combined with PDO responses to microtubule and topoisomerase inhibitors, thereby enabling us to explore the relationship between target antigen abundance and payload efficacy. This allows us to generate data-driven hypothesis that were then validated in vitro on a pool of CRC and PDAC PDOs. Results: We identify patient subgroups by combining the RNA expression level and payload efficacy for ADCs against HER2 and CEACAM5. We systematically matched the RNA expression levels and histology for the corresponding proteins. Then we confirmed the response of the PDOs extracted from the tumors of these patients in vitro. We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC and PDAC. Citation Format: Lélia Polit, Gizem Altay, Mia Cabantous, Anna-Rose Gryspeert, Jérome Cartry, Jacques RR. Mathieu, Sabrina Bedja, Alice Boileve, Michel Ducreux, Sophie Postel-Vinay, Fanny Jaulin, Gustave Ronteix. Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in digestive 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 5980.
Abstract 1539: Lactate induced c-Myc lactylation drives prostate cancer progression by influencing gene transcription
Authors: Mithu Howlader, Amos Olalekan Akinyemi, Md Rakibul Alam, Jianlin Wang, Lixiang Gu, Zhiguo Li
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) is a leading cause of cancer-related morbidity and mortality, characterized by complex metabolic reprogramming that supports tumor growth and progression. Recently, lactate has emerged as a critical factor in PCa metabolism, produced via aerobic glycolysis and influenced by oncogene/tumor suppressor gene mutations, androgen signaling, and hypoxia. Glycolytic cancer cells and cancer-associated fibroblasts can secrete lactate, fostering "symbiotic" interactions with oxidative cancer cells through lactate shuttling. Lactate accumulation subsequently promoting the lactylation of proteins which is a novel post-translational modification involving proteins that is induced by lactate. The Warburg effect emphasizes the importance of lactylation in cancer biology, influencing gene transcription and supporting rapid tumor growth. Excessive lactate production and rapid lactate transport in cancer cells are mainly driven by the upregulation of c-Myc which is a master regulator of multiple biological programs. Its persistent activation results in abnormal expression of glycolytic enzymes and lactate transporters, contributing to PCa progression. While c-Myc undergoes various post-translational modifications, the potential for c-Myc lactylation and its role in PCa development remain unexplored. Preliminary studies indicate that sodium lactate exposure increases lysine lactylation in PCa cells. We also show that c-Myc oncogene is lactylated. The lactylation of c-Myc not only promotes tumor growth but also contributes to the metabolic flexibility of PCa, enabling them to thrive in hypoxic and nutrient-deprived environments. Understanding the molecular mechanisms underlying c-Myc lactylation provides new insights into PCa biology and opens potential avenues for therapeutic intervention targeting metabolic pathways. Citation Format: Mithu Howlader, Amos Olalekan Akinyemi, Md Rakibul Alam, Jianlin Wang, Lixiang Gu, Zhiguo Li. Lactate induced c-Myc lactylation drives prostate cancer progression by influencing gene transcription [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 1539.