tbuckley/cabot-search huggingface dataset:
Abstract 4565: CANARy-TF: an improved copy number and tumor fraction estimator for liquid biopsy applications
Authors: Diego Almanza, Takeshi Sugio, Emily Hamilton, David Kurtz, Maximilian Diehn, Mohammad Shahrokh Esfahani, Ash A. Alizadeh
Journal: Cancer Research (2025)

Abstract Background: Accurate detection of copy number alterations (CNAs) and reliable estimation of tumor fraction from liquid biopsies are crucial for effectively triaging patient samples in large clinical trials. This is particularly vital in scenarios where variant allele frequency (VAF) data is unavailable, yet an estimation of tumor fraction remains necessary. We hypothesize that specific characteristics of circulating free DNA (cfDNA) can enhance the performance of algorithms aimed at detecting CNAs and estimating tumor fraction. Methods: We introduce CANARy-TF (Copy number ANomaly Assessment and RecoverY Tumor Fraction), a novel algorithm designed to accurately identify CNAs and estimate tumor fraction from low-pass whole-genome and off-target sequencing. CANARy-TF utilizes sequencing coverage data to pinpoint amplifications and deletions by comparing samples against a panel of normals. Additionally, it incorporates unique cfDNA features, such as fragment size and shifts in the distribution of wildtype/mutant fragments, to improve tumor fraction estimation. Results: The performance of CANARy-TF was evaluated on a cohort of 23 cfDNA samples from patients with non-small cell lung cancer (NSCLC), alongside 149 cfDNA samples from healthy individuals as a background population. For all samples, tumor-informed VAF data were available. Analysis revealed a strong correlation between true VAF and the estimated tumor fraction by CANARy-TF, with a Spearman’s rho of 0.86 (p-value = 1.38e-07). In silico mixtures representing tumor prevalence from 0.001% to 5% were generated, demonstrating a limit of detection for the algorithm at around 1%. Conclusion: CANARy-TF effectively estimates CNAs and tumor fraction from plasma cfDNA samples. Notably, this algorithm is robust when applied to low-pass whole-genome sequencing, offering an efficient solution for triaging samples in both clinical settings and liquid biopsy studies. Citation Format: Diego Almanza, Takeshi Sugio, Emily Hamilton, David Kurtz, Maximilian Diehn, Mohammad Shahrokh Esfahani, Ash A. Alizadeh. CANARy-TF: an improved copy number and tumor fraction estimator for liquid biopsy applications [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 4565.
Abstract 4176: Targeting KRAS selectively induce metabolic reprogramming in pancreatic cancer
Authors: Matthew Cheung, Laiba Shiekh, Don-Gerard Conde, Chiamaka Ezeh, Zeribe Nwosu
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease largely due to the lack of effective treatments that overcome the tumor drug resistance. Oncogenic KRAS mutations contribute to most PDAC and drive multiple metabolic pathways to promote tumor growth. Despite this predominant role of KRAS, the inhibition of KRAS/MAPK pathway often leads to resistance via mechanisms that remain unclear. Pharmacological inhibition of the KRAS/MAPK pathway produces varying and context-dependent responses in different phenotypes of pancreatic cancer cells. Specifically, while KRAS/MAPK inhibition using drugs such as MRTX1133 and Trametinib suppresses growth in some cell lines, the same treatment induces or does not alter the growth of other cell lines, and selectively impacted cell migration. Metabolic activity was suppressed in cells with inhibited growth but accelerated in cells where KRAS/MAPK inhibition promoted growth. Analysis of gene expression profile of human PDAC and KRAS-driven mouse tumors identified nutrient transporters that are upregulated upon KRAS induction, but further upregulated by KRAS inhibition. Our study reveals context-dependent response to KRAS inhibition in PDAC and suggests targeting nutrient transporters to overcome therapeutic resistance. Laiba Shiekh and Matthew Cheung contributed equally to this work. Citation Format: Matthew Cheung, Laiba Shiekh, Don-Gerard Conde, Chiamaka Ezeh, Zeribe Nwosu. Targeting KRAS selectively induce metabolic reprogramming 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 4176.
Abstract 5058: Evaluation of false positive and false negative errors in targeted next generation sequencing
Authors: Chunghwan Hong, Youngbeen Moon, Hye Won Choi, Eun-Kyung Kang, Jong-Kwang Kim, Young-Ho Kim, Dong-eun Lee, Tae-Min Kim, Seong Gu Heo, Namshik Han, Kyeong-Man Hong
Journal: Cancer Research (2025)

Abstract Background: Next-generation sequencing (NGS) has emerged as a vital diagnostic tool for various diseases; however, errors associated with NGS present significant challenges to its clinical implementation. Specifically, in cancer diagnostics, the analysis of low-level mutations is complicated by contamination from normal cells and tumor heterogeneity. Results: In targeted NGS (T-NGS) analyses involving reference-standard samples consisting of mixtures of homozygous Hydatidiform mole DNA and blood genomic DNA at varying ratios from four certified NGS service providers, we observed considerable variability in both the lower detection limits of variants (16.3-fold difference, ranging from 1.51% to 24.66%) and false positive (FP) error rates (4280-fold difference, ranging from 5.814 × 10^-4 to 1.359 × 10^-7). The commercially available Dragen system for bioinformatics analysis reduced FP errors in results from companies BB and CC; however, inherent errors from the raw NGS data remained. Adjustments to bioinformatics parameters aimed at increasing sensitivity (by less than two times) substantially elevated FP error rates (by 610 to 8200 times). Additionally, we identified issues such as biased base calling during bioinformatics analysis and a high frequency of false negative (FN) errors in HLA regions. Conclusion: T-NGS results from certified NGS service providers reveal considerable variability in sensitivity and FP error rates, underscoring the necessity for enhanced quality control measures in the clinical application of T-NGS. Furthermore, our study suggests that mixtures of homozygous and heterozygous DNA can serve as effective reference-standard materials for T-NGS quality control. Citation Format: Chunghwan Hong, Youngbeen Moon, Hye Won Choi, Eun-Kyung Kang, Jong-Kwang Kim, Young-Ho Kim, Dong-eun Lee, Tae-Min Kim, Seong Gu Heo, Namshik Han, Kyeong-Man Hong. Evaluation of false positive and false negative errors in targeted next generation sequencing [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 5058.
Abstract 5428: Detachment from the extracellular matrix induces loss of the mitochondrial phosphatase PGAM5 in cancer cells
Authors: Matthew Fink, Zachary Schafer
Journal: Cancer Research (2025)

Abstract Cancer cells often experience altered mitochondrial metabolism due to loss of integrin-mediated attachment to the extracellular matrix (ECM). Relatedly, work from our lab has revealed that ECM-detached cells undergo mitophagy, which subsequently results in the activation of cell death pathways. Cancer cells, however, can circumvent the induction of mitophagy during ECM-detachment to promote their viability, however, the mechanisms underlying mitophagy regulation during ECM-detachment remain poorly understood. The mitochondrial phosphatase PGAM5 is a part of a proteinaceous complex that initiates mitophagy during ECM-detachment, but its regulation in this context has not been extensively studied. Interestingly, we find that certain cancer cell lines have an innate ability to reduce the levels of PGAM5 protein when cultured under ECM-detached conditions. We find that this phenomenon is primarily due to alterations in PGAM5 transcription, rather than from alterations in protein stability. Given that ECM-detachment has been previously shown to impair proliferation, we analyzed PGAM5 expression in ECM-attached cells treated with CDK4/6 inhibitors. Our data suggest that expression of PGAM5 is indeed linked to proliferation, as arresting cells in G1 results in decreased PGAM5 expression. We also examined the consequences of reduced PGAM5 on mitochondrial dynamics. Previous research has discovered that PGAM5 dephosphorylates Drp1, a key regulator of mitochondrial fission. Indeed, we observe that decreased expression of PGAM5 (both during ECM-detachment and after treatment with CDK4/6 inhibitors) results in elevated phosphorylation of Drp1, suggesting an increase in mitochondrial fusion in detached and G1 arrested cells are likely. These data collectively support the conclusion that ECM-detachment causes changes in mitochondrial dynamics as a consequence of impaired proliferation and subsequent loss of PGAM5. Citation Format: Matthew Fink, Zachary Schafer. Detachment from the extracellular matrix induces loss of the mitochondrial phosphatase PGAM5 in cancer cells [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 5428.
Abstract 5461: BG-C477, a novel topoisomerase 1 inhibitor-based ADC, exhibits antitumor activity in carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-expressing preclinical models
Authors: Daochuan He, Yiren Xiao, Zhuo Li, Jie Li, Hongyu Chen, Weijie Li, Huang Yan, Kunji Liu, Yang Lyu, Qingsong Hu, Mengjia Wang, Lai Xu, Zhitao Wan, Xiaomin Song, Yu Shen, Lai Wang
Journal: Cancer Research (2025)

Abstract CEACAM5 (CEA) is a cell surface glycoprotein highly expressed in many cancers, including colorectal cancer (CRC), gastric cancer (GC), lung and pancreatic cancers. BG-C477 is a novel ADC that is composed of a CEACAM5-specific antibody conjugated to Top1i payloads (drug-to-antibody ratio = 8) via a cleavable linker. It remains stable in human plasma and mice blood circulation. BG-C477 showed specific binding to CEA-expressing MKN45 cells and stronger internalization activity compared to anti-CEA DM4 ADC. BG-C477 exhibited robust and CEA-dependent cytotoxicity in cell lines with different CEA expression levels. A potent bystander effect of BG-C477 was observed in co-culture killing assay with mixed CEA-positive MKN45 and -negative HCT116 cells, indicating the potential to treat tumors with heterogeneous CEA expression. In the animal studies, BG-C477 demonstrated potent and dose-associated single-agent efficacy in multiple CEA-expressing cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Moreover, BG-C477 exhibited superior antitumor efficacy in GC and CRC PDX models that anti-CEA DM4 ADC was ineffective. In summary, BG-C477 is a promising CEA targeting ADC with great anti-tumor activity across multiple types of tumors. The first in human study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of BG-C477 is ongoing (NCT06596473). Citation Format: Daochuan He, Yiren Xiao, Zhuo Li, Jie Li, Hongyu Chen, Weijie Li, Huang Yan, Kunji Liu, Yang Lyu, Qingsong Hu, Mengjia Wang, Lai Xu, Zhitao Wan, Xiaomin Song, Yu Shen, Lai Wang. BG-C477, a novel topoisomerase 1 inhibitor-based ADC, exhibits antitumor activity in carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-expressing preclinical 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 5461.
Abstract 2550: Chemotherapy-induced senescence of cancer-associated fibroblasts promotes gastric cancer progression and resistance to chemotherapy
Authors: In-Hye Ham, Yulim Lee, Hur Hoon
Journal: Cancer Research (2025)

Abstract Purpose: Chemotherapies for patients with gastric cancers (GCs) has been shown disappointing results in the clinics. The cancer-associated fibroblasts (CAFs) could be considered one cause of the resistance to chemotherapy in GCs. However, the chemotherapy-induced reprogramming of CAFs and its effects on GC progression and the resistance to chemotherapy has not been elucidated. Methods: IncuCyte and transcriptome were used to identify chemotherapy-induced senescence of CAFs. Screening for drugs to inhibit senescence of CAFs was performed. The cell proliferation and migration assays and phospho-protein array were performed to investigate the effects of senescent CAFs on GC cells. Inhibitory effects of screened drugs on CAFs were also evaluated in experimental models. Senescent CAFs and their clinical meanings were also investigated in the human GC tissues undergoing preoperative chemotherapies. Results: Chemotherapy could alleviate proliferation and widen cytoplasm of CAFs. Some secretory molecules like TNF-α were upregulated in the CAFs with chemotherapy. Chemotherapy-treated CAFs increased the resistance to chemotherapy and the migratory potentials of GC cells. The COX2 inhibitor, one of the screened drugs, has inhibitory effect on chemotherapy-induced senescence CAFs. Consequently, it could suppress GC progression and resistance to chemotherapy. The GC patients with senescent CAFs were significantly correlated with poor histologic response to chemotherapy. Conclusions: In this study, we are convinced that the chemotherapy-induced senescence of CAFs could have a significant effect on progression and resistance to chemotherapy in GC. Inhibitory drugs for chemotherapy-induced senescence of CAFs could be used to overcome the CAF-induced resistance to the chemotherapy in GCs. Citation Format: In-Hye Ham, Yulim Lee, Hur Hoon. Chemotherapy-induced senescence of cancer-associated fibroblasts promotes gastric cancer progression and resistance to chemotherapy [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 2550.
Abstract 4302: Loss of carnitine acyl-carnitine carrier induced tumor regression by mTOR inactivation
Authors: Joon Hee Kang, Ho Lee, Sang Myung Woo, Wonyoung Choi, Sung Hoon Sim, Jung Won Chun, Soo-Youl Kim
Journal: Cancer Research (2025)

Purpose: We found that most ATP production in cancer cells depends on fatty acid oxidation (FAO). However, the direct link between FAO and cancer promotion has not been interpreted. Therefore, we propose that blocking FAO in cancer may prevent pancreatic cancer growth promotion by blocking its ATP production. Experimental Design: To block FAO, CAC (carnitine-acylcarnitine carrier, gene: SLC25A20) in the mitochondria inner membrane was knocked down in cancer cells, which was implanted for xenograft in mice. To compare cancer development, survival rates and histopathological differences were analyzed with KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) and KPC/Cac+/- mice. Results: By CAC knockdown, the cancer cells reduced ATP production and decreased cell growth. Proteomic analysis showed that CAC knockdown significantly reduced cancer cell growth following mTOR inactivation by reduced ATP production, consequently leading to cell death. Xenografts using CAC knockdown PDAC cells showed up to 80% decrease of tumor growth compared to the control. Furthermore, the median survival of KPC/Cac+/- mice was increased by 3.1 weeks compared to KPC mice. Conclusion: Blocking FAO by CAC knockdown significantly suppressed tumor growth by mTOR inactivation through ATP depletion in pancreatic cancer cells. mTOR inactivation by CAC knockdown, consequently, decreased levels of cyclin D and PARP, which were followed by cell cycle arrest and cell death. Thus, even if signal transduction is induced by various growth receptors, mTOR cannot be activated when ATP levels fall below the Km value. Funding source: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to SK (NRF-2019M3A9G1104345) and by a grant from the National Cancer Center of Korea to WC (NCC 2410891-1) and JWC (NCC 2410892-2). Citation Format: Joon Hee Kang, Ho Lee, Sang Myung Woo, Wonyoung Choi, Sung Hoon Sim, Jung Won Chun, Soo-Youl Kim. Loss of carnitine acyl-carnitine carrier induced tumor regression by mTOR inactivation [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 4302.
Abstract 4189: CRISPR-edited cell lines targeting key molecular pathways: Accelerating the development of synthetic lethal therapeutics beyond PARP inhibitors
Authors: Yue Huang, Yunpeng Zhai, Yan Feng, Xinyue Jia, Xiaohuan Zhang, Jinying Ning, Feng Hao
Journal: Cancer Research (2025)

Abstract Synthetic lethality (SL) has emerged as a highly promising therapeutic strategy, gaining significant attention in the field of cancer treatment in recent years. The principle behind SL is that the simultaneous loss or inhibition of two genes results in cell death, while the inhibition of only one gene does not. SL drugs exploit this mechanism by targeting the partner gene of an already inactivated or mutated gene in cancer cells, inducing their death. This approach allows for the precise targeting of genetic vulnerabilities specific to cancer cells, sparing normal tissues from damage. Additionally, SL therapies expand the range of druggable targets, including proteins that are difficult to inhibit with traditional small molecules. By affecting both enzymatic and non-enzymatic protein functions, SL therapies reduce the risk of developing drug resistance, providing an effective option for treating cancers that are resistant to conventional therapies.Kyinno offers an extensive collection of knockout cell lines targeting a range of genes associated with synthetic lethality, including SHLD2, P53, T53BP1, AQR, ATRX, SETD2, ATM, WRN, BRCA1, and BRCA2. These cell lines, developed using the CRISPR/Cas9 genome editing technique and validated through sequencing and western blot analysis, are crucial for investigating the complex mechanisms underlying synthetic lethality and for identifying novel therapeutic strategies in cancer treatment. For example, our knockout lines for BRCA1 and BRCA2 enable researchers to investigate vulnerabilities in homologous recombination repair, paving the way for the development of innovative PARP inhibitors and targeted therapies. Additionally, lines with deletions in ATM and WRN provide essential insights into DNA damage response pathways, which can enhance the effectiveness of DNA-damaging agents. The diverse range of gene knockouts, including those involved in cell cycle regulation, DNA repair, and apoptosis, allows for comprehensive studies into the synergistic effects of dual gene inhibition. By utilizing our extensive library of synthetic lethality cell lines, researchers can effectively validate hypotheses, screen novel drug candidates, and optimize combination therapies to improve outcomes for patients with resistant cancers. We highly recommend these resources for advancing research in synthetic lethality and targeted cancer therapies. Citation Format: Yue Huang, Yunpeng Zhai, Yan Feng, Xinyue Jia, Xiaohuan Zhang, Jinying Ning, Feng Hao. CRISPR-edited cell lines targeting key molecular pathways: Accelerating the development of synthetic lethal therapeutics beyond PARP inhibitors [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 4189.
Abstract 5312: Murine syngeneic tumor model characterization by ultrahigh-plexed immunofluorescence imaging
Authors: Jaimee Wong, Ngan Doan, Andrew Woolley, Anandi Sawant, Shilpa Keerthivasan, Sunitha Bachawal, Jennifer Sahni, Nicholas Wilson, Amanda Mikels Vigdal, Xiaoyun Liao
Journal: Cancer Research (2025)

Abstract Murine syngeneic tumor models are widely used tools to demonstrate efficacy and the mechanism of novel anticancer immunotherapies. Each model is likely to have a unique tumor microenvironment (TME) with immune cells, fibroblasts, endothelial cells and extracellular matrix that may reflect a variety of TME profiles in humans. Baseline characterization of tumor TME features of each model paired with therapy-based mechanistic studies can confirm pharmacodynamic (PD) biomarker hypotheses and inform combination strategies. However, a comprehensive dataset of TME compositions and spatial information is unavailable. PhenoCycler is an ultrahigh-plexed spatial biology imaging platform that can detect up to 100 markers on formalin fixed paraffin embedded (FFPE) sections at a single cell resolution using cyclic detection of DNA-conjugated antibodies. Very few publications have used Phenocycler technology to image murine FFPE tissues. In this study, we constructed a FFPE tissue microarray (TMA) block that includes 12 commonly used preclinical murine models of breast, colon, lung, pancreatic ductal, renal and bladder carcinomas with duplicate cores, and built a 29-marker panel to characterize the complexity of the TME of these models. Our data showed distinct TMEs in the different models and cell-cell interactions that differed depending on the tumor type examined. For instance, Py2T and Pan02 are cancer associated fibroblast (CAF) and macrophage enriched tumors whereas MC-38 tumors have low levels of CAF and T cell infiltration. Based on these analyses, the EMT6 tumor model, an immunocompetent triple negative mammary carcinoma with adequate extracellular matrix, was selected for an in vivo pharmacology study for a novel anti-stroma immunotherapy. Evaluation of whole tissue tumor samples from the study revealed significant increases in CD8+ T cell infiltration and a reduction of COL1A1 expression in treated tumors compared to vehicle group tumors consistent with antitumor efficacy. Our study demonstrated that ultrahigh-plexed immunofluorescence imaging is a powerful technology that can efficiently assist in vivo model selection and support biomarker discovery, especially in combination with a TMA section that can include multiple tumor models. Citation Format: Jaimee Wong, Ngan Doan, Andrew Woolley, Anandi Sawant, Shilpa Keerthivasan, Sunitha Bachawal, Jennifer Sahni, Nicholas Wilson, Amanda Mikels Vigdal, Xiaoyun Liao. Murine syngeneic tumor model characterization by ultrahigh-plexed immunofluorescence imaging [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 5312.