tbuckley/cabot-search huggingface dataset:
Abstract 2284: Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits
Authors: Younghun Han, Vikram Shaw, Jinyoung Byun, Rikita Hatia, Katherine McGlynn, Lewis Roberts, Manal Hassan, Christopher I. Amos
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of non-viral liver diseases. Genome-wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co-development with non-viral HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between non-viral HCC with 923 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB) cohort. We observed a SNP-array heritability (h2 obs) of 0.20 for non-viral HCC. Next, we estimated the pairwise genetic correlation between non-viral HCC and heritable (h2 obs &amp;gt; 0.02) UKBB traits, identifying significant positive genetic correlations between non-viral HCC and blood-based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between non-viral HCC and diseases associated with metabolic dysfunction-associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Non-viral HCC was negatively associated with filtered coffee intake but positively associated with instant coffee intake. In addition, smoking behavior and the amount of alcohol consumption in the UKBB cohort showed a positive association with non-viral HCC. Our study provides an atlas of cross-trait genetic correlations in non-viral HCC. Taken together, our results demonstrate possible polygenic pleiotropy between non-viral HCC and different phenotypic traits. The results support further exploration of the predictive power of blood-based biomarkers and selected behaviors for inferring HCC development among non-viral individuals. Citation Format: Younghun Han, Vikram Shaw, Jinyoung Byun, Rikita Hatia, Katherine McGlynn, Lewis Roberts, Manal Hassan, Christopher I. Amos. Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits [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 2284.
Abstract 2626: Leveraging FFPE single-nucleus RNA-sequencing for Osteosarcoma
Authors: Danh Truong, Clement Agyemang, Davis Ingram, Alexander Lazar, Valerae O. Lewis, Joseph Ludwig
Journal: Cancer Research (2025)

Abstract Osteosarcoma (OS), a heterogeneous class of bone sarcomas, can be subclassified based on predominant histological features. This molecular heterogeneity cannot fully be resolved with bulk sequencing. However, due to the rarity of several OS subtypes, including low-grade and small-cell, parosteal, periosteal, and high-grade surface, acquiring fresh specimens for single-cell omics is difficult. Logistical challenges exist when acquiring fresh specimens, such as transportation or adequate storage. Here, we leverage archival formalin-fixed paraffin-embedded (FFPE) samples of OS, which are routinely processed and preserved in pathology laboratories. We utilized 10x Flex assay to perform single-nucleus RNA-sequencing (snRNA-seq) from FFPE samples of OS, including osteoblastic OS, chondroblastic OS, low-grade, and periosteal. We compared fixed-frozen to FFPE samples to determine if both methods yielded concordant results. Two 25 μm FFPE scrolls and matched fixed-frozen tissue of approximately 60 mg were dissociated using the gentleMACs Dissociator. After confirming adequate cell count, we performed snRNA-seq on the fixed samples using the 10x Flex assay. Fixed-frozen (5201±3410 cells) had higher cell counts than FFPE (1185±823 cells), which may be attributed to tissue area in the FFPE scrolls. The confidentially mapped reads were similar for fixed-frozen (64%±13%) and FFPE (55%±17%). Higher UMIs and genes were detected in fixed-frozen (8566±110 UMIs and 2342±15 genes detected) than in FFPE (1464±25 UMIs and 835±9 genes detected). Regardless of specimen type, we detected the subtype-specific gene expression. Fixed-frozen and FFPE specimens of osteoblastic OS expressed osteoblastic markers, SPP1, CHD11, and IBSP. Chrondroblastic markers (SOX9 and ACAN) were expressed in both conditions for chondroblastic OS. Significantly, CDK4 and MDM2 were overexpressed in low-grade OS due to the amplification of CDK4 and MDM2 copy numbers, confirmed by CopyKAT and inferCNV. Overall, we found that the 10x Flex-based snRNA-seq adequately preserved each OS subtype's biology. FFPE had lower quality control metrics than fixed-frozen, possibly due to the smaller amount of tissue available from the scrolls. Future work will investigate the common theme of genetic drift from normal osteoblasts and their varied degrees of dedifferentiation observed along mesenchymal lineages among OS subtypes. Citation Format: Danh Truong, Clement Agyemang, Davis Ingram, Alexander Lazar, Valerae O. Lewis, Joseph Ludwig. Leveraging FFPE single-nucleus RNA-sequencing for Osteosarcoma [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 2626.
Abstract 3921: Development of a KRAS-G12C-driven pancreatic cancer mouse model
Authors: Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Dean N. Pan, Jangho Park, Yiming Cai, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying
Journal: Cancer Research (2025)

Abstract KRASG12C inhibitor (G12Ci) has produced encouraging, albeit mild clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment remains the major challenge due to the lack of faithful preclinical models. To better understand the tumor biology of the KRASG12C allele, we established a mouse model engineered with the LSL-KrasG12C, conditional p53 knockout (p53L), and pancreatic-specific p48-Cre alleles. The resulting p48-Cre LSL-KrasG12C p53L/+ (KCPC) mice exhibit decreased number and area of PanIN/ADM lesions compared to age-matched KrasG12D-driven controls (KDPC). The decreased neoplastic activity of KrasG12C aligns with decreased downstream signaling (phospho-ERK and phospho-AKT) and cell proliferation (Ki67) in premalignant epithelial cells, suggesting that KRASG12C is a less potent oncogenic allele compared to KRASG12D. Compared to KRASG12D, KRASG12C failed to induce complete ADM which is characterized with the transdifferentiating of acinar cells into progenitor-like ductal cells. The tumor microenvironment of KCPC mice is less immunosuppressive than that of KDPC, which may partially explain the slower progression of KCPC tumor. The relatively weak tumor development in KCPC model results in significantly prolonged median overall survival compared to KDPC model. Histopathology analysis of advanced tumors from the KCPC model revealed similar histological features of ductal adenocarcinoma compared to KDPC model or human PDAC. As for KRAS downstream signaling, PDAC lesions from the KCPC and KDPC models exhibited similar phospho-ERK, phospho-MEK and phospho-S6K1. Both the total KRAS level and the amount of active form of KRAS are also comparable between the two groups. Interestingly, phospho-AKT level was lower in KCPC than in the KDPC tumor cells. Together, our data indicates that, while KRASG12C-driven PDAC premalignant lesions exhibit distinctive molecular features compared to the KRASG12D-driven ones, there is no obvious cellular or molecular difference between the two KRAS genotypes once the tumor progresses to an advanced stage. Citation Format: Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Dean N. Pan, Jangho Park, Yiming Cai, Andrea Viale, Huamin Wang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying. Development of a KRAS-G12C-driven pancreatic cancer mouse model [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 3921.
Abstract 2619: Exploring the genomic landscape of pediatric chronic myeloid leukemia stem cells
Authors: Ryan S. Sathianathen, Julietta Picco, Hye Na Kim, Minyoung Youn, Ramesh Nair, Nobuko Hijiya, Kathleen M. Sakamoto
Journal: Cancer Research (2025)

Abstract Pediatric chronic myeloid leukemia (CML) accounts for 2-9% of leukemias in children. CML in children has been reported to present with a more aggressive clinical manifestation than adult CML, including a higher white blood count and larger spleens. The molecular basis for these clinical differences remains unknown. Therefore, we hypothesize that the molecular pathogenesis of pediatric CML differs from that of adult CML. Furthermore, CML relapse and resistance to tyrosine kinase inhibitors are due to the persistence of CML stem cells. Bulk RNA-seq data with mRNA from bone marrow (BM) CD34+ cells previously demonstrated differential gene expression and uniquely enriched pathways in pediatric CML compared to adult CML stem cells. Our data also showed significant downregulation of Rho pathway-related genes such as ARGHAP27, VAV2, and DLC1, suggesting different molecular pathways in pediatric and adult CML stem cells. To study the clonal heterogeneity and diversity of pediatric CML stem cells, we performed single-cell RNA seq on CD34+ cells from pediatric CML (n=7) and healthy pediatric (n=2) BM samples using the Stem Pro CD34+ system (Miltenyi Biotec, Inc.) and Chromium Next GEM Single Cell 3’ kit from 10X Genomics. Our preliminary data show 13 clusters from CML and healthy CD34+ cells based on gene expression. Overall, CML clusters show a significant downregulation of immune related genes compared to healthy BM clusters. Pathway enrichment analysis shows differential enrichment of immune-related and inflammatory signaling pathways, such as the immune activation and T cell inhibitory pathways in pediatric CML. Our results suggest that immune dysregulation in pediatric CML stem cells contributes to disease pathogenesis. Current work focuses on characterizing 1) the role of immune-related genes in pediatric CML stem cells and their impact on T cell response and 2) cell surface markers of pediatric CML stem cells to identify potential targets for immunotherapy. Citation Format: Ryan S. Sathianathen, Julietta Picco, Hye Na Kim, Minyoung Youn, Ramesh Nair, Nobuko Hijiya, Kathleen M. Sakamoto. Exploring the genomic landscape of pediatric chronic myeloid leukemia stem 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 2619.
Abstract 2285: Utility of ctDNA to detect minimal residual disease in colorectal cancer: A systematic review and network meta-analysis
Authors: Tung Hoang, Moon Ki Choi, Jae Hwan Oh, Jeongseon Kim
Journal: Cancer Research (2025)

Abstract Importance: Circulating tumor DNA (ctDNA) has shown promise as a biomarker for predicting minimal residual disease (MRD) in non-metastatic resected colorectal cancer (CRC) patients and guiding treatment decisions. A comprehensive review of clinical settings and optimal timing for ctDNA use in resected CRC patients is needed. Objective: To examine the study designs and settings of ongoing clinical trials that use ctDNA to guide treatment decisions and determine the best timing for detecting MRD in non-metastiatic CRC. Data sources: A search of studies published before October 2024 was conducted using PubMed, Embase, Web of Science, Cochrane Library, and clinicaltrials.gov for records in English, including clinical trials and prospective studies. Study selection: We included studies of non-metastatic resected CRC patients with ctDNA testing done post-surgery (for clinical trials) or at any time (for prospective studies), reporting recurrence, relapse, or survival outcomes. Data extraction and synthesis: Data on CRC stage, intervention, comparison, and endpoints for clinical trials, as well as the timing of ctDNA testing and effect size of the association with CRC prognosis for prospective studies, were extracted. Main outcomes and measures: The ctDNA settings from clinical trials were categorized by randomization to ctDNA testing, treatment options based on ctDNA results, and the timing of ctDNA testing relative to adjuvant therapy. A network meta-analysis using a frequentist approach was conducted to examine pairwise associations of different ctDNA timing strategies with MRD, defined as recurrence, relapse, and progression. Results: The main approaches in ctDNA-based interventional trial designs were categorized as ctDNA-guided treatment, ctDNA-by-treatment, ctDNA-guided surveillance, and ctDNA-enriched adjuvant therapy for guiding treatment decisions, including both escalation and de-escalation strategies, and surveillance. Overall, both preoperative and postoperative ctDNA detection were linked to higher risks of progression, with pooled HRs (95% CIs) of 5.23 (2.10-13.00) and 7.95 (5.30-11.91), respectively. Among timing strategies, ctDNA testing after adjuvant therapy was the most effective for identifying high-risk patients, strongly suggesting the presence of residual disease. Conclusions and relevance: This study comprehensively reviewed clinical settings of ctDNA in ongoing trials and provided evidence supporting the selection of post adjuvant therapy as optimal timing for ctDNA testing. Citation Format: Tung Hoang, Moon Ki Choi, Jae Hwan Oh, Jeongseon Kim. Utility of ctDNA to detect minimal residual disease in colorectal cancer: A systematic review and network meta-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 2285.
Abstract 3916: Breast cancer brain metastasis development induced by intracarotid injection of MDA-MB 231 human breast cancer cells in mice
Authors: Romain Roth Dit Bettoni, Nicolas Hoffmann, Jordan Longin, Peggy Provent, Ismahene Benzaid, Marc Hillairet De Boisferon
Journal: Cancer Research (2025)

Abstract Breast cancer is the most common malignancy in women worldwide. Breast cancer can be divided into four types based on molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (Her2) positive, and triple negative breast cancer (TNBC). These subtypes have very different prognoses and treatment methods. Herceptin, a treatment specifically directed against Her2 (overexpressed in 20–25% of breast cancers), has been widely used and improves the prognosis for Her2-positive breast cancer. TNBC accounts for only 15–20% of breast cancers and is considered as the most aggressive breast cancer. This subtype does not express estrogen receptor (ER), progesterone receptor (PR), and Her2. Additionally, it is usually identified at an advanced stage of cancer progression and often results in metastases to the brain, bones, lungs, and liver. Human subcutaneous tumors represent a small fraction of cancers that are easy to treat by surgery and chemotherapy and are technically easy to recapitulate in animals. In contrast, high grade breast cancer and metastases represent a leading cause of cancer-related mortality for which more relevant animal tumor models are required. Additionally, the poor prognosis of metastases is badly increased in the brain, particularly due to the difficulty for novel therapies to overcome the blood brain barrier. There are very few animal models exclusively focused on the development of brain metastases, and most are based on stereotactic intracranial inoculation of cells. This injection mode rather mimics the onset of primary tumors than metastases, as it leads to the formation of single tumors and does not recapitulate the extravasation and seeding events of the metastatic cascade. In this poster we show a new TNBC mouse model of brain metastasis. We induced brain metastases by intracarotid injection of TNBC cells, thus recapitulating the tumor cells’ pathway to the brain. We evaluated the metastases progression by morphological T2 weighted MRI imaging. In parallel, we assessed the blood brain barrier integrity by T1 weighted imaging after Gd-DOTA injections and followed edema formation by FLAIR MRI. Citation Format: Romain Roth Dit Bettoni, Nicolas Hoffmann, Jordan Longin, Peggy Provent, Ismahene Benzaid, Marc Hillairet De Boisferon. Breast cancer brain metastasis development induced by intracarotid injection of MDA-MB 231 human breast cancer cells in mice [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 3916.
Abstract 3920: The role of humanized monoclonal antibody ALT-100 in reducing cancer-induced bone pain: A murine animal model study
Authors: Nikhil C. Mathur, Ethan Villarroel, Isabella Villarroel, Erfan Bahramnedjad, Sally Dickinson, Joe G. Garcia, Tally Largent-Milnes, Todd W. Vanderah
Journal: Cancer Research (2025)

Abstract Breast cancer commonly metastasises to the bone promoting a combination of inflammatory and neuropathic mechanisms. This leads to different perceptions of pain with a reported 30-50% of all cancer patients and 75-90% of late-stage patients having cancer-induced bone pain (CIBP). Thus, there is a need for therapeutic interventions to decrease pain caused by the mechanisms of CIBP. Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) is a cytokine overexpressed in metastatic breast carcinoma that binds to Toll-like Receptor 4 (TLR4), triggering a signaling cascade through Nuclear Factor kappa beta (NFk-B) and resulting in inflammation, osteoclastogenesis, and severe bone pain. To assess the impact of eNAMPT on CIBP, ALT-100, a monoclonal antibody neutralizing eNAMPT, was tested in a murine CIBP model. The left femur of C57BL/6J female mice was inoculated with EO771 breast cancer cells and allowed 7 days for recovery from tumor growth and the development of cancer-induced pain. Behavioral data were collected to evaluate ALT-100's effectiveness in reducing pain. Four groups were used: sham + saline, sham + ALT-100, cancer + ALT-100, and cancer + saline, with ALT-100 dosed at 4 mg/kg. Pain was assessed on days 0, 7 (pre- and 2 hours post-injection of ALT-100), 10, and 14 using flinching and guarding behavior tests. A two-way ANOVA and Tukey's multiple comparisons test indicated that ALT-100 significantly reduced pain compared to the cancer + saline group. Bone scoring on days 0 and 14 showed no significant differences in bone lesions and fractures between cancer + ALT-100 and cancer + saline groups. To test ALT-100's efficacy in inhibiting osteoclastogenesis in vitro, RAW 264.7 macrophage cells were plated in five groups exposed to different drug combinations: media, eNAMPT, ALT-100, 1:1 eNAMPT + ALT-100, and 1:2 eNAMPT + ALT-100. After 5 days a marker for osteoclastogenesis, Tartrate-Resistant Acid Phosphatase staining, was measured demonstrating that cells treated with ALT-100 + eNAMPT had significantly fewer osteoclasts than those treated with eNAMPT alone. Together these results indicate that ALT-100 inhibits metastatic breast cancer pain and eNAMPT-induced osteoclast differentiation. Citation Format: Nikhil C. Mathur, Ethan Villarroel, Isabella Villarroel, Erfan Bahramnedjad, Sally Dickinson, Joe G. Garcia, Tally Largent-Milnes, Todd W. Vanderah. The role of humanized monoclonal antibody ALT-100 in reducing cancer-induced bone pain: A murine animal model study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3920.
Abstract 3020: A novel, highly selective and potent FGFR4 inhibitor HJ-217 for the treatment of liver cancer
Authors: Fengtian Du, Xiangyu Yang, Longjun Yang, Huiqiao Ling, Na Guo, Lina Zhang, Li Tao
Journal: Cancer Research (2025)

Abstract Background: Hepatocellular Carcinoma (HCC) is a very aggressive malignant cancer characterized by high incidence and mortality rates, which signs it continues to be a challenge for today's therapeutics. Aberrant FGF19-FGFR4 signaling occurs in approximately 30% of HCC patients and drives tumorigenesis and progression. Therefore, selectively targeting and inhibiting FGFR4 is a promisingly effective and safe therapeutic approach. Methods and Results: Here, we report a novel, highly active, and selective oral small molecule FGFR4 inhibitor HJ-217. HJ-217 exhibited significant inhibitory activity against FGFR4 kinase with the IC50 less than 1nM and showed high selectivity over FGFR1-3 subtypes as well as over 400 other kinases (with all IC50 greater than 1000 nM). HJ-217 demonstrated remarkable inhibition on cell proliferation in Hep3B liver cancer cell line and antitumor efficacy in Hep3B subcutaneous xenograft mouse model (CDX). HJ-217 has exhibited good therapeutic efficacy and low side effects in HCC treatment in clinical study. Conclusions: Our study indicates that HJ-217 is a highly selective FGFR4 inhibitor with encouraging antitumor activity, which may provide an effective treatment for HCC patients. Citation Format: Fengtian Du, Xiangyu Yang, Longjun Yang, Huiqiao Ling, Na Guo, Lina Zhang, Li Tao. A novel, highly selective and potent FGFR4 inhibitor HJ-217 for the treatment of liver 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 3020.