tbuckley/cabot-search huggingface dataset:
Abstract 1924: Urine extracellular vesicles derived CA9 and CIZ1 as non-invasive biomarkers for early diagnosis of clear cell renal cell carcinoma
Authors: Xiyi Wei, Xi Zhang, Xinghan Yan, Zijie Yu, Weiyu Kong, Yize Li, Chao Qin, Hongwei Liang
Journal: Cancer Research (2025)

Abstract Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system, with clear cell renal cell carcinoma (ccRCC) being the most prevalent pathological subtype. Metastasis is observed in 20-30% of patients at initial diagnosis, and 20% of cases develop metastasis even after surgery, resulting in poor prognosis due to insensitivity to radiotherapy and chemotherapy. Early and accurate diagnosis is critical to improving outcomes and survival rates. However, specific humoral markers for non-invasive early screening and diagnosis of RCC are currently lacking. Urinary extracellular vesicles (EVs) have emerged as promising biomarkers for urinary system diseases due to their stability and ease of collection. In this study, we conducted a comprehensive analysis of urine EVs to identify specific biomarkers for ccRCC. Urine samples were collected from 100 healthy donors, 100 renal cyst patients, and 300 RCC patients (200 ccRCC, 50 papillary RCC [pRCC], and 50 chromophobe RCC [chRCC]). Agglutinin-coupled magnetic beads were employed to enrich exosomes, followed by proteomic analysis to identify differential protein expression. Results revealed significant upregulation of CA9 and CIZ1 proteins in urine EVs from ccRCC patients compared to controls. Importantly, these proteins were elevated in early-stage and small-sized ccRCC cases. Stability testing demonstrated that CA9 and CIZ1 proteins in EVs maintained stability over time and increased with urine volume. Diagnostic efficacy was evaluated in a larger cohort (1, 500 cases) using receiver operating characteristic (ROC) curve analysis. CA9 and CIZ1 achieved area under the curve (AUC) values of 0.8917 and 0.8843, respectively, in distinguishing ccRCC from normal and other RCC cases. A combined model of the two markers achieved the highest discriminative power, with an AUC of 0.9633, sensitivity of 96.52%, and specificity of 86.69%. This study highlights the potential of CA9 and CIZ1 in urine-derived EVs as non-invasive biomarkers for ccRCC diagnosis. These findings provide a foundation for novel early screening methods and lay the groundwork for future research to validate these biomarkers in larger cohorts and investigate their stage-specific expression, ultimately facilitating personalized diagnosis and treatment of ccRCC. Citation Format: Xiyi Wei, Xi Zhang, Xinghan Yan, Zijie Yu, Weiyu Kong, Yize Li, Chao Qin, Hongwei Liang. Urine extracellular vesicles derived CA9 and CIZ1 as non-invasive biomarkers for early diagnosis of clear cell renal cell carcinoma [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 1924.
Abstract 1747: Targeting NRF2-responsive kinases for the treatment of esophageal squamous cell carcinoma
Authors: Boopathi Subramaniyan, Zhaohui Xiong, Yahui Li, Chorlada Paiboonrungruang, Francis Spitz, M. Ben Major, Xiaoxin Chen
Journal: Cancer Research (2025)

Abstract Esophageal squamous cell carcinoma (ESCC) ranks as the 8th most commonly diagnosed cancer and the 6th leading cause of cancer-related deaths worldwide. NRF2 has been identified as a bona fide cancer driver in human ESCC, with mutation rates ranging from 10% to 22%. Hyperactivation of NRF2 promotes tumor growth, metastasis, and resistance to conventional therapies in ESCC. Evidence suggests that NRF2 also regulates kinases influencing ESCC phenotypes, though the specific kinases involved are yet to be identified. NRF2 ChIP-seq analysis revealed enrichment of 42 kinases, including Akt2 and Pkm, and 31 phosphatases, such as Pten and Dusp16, in the Keap1-/- mouse esophagus compared to wild-type tissue. We confirmed NRF2 binding at the promoter regions of Akt2 and Pten. mRNA expression profiling revealed enrichment of the PI3K/AKT, RAS, ERK, and GSK3β signaling pathways in the Keap1-/- esophagus relative to Nrf2-/-;Keap1-/- esophagus. Immunohistochemical staining showed overexpression of pAKT, p-mTOR, pS6, and PKM2 in the esophagus of both Keap1-/- and Sox2CreER;LSL-Nrf2E79Q/+ mice. Using PhosphoExplorer and PamChip arrays, we identified several kinases, including PI3K, as NRF2-responsive kinases in NRF2W24C-KYSE70 cells compared to isogenic NRF2null-KYSE70 cells, as well as in Sox2CreER;LSL-Nrf2E79Q/+ mouse esophageal epithelium versus wild-type tissue. In NRF2null-KYSE70 cells, expression of pAKT, pS6, p-PTEN, PIK3CA, AREG, and pEGFR was significantly downregulated compared to NRF2W24C-KYSE70 cells. Similar results were seen in NRF2D77V-KYSE180 cells treated with NRF2 siRNA. Furthermore, NRF2null-KYSE70 cells showed increased sensitivity to EGFR inhibitor (Gefitinib), PIK3CA inhibitor (Alpelisib), and AKT inhibitor (Capivasertib), compared to NRF2W24C-KYSE70 cells. Notably, Alpelisib and an NRF2 inhibitor (Pyrimethamine) synergistically suppressed NRF2W24C-KYSE70 cell growth. Consistent with these findings, pNRF2 expression correlated with PI3K signaling proteins, including pAKT and p-mTOR, in human ESCC tissues. These studies highlight the potential of combining an NRF2 inibitor with a PI3K pathway inhibitor as a promising therapeutic strategy for ESCC. Citation Format: Boopathi Subramaniyan, Zhaohui Xiong, Yahui Li, Chorlada Paiboonrungruang, Francis Spitz, M. Ben Major, Xiaoxin Chen. Targeting NRF2-responsive kinases for the treatment of esophageal squamous cell carcinoma [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 1747.
Abstract 4236: Effects of a DNMT1-selective inhibitor on T-cell activity and tumor cells intrinsic pro-inflammatory response
Authors: Shane W. O'Brien, Satyajit Rajapurkar, Anthony Della Pietra, Helen Sun, Andrew Fedoriw, Michael McCabe, Melissa Pappalardi
Journal: Cancer Research (2025)

Abstract Previous studies indicate that while combinations of DNA methyltransferase inhibitors, such as decitabine or 5-azacytadine, with immunotherapies has shown potential in activating anti-tumor activity, their limited clinical success could be attributed to the systemic delivery and toxic effects on the immune cells in the microenvironment, which may explain the lack of activity in clinical trials. To explore the potential of combining an epigenetic inhibitor with an immunomodulatory agent, the effects of a DNMT1 inhibitor on T-cell activity and intrinsic pro-inflammatory responses in tumor cells were examined. Human and mouse cancer cell lines or isolated T-cells were treated with DNMT1-selective inhibitors and assessed for gene expression, global DNA methylation, mass cytometry, fluorescent cytometry, and chemokine ELISA. DNMT1-selective inhibitors triggered a pro-inflammatory transcriptional response in human cancer cell lines similar to decitabine. In human T-cells, DNMT1 inhibition reduced proliferation and increased markers of both anti-inflammatory and pro-inflammatory phenotypes, with these changes being reversible upon compound removal. Mouse T-cells similarly exhibited temporary loss of proliferation and increased anti-inflammatory and pro-inflammatory phenotypes. Additionally, DNMT1 inhibition elevated the expression of anti-inflammatory cytokines IL-10 and IL-4 in both human and mouse T-cells. Notably, DNMT1 inhibition resulted in a lasting pro-inflammatory transcriptional response in malignant cancer cell lines, whereas the effect on normal cells was reversible. In summary, DNMT1-selective inhibitors may boost the efficacy of immuno-oncology therapies by inducing a pro-inflammatory response in cancer cell lines while minimizing impact on T-cells through alternative dosing schedules. Further research is required to compare DNMT1-selective inhibitors with traditional HMAs and to study the interaction between immune and cancer cells in vivo. Identifying biomarkers for patient stratification could help optimize treatment strategies. This study highlights the importance of evaluating the impact of small molecule inhibitors on both tumor characteristics and immune responses to optimize conditions for effective anti-tumor responses. Citation Format: Shane W. O'Brien, Satyajit Rajapurkar, Anthony Della Pietra, Helen Sun, Andrew Fedoriw, Michael McCabe, Melissa Pappalardi. Effects of a DNMT1-selective inhibitor on T-cell activity and tumor cells intrinsic pro-inflammatory response [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 4236.
Abstract 2135: QLS4131, a proprietary T cell engager targeting both BCMA and GPRC5D for the treatment of multiple myeloma
Authors: Liuqing Yang, Hongliang Qian, Juan Luo, Ke Liu, Ling Zhang, Shuyong Zhao, Hua Ying, Weikang Tao
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) is a genetically complex and heterogeneous malignancy with poor prognosis. Despite recent advances in the development of new therapeutics, clinical management of MM remains a big challenge largely due to quick emergence of drug resistance. Thus, novel therapies which can cause deeper response or overcome drug resistance are highly desired. It has been found that both BCMA and GPRC5D are overexpressed in MM in a manner of either co-expression or mono-expression. In fact, T cell engagers (TCE) targeting either BCMA or GPRC5D alone have been approved by FDA for MM treatment. Hence, TCE target both BCMA and GPRC5D have a great potential to demonstrate superior efficacy and overcome resistance to TCE only targeting a single antigen. QLS4131 demonstrated a higher affinity for MM tumor cell lines when compared to JNJ-79635322, which is a clinical stage TCE targeting both BCMA and GPRC5D developed by Janssen Research &amp; Development. QLS4131 was capable of effectively depleting both dual (BCMA and GPRC5D) and single (BCMA or GPRC5D) target-expressing cells, and its cytotoxicity was substantially more potent than JNJ-79635322. Meanwhile, the level of IL-6 cytokine release was comparable to that of JNJ-79635322. Additionally, QLS4131 maintained robust TDCC activity even in the presence of 2.5 µg/mL soluble BCMA. The single-dose PK evaluation revealed linear pharmacokinetic characteristics with a half-life (T1/2) of approximately 120 hours, it also demonstrated high bioavailability (79.83%) when SC dosing. In in vivo pharmacology studies, QLS4131 could inhibit tumor growth in a dose-dependent manner and even induce tumor regression and exhibited superior antitumor efficacy related to JNJ-79635322. QLS4131 was well tolerated in a cyno monkey QW x 4 GLP toxicity study. Skin and nail toxicity (related to the GPRC5D target) was not observed. The HNSTD was 2 mpk for both intravenous and subcutaneous injections. In conclusion, the excellent efficacy, favorable PK, and safety profile support the potential of QLS4131 as a novel therapeutic agent to address the significant unmet needs in multiple myeloma. A Phase 1 dose-escalating study of QLS4131 in multiple myeloma is currently underway (NCT06500507). Citation Format: Liuqing Yang, Hongliang Qian, Juan Luo, Ke Liu, Ling Zhang, Shuyong Zhao, Hua Ying, Weikang Tao. QLS4131, a proprietary T cell engager targeting both BCMA and GPRC5D for the treatment of multiple myeloma [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 2135.
Abstract 3846: BNIP3-dependent muscle atrophy in cancer cachexia promotes PDAC progression
Authors: Alexandra Sophia Ware, Elizabeth C. Foster, Kay F. Macleod
Journal: Cancer Research (2025)

Abstract Cancer cachexia is a debilitating effect of several human cancers, including pancreatic ductal adenocarcinoma (PDAC), that involves involuntary body weight loss due to wasting of skeletal muscle (with or without loss of adipose tissue). Cancer cachexia negatively affects the long-term survival of cancer patients, partly due to reduced tolerance of and response to therapy, and increased mortality due to cardiac and respiratory failure. Here, we present new data demonstrating a role for the mitochondrial cargo receptor BNIP3 in driving muscle atrophy during cachexia caused by PDAC in genetically engineered mouse models. Muscle-specific deletion of BNIP3 in CB mice (Mck-Cre;Bnip3fl/fl) inhibited muscle atrophy in the KPF (FSF-KRasG12D;p53 Frt/+;p48-FlpO) mouse model of PDAC such that skeletal muscle in age-matched compound KPFCB mice (FSF-KRasG12D;p53 Frt/+;p48-FlpO; Mck-Cre;Bnip3fl/fl) exhibited increased weight, increased myofiber cross-sectional area, and decreased expression of muscle atrogenes MuRF1 and Atrogin1, compared to KPF mice. Orthotopic injection of KPF and KPC PDAC lines and sub-cutaneous injection of LLC lung tumor lines similarly revealed key differences in muscle atrophy between WT and CB mice. The sustained health of myofibers in KPFCB mice compared to KPF mice was associated with increased mitochondrial mass, increased mTOR activity, and decreased autophagy markers. In addition to limiting muscle atrophy, loss of BNIP3 in muscle attenuated PDAC tumorigenesis with tumors exhibiting delayed progression from pre-malignant pancreatic intra-epithelial neoplasia (PanINs) to PDAC, and muscle-specific loss of BNIP3 extended lifespan of KPF mice. These findings indicate that degradation of muscle driven by BNIP3-dependent mitophagy is “feeding” the PDAC tumor via factors circulating in plasma. Steady state metabolomics revealed that purines were amongst the most down-regulated metabolites in muscle and plasma of cachectic mice consistent with a model in which BNIP3-dependent mitophagy in muscle is limiting 1C metabolism due to decreased mitochondrial mass. Together, our findings identify BNIP3 as a molecular target in muscle for therapeutic intervention to limit both cancer cachexia and tumor progression. Citation Format: Alexandra Sophia Ware, Elizabeth C. Foster, Kay F. Macleod. BNIP3-dependent muscle atrophy in cancer cachexia promotes PDAC progression [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 3846.
Abstract 2240: High dose acetaminophen re-polarizes CD11B+ cells in the tumor microenvironment towards an activated macrophage phenotype
Authors: Allyn Bryan, Pavani Pingali, Bhaumik Patel, Won Sok Lee, Joseph Landry, Alexander J. Neuwelt
Journal: Cancer Research (2025)

Background: High dose acetaminophen (AAP) has demonstrated promising results in early phase clinical trials. When administered concurrently with the CYP2E1 inhibitor fomepizole, AAP can be dose-escalated 100-fold relative to standard dosing without liver toxicity and without compromising anti-tumor activity. The present study aims to characterize the effects of high dose AAP on the tumor immune microenvironment. Methods: The current study used a 23-plex flow cytometry panel to study AAP induced changes in the tumor immune microenvironment of syngeneic mouse breast tumors. AAP-induced changes in macrophage phenotype were studied in vitro using phagocytosis and antigen presentation assays, both alone and in combination with PD-1 antibody therapy. Results: Flow cytometric analysis of the tumor immune micro-environment revealed that the vast majority of CD45+ cells in triple negative breast cancer model are CD11B+ cells of the innate immune system. The CD11B+ cells in the tumor micro-environment of vehicle-treated mice were mostly comprised of GR1+ myeloid derived suppressor cells. On the other hand, the CD11B+ cells in the high dose AAP-treated mice were mostly of the activated macrophage phenotype (F4/80+CD80+MHCII+). Other observed changes within the tumor of AAP-treated mice include a large influx of B-cells, NK-cells and T-cells. Given the increased number of activated macrophages observed in the AAP-treated tumors, in vitro studies were performed to better understand AAP effects on macrophage function. It was demonstrated that AAP enhances phagocytosis as well as antigen presentation by macrophages to antigen-reactive T-cells. These effects are amplified when PD-1 antibodies are combined with AAP in the in vitro antigen presentation assay. Furthermore, AAP has synergistic anti-tumor activity in vivo when combined with PD-1 antibody therapy, an effect that is macrophage dependent. Conclusion: High dose AAP can be administered safely when combined with fomepizole-based rescue in mouse models. The present study demonstrates profound AAP-induced changes in the tumor immune microenvironment, particularly within the phenotype of CD11B+ cells of the innate immune system leading to increased “M1” type macrophages in the tumor immune microenvironment. Citation Format: Allyn Bryan, Pavani Pingali, Bhaumik Patel, Won Sok Lee, Joseph Landry, Alexander J. Neuwelt. High dose acetaminophen re-polarizes CD11B+ cells in the tumor microenvironment towards an activated macrophage phenotype [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 2240.
Abstract 2134: KA-2886-LD38: a bispecific antibody-drug conjugate (ADC) targeting both EGFR and MET, incorporating a novel linker-payload that inhibits DNA topoisomerase I
Authors: Guojin Wu, Chuanying Xu, Weihong Nian, Zhengcheng Guo, Jiabei Liang, Feng He, Qing Zhou, Jinying Ning
Journal: Cancer Research (2025)

Abstract Epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) are frequently co-expressed in multiple solid cancers, and over-activation of MET signaling is one of the major mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). Antagonistic bispecific antibodies targeting both EGFR and MET have been shown to overcome this resistance. KA-2886-LD38 is a bispecific ADC targeting both EGFR and MET. It is a bispecific common light chain IgG1 , conjugated with LD-38, an Escugen proprietary ADC platform composed of TopIi payload and highly hydrophilic stable cleavable linker. It binds to MET with an affinity of 0.02 nM and to EGFR with an affinity of 1 nM. KA-2886-LD38 blocks the binding of HGF to MET with an IC50 of about 0.3 nM and the interaction of EGF with EGFR with an IC50 of about 2 nM. Compared to the benchmark ADC AZD9592, KA-2886-LD38 exhibits a similar internalization rate when binding to tumor cells but demonstrates significantly stronger cytotoxicity and bystander killing activity across different tumor cell lines in vitro. Additionally, in xenograft mouse tumor models with various tumor types, including NSCLC, head and neck squamous cell carcinoma, colorectal cancer, esophageal squamous cell carcinoma, and triple-negative breast cancer, KA-2886-LD38 showed much stronger in vivo efficacy compared to AZD9592. Moreover, KA-2886-LD38, when combined with osimertinib, also demonstrated a combination inhibitory effect on H1975 tumor growth. KA-2886-LD38 is well-tolerated at doses up to 30 mg/kg in EGFR and MET humanized genetically modified mice, and toxicity studies in monkeys are ongoing. These results suggest that KA-2886-LD38 has remarkable potential in the landscape of anti-EGFR/cMet therapies. Citation Format: Guojin Wu, Chuanying Xu, Weihong Nian, Zhengcheng Guo, Jiabei Liang, Feng He, Qing Zhou, Jinying Ning. KA-2886-LD38: a bispecific antibody-drug conjugate (ADC) targeting both EGFR and MET, incorporating a novel linker-payload that inhibits DNA topoisomerase I [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 2134.
Abstract 2408: Bioinformatics analysis of genes that confers apoptosis resistance to EGFR-PI3K co-targeting
Authors: Adeoluwa Adeluola, Humaira Noor, A.R.M. Ruhul Amin
Journal: Cancer Research (2025)

Abstract Background: Large scale genomic studies have identified the overexpression of epidermal growth factor receptor (EGFR) and constitutive activation of the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) pathway as common genetic aberrations in head and neck cancer. Previously, we reported that the combination of EGFR inhibitor erlotinib with PI3K inhibitor BKM120 had synergistic effects and induced efficient apoptosis in a panel of head and neck cancer cell lines, but some cells were still resistant. The purpose of the current study is to identify molecular pathways that confer resistance to EGFR and PI3-K co-targeting through RNA-Seq and bioinformatics analysis. Methods: JHU022, a cell line resistant to EGFR and PI3K co-targeting was treated with the combination of erlotinib and BKM120 ± dasatinib (Src inhibitor) or crizotinib (Met inhibitor) for 24h. Total RNA was isolated and used for RNASeq analysis. In order to identify major pathways that were associated with resistance to EGFR and PI3K co-targeting, bioinformatics pathway analysis was conducted using 2-folds differentially expressed genes. The mRNA expression levels of selected differentially expressed genes were confirmed by qPCR. Results: FDR of ≥0.1% and fold-change of ≥2.0 were used as cut-off for selecting differentially expressed genes. A total of 961 genes were modulated by the combination of erlotinib and BKM120, 2205 by the combination of erlotinib, BKM120 and dasatinib, and 2251 by the combination of erlotinib, BKM120 and crizotinib when compared with untreated control. The addition of crizotinib to the combination of erlotinib and BKM120 resulted in the modulation of 624 genes, while the addition of dasatinib to erlotinib and BKM120 modulated 555 genes. KEGG pathway analysis identified DNA replication, cell cycle, mismatch repair, base excision repair, homologous recombination etc. as the major pathways affected by double and/or triple drug treatment. E2F targets, G2-M checkpoint, Myc targets were the common pathways identified by MSigDB analysis using differentially expressed genes. These pathways were also identified as major affected pathways in GO_Biological_Processes_2021 analysis. Conclusions: SRC-Met signaling confers resistance to EGFR and PI3K co-targeting by modulating genes associated with cell cycle, DNA replication, and cellular response to DNA damage. Grant Support: R15DE032063 and P20GM103434 Citation Format: Adeoluwa Adeluola, Humaira Noor, A.R.M. Ruhul Amin. Bioinformatics analysis of genes that confers apoptosis resistance to EGFR-PI3K co-targeting [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 2408.