tbuckley/cabot-search huggingface dataset:
Abstract 137: Type XII collagen is elevated in serum from patients with solid tumors: A non-invasive biomarker of activated fibroblasts
Authors: Marina Crespo-Bravo, Annika Hettich, Jeppe Thorlacius-Ussing, Thomas R. Cox, Morten A. Karsdal, Nicholas Willumsen
Journal: Cancer Research (2025)

Background: The tumor microenvironment (TME) and extracellular matrix (ECM) are critical to tumor progression and treatment outcomes. Collagens, the main ECM components, influence cell signaling, migration, and tumor invasion. Type XII collagen is essential for type I collagen assembly and stabilizes the ECM. It is predominantly produced by cancer-associated fibroblasts (CAFs), and its upregulation is linked to poor survival in several cancers. This study developed and validated an ELISA to measure circulating type XII collagen as a potential cancer biomarker. Methods: A monoclonal antibody targeting the C-terminal of type XII collagen was used to develop a competitive ELISA (nordicPRO-C12) for detecting type XII collagen fragments in serum from cancer patients (n=230) and healthy controls (n=33). Type XII collagen expression was also assessed by Western blot in supernatants and lysates from CAFs and normal fibroblasts (NFs) derived from pancreas, lung, colon, and breast tissues, under both TGFβ-stimulated and non-stimulated conditions. Results: The nordicPRO-C12 assay showed high specificity and robustness, detecting significantly elevated serum PRO-C12 levels in patients with prostate, breast, melanoma, lung, gastric, pancreatic, head and neck, and colorectal cancers (p &amp;lt; 0.005 for all). The assay effectively distinguished cancer patients from healthy controls, with high AUROCs for breast (0.95), prostate (0.92), lung (0.92), gastric (0.88), melanoma (0.83), pancreatic (0.80), and head and neck cancers (0.76). These findings were supported by COL12A1 expression data from TCGA and GTEx. Western blot analysis confirmed increased type XII collagen expression in both CAFs and NFs after TGFβ stimulation, highlighting TGFβ's role in ECM remodeling and type XII collagen regulation in cancer and normal microenvironments. Conclusion: This study highlights PRO-C12 as a promising non-invasive biomarker for cancer detection and monitoring. The ability to quantify type XII collagen fragments provides insights into cancer progression. While these results are encouraging, further studies are required to validate PRO-C12's diagnostic and prognostic potential across cancers, potentially expanding its application to clinical practice. Citation Format: Marina Crespo-Bravo, Annika Hettich, Jeppe Thorlacius-Ussing, Thomas R. Cox, Morten A. Karsdal, Nicholas Willumsen. Type XII collagen is elevated in serum from patients with solid tumors: A non-invasive biomarker of activated fibroblasts [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 137.
Abstract 1058: The prediction of positive prostate biopsies in men is significantly enhanced when PVT1 Exon 4A is combined with serum Prostate Specific Antigen (PSA)
Authors: Tinovimba L. Hove, Rachel E. Sexton, Michael Liss, Robin Leach, Emmanuel Asante-Asamani, Olorunseun O. Ogunwobi
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) remains a significant public health challenge, ranking as the second leading cause of cancer-related deaths among men in the United States. Current diagnostic approaches, predominantly centered on prostate-specific antigen (PSA) testing, often lead to overdiagnosis and unnecessary biopsies. The long nonprotein coding gene, PVT1 (plasmacytoma variant translocation 1), has shown promise as a biomarker, being upregulated in PCa and associated with disease progression and metastasis. This study investigates the potential of incorporating PVT1 biomarkers to improve diagnostic accuracy for PCa detection, focusing on both the general population and men of African ancestry, who are disproportionately impacted by PCa incidence and mortality.A total of 144 serum samples were analyzed, with 72 samples from men diagnosed with PCa and 72 from men without cancer. Serum levels of PVT1 Exons 4A, 4B, and 9 were quantified using digital PCR. Multiple logistic regression models were developed to predict cancer status based on PSA alone, PVT1 biomarkers alone, and combinations of PSA with PVT1 biomarkers. Model performance was assessed using stratified k-fold cross-validation, with comparisons made using likelihood ratio tests, and z-tests for statistical significance.The results show that combining PSA with PVT1 Exon 4A improves specificity in predicting cancer status in the general population from 0.45 to 0.54 while maintaining sensitivity at 0.81. Within the subpopulation of men of African Ancestry, PVT1 Exon 4A alone achieves an accuracy of 0.75 with a sensitivity of 1.0 and specificity of 0.5 compared to PSA alone which had an accuracy of 0.38, sensitivity of 0.5 and specificity of 0.25.This study underscores the potential clinical utility of integrating PVT1 biomarkers into prostate cancer screening programs. The inclusion of Exon 4A enhanced PSA-based prediction by addressing its limitations in overdiagnosis and unnecessary biopsies, providing a balanced improvement in diagnostic performance. By improving the accuracy of PCa detection while reducing the burden of overdiagnosis, this approach provides significant value for healthcare providers, diagnostic laboratories, and insurers aiming to enhance early detection and equitable screening outcomes. Citation Format: Tinovimba L. Hove, Rachel E. Sexton, Michael Liss, Robin Leach, Emmanuel Asante-Asamani, Olorunseun O. Ogunwobi. The prediction of positive prostate biopsies in men is significantly enhanced when PVT1 Exon 4A is combined with serum Prostate Specific Antigen (PSA) [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 1058.
Abstract 1073: Integrated single cell atlas of human breast cancer enables highly-resolved analysis of tumor heterogeneity and metabolic comorbidities
Authors: Andrew D. Chen, Christina Ennis, Lina Kroehling, Gerald Denis, Stefano Monti
Journal: Cancer Research (2025)

Abstract Single cell transcriptomics (scRNAseq) remains the method of choice to quantify and annotate cellular heterogeneity in the tumor and its microenvironment (TME), yet most studies are under-powered to associate changes in tumor heterogeneity with phenotypes such as tumor subtype, grade, and patient age, among others. In this study, we created an integrated atlas of human breast cancer (BC), the largest resource of its kind, totaling more than 700, 000 cells across 145 patients, and optimized computational methods to benchmark integration performance, and robustly perform hierarchical cell type annotation. By combining single profiles, a higher-resolution annotation of immune, stromal, and epithelial cell types was achieved. Further, using this integrated atlas, differential abundance analyses identified significant changes in immune and stromal cell type composition associated with tumor grade, subtype, and inferred metabolic comorbidities. For insulin resistance and obesity, we identified significant expansion in exhausted CD4 T Cell populations and interferon signalling in CD8 and macrophage populations. These changes in TME heterogeneity were not discernible or had effects in discordant directions when the analysis was limited to individual BC studies, highlighting the need for atlas-based mega-analysis approaches. This highly-resolved integrated scRNAseq BC atlas represents a valuable resource for hypothesis-driven analyses of tumor heterogeneity. Citation Format: Andrew D. Chen, Christina Ennis, Lina Kroehling, Gerald Denis, Stefano Monti. Integrated single cell atlas of human breast cancer enables highly-resolved analysis of tumor heterogeneity and metabolic comorbidities [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 1073.
Abstract 250: TMEM97/sigma 2 receptor increases androgen receptor activities to regulate prostate cancer cell growth and sensitivity to castration therapy
Authors: Daotai Nie, Xiangwei Fang, Yuanqin Zhang, Jiuhui Wang
Journal: Cancer Research (2025)

Abstract Prostate cancer is one of the most common cancers in men. Suppression of androgen receptor (AR) activity by androgen depletion or direct AR antagonist treatment, although initially effective, leads to emergence of castration-resistant prostate cancer. Sigma 2 receptor (σ2R) has been implicated in carcinogenesis including prostate cancers. Its molecular identity remained elusive until 2017 that transmembrane protein 97 (TMEM97) was identified as the bona fide sigma 2 receptor. Here we report that TMEM97/σ2R expression was elevated in prostate tumors of higher malignancy and advanced stages, and was associated with reduced survival of prostate cancer patients. Via in-vitro studies, increased expression of TMEM97 enhanced prostate cancer cell proliferation, clonogenicity, and resistance to enzalutamide. Knockdown of σ2R expression reduced prostate cancer cell growth and clonogenicity, and sensitized LNCaP and castration resistant 22Rv1 cells towards enzalutamide. There was a positive correlation between TMEM97 and AR expressions in prostate tumors. Knockdown of σ2R expression reduced the protein levels of AR and its AR-V7 variant under hormone deprivation condition. Decreased TMEM97 expression also downregulated AR activities as evidenced by reduced expression of AR target genes. PB-28, a known σ2R agonist, can stimulate AR target genes expressions while antagonist decreased them. SM21, a σ2R antagonist, presented synergism when combined with enzalutamide in the treatment of prostate cancer cells. Our findings suggest a potential approach targeting TMEM97/σ2R to reduce castration resistance. Citation Format: Daotai Nie, Xiangwei Fang, Yuanqin Zhang, Jiuhui Wang. TMEM97/sigma 2 receptor increases androgen receptor activities to regulate prostate cancer cell growth and sensitivity to castration therapy [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 250.
Abstract 1130: Race and sex differences in TP53 mutation in head and neck cancer
Authors: Nosayaba Osazuwa-Peters, May Z. Gao, Tammara L. Watts, Rong Jiang
Journal: Cancer Research (2025)

Abstract Importance: Head and neck cancer (HNC) is one of the most disparate cancers, with the Black vs. White survival difference being the third worst survival gap of all cancers. It is also a male-dominated cancer, with up to 75% of new cases in males. There remains several gaps in our understanding of the genetic basis for race and sex disparity in HNC, including paucity in characterizing differences in common genetic mutations in HNC, such as TP53 mutations. Objective: To characterize the genetic differences in HNC by race and sex through 1) examining prevalence of TP53 mutation by race, and 2) differences in mutation by sex. Design: Retrospective cohort study. Setting: The AACR GENIE consortium level v17.4 dataset for patients with confirmed diagnosis of HNC, independent of HPV status. Main Outcomes and Measures: First, we estimated the rate of TP53 mutation in our HNC cohort (n = 2, 352). We also estimated relative risk (RR) for TP53 mutation by race, and then adjusted age, and sex. We also estimated differences in TP53 mutation by sex, reporting false discovery (q-value) rate as appropriate. Finally, we estimated adjusted hazard ratio for mortality for TP53, adjusting for clinical and nonclinical variables in the model. Results: In the entire cohort, the rate of TP53 mutation was 48.7%. However, there were only 109 patients in our cohort of 2, 352 patients that self-identified as Black patients, and among these, 60 (55.1%) had TP53 mutation. After adjusting for age and sex, compared to White patients, we found aRR for TP53 = 1.17 for Black patients (95% CI: 0.98, 1.39), and for other minority race and ethnic groups together aRR = 1.17 (95% CI: 1.06, 1.29). By sex, we found a significantly higher prevalence of mutant TP53 in female vs. males patients (57.8% vs. 45.3%, q-value &amp;lt;0.0001). TP53 mutation was associated with significantly increased hazard of mortality (aHR = 1.58; 95% CI: 1.30, 1.91). Conclusion and Relevance: TP53 mutation is very common in HNC, and about one out of every two patients with HNC may have a TP53 mutation based on our results. There may be differences in TP53 mutations in HNC by race and sex, an important finding given the mortality implications of TP53 mutations in HNC. Citation Format: Nosayaba Osazuwa-Peters, May Z. Gao, Tammara L. Watts, Rong Jiang. Race and sex differences in TP53 mutation in head and neck 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 1130.
Abstract 1080: Transforming cancer genomics research: A platform for integrated exploration of COSMIC resources
Authors: Helder Pedro, Zbyslaw Sondka
Journal: Cancer Research (2025)

Abstract The Catalogue of Somatic Mutations in Cancer (COSMIC) is a vital resource for cancer genomics, offering extensive data on somatic mutations, cell lines, and mutation signatures. While the existing COSMIC dataset provides wealth of diverse, high-quality information, accessing and fully utilising it requires significant processing and expertise in data analysis. To address this, we are developing a new suite of tools to enhance COSMIC data integration, usability and exploration.The Cell Line Explorer serves as a starting point for this suite, enabling users to easily access and analyse COSMIC data related to specific cell lines. This tool integrates genetic variants with annotations and reference datasets, providing dynamic insights into clinical significance. Beyond the cell lines mutation catalogue, the platform connects to key COSMIC resources, including the Cancer Gene Census, Actionability, Cancer Mutation Census, Mutational Signatures, and COSMIC3D. This integration allows users to derive deeper insights, and easily correlate mutation data with functional impact and potential clinical significance.The tools are designed for flexibility and scalability, meeting the needs of diverse users, from computational researchers, clinicians seeking actionable insights, educators incorporating bioinformatics into their teaching, and individuals with limited bioinformatics expertise who require intuitive solutions. With its intuitive interface and robust integration of COSMIC resources, this platform lowers the barriers to access and streamline complex analyses, providing researchers with powerful tools to explore and analyse cancer genomic data at unprecedented depth. Citation Format: Helder Pedro, Zbyslaw Sondka. Transforming cancer genomics research: A platform for integrated exploration of COSMIC resources [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 1080.
Abstract 1726: Preclinical development of APL-045: A selective PERK inhibitor targeting ER stress pathways in cancer
Authors: Krishna Kolluri, Clara Stead, Susanne Wright, Paul Glossop, Emmanuel Demont, Richard Butt, Nadine Clemo
Journal: Cancer Research (2025)

Abstract The unfolded protein response (UPR) is a critical component of the integrated stress response (ISR) pathway, activated in response to the accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER). A key mediator in this pathway is protein kinase RNA-like ER kinase (PERK), which becomes active under conditions of ER stress. Upon activation, PERK phosphorylates eIF2α, temporarily halting general protein translation to reduce the burden on the ER. Cancer cells can exploit PERK signalling to enhance their survival and proliferation under stress, leveraging this pathway to adapt to UPR triggered by hypoxic, nutrient-deprived tumour microenvironments, or as a response to anticancer therapies. Inhibition of PERK is therefore a promising therapeutic target in oncology. APL-045 is a novel, selective, ATP-competitive inhibitor of PERK. APL-045 demonstrated potent inhibition of PERK, with a Ki of 4.6 nM and IC50 for eIF2α phosphorylation inhibition of 20 nM. Selectivity screening showed high specificity, with very limited off-target effects among 468 kinases tested in a Kinome Scan®. In vitro studies demonstrated that APL-045 effectively inhibited downstream effectors of the PERK-mediated UPR pathway, ATF4 and CHOP, in a dose-dependent manner with the IC50 values ranged from 50 to 250 nM across renal cell carcinoma (RCC) and colorectal cancer cell lines. In vivo, APL-045 significantly reduced tumour volume in 786-O RCC xenograft models, achieving over 95% tumour growth inhibition after three weeks of treatment. These findings underscore the potential of APL-045 as a promising therapeutic candidate for cancers driven by PERK-dependent pathways. APL-045 has a highly favourable pharmacokinetic profile, with good solubility, high permeability, and robust metabolic stability in both microsomal and hepatic assays in rodent, dog and human in vitro systems. These properties have translated to high bioavailability. This favourable profile is projected to represent a best-in-class PERK inhibitor. These data describe the efficacy and drug-like properties of APL-045, a candidate stage, best-in-class PERK inhibitor poised to progress into IND-enabling and clinical studies. Citation Format: Krishna Kolluri, Clara Stead, Susanne Wright, Paul Glossop, Emmanuel Demont, Richard Butt, Nadine Clemo. Preclinical development of APL-045: A selective PERK inhibitor targeting ER stress pathways in 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 1726.
Abstract 340: GenSci139, a highly differentiated EGFR×HER2 bispecific ADC, for the treatment of multiple solid tumors
Authors: Xiaojuan Chai, Fu Li, Hongmei Xie, Yuting Lu, Nan Li, Hanxi Yu, Li Tong, Weiming He, Wenqiang Zhai, Fanglong Yang, John L. Xu
Journal: Cancer Research (2025)

Abstract Background: Enhertu®/DS-8201, a HER2-directed ADC, has been used for the treatment of multiple tumor types, including HER2-positive and HER2-low breast cancer, HER2-mutant NSCLC, HER2-positive gastric cancer, etc. Despite Enhertu’s success as a breakthrough therapy, significant unmet need remains in the HER2-low settings and in the occurrence of secondary resistance. Dual targeting of EGFR and HER2 represents a promising approach to the treatment of HER2-low patients and to overcoming drug resistance, as they are both oncogenic drivers and widely co-expressed. We developed GenSci139, an EGFR×HER2 bispecific ADC with a highly stable but cleavable linker and a potent topoisomerase 1 inhibitor payload, using our proprietary platform technologies. Preclinical studies are underway to evaluate the potential of GenSci139 as a novel targeted therapy across multiple solid tumor types. Methods: GenSci139’s plasma stability, in vitro cellular binding, internalization, cytotoxicity, and bystander effect, and blocking activity of GenSci139 or its parental bispecific antibody on EGFR/HER2 signaling in a number of human cancer cell lines were characterized. In vivo anti-tumor activity of GenSci139 was evaluated in a number of human cancer CDX models in mice. In addition, the ability of GenSci139 to induce immunogenic cell death (ICD) in tumor cell cultures was assessed. Results: GenSci139 showed much better in vitro plasma stability than DS-8201, suggesting a favorable PK and safety profile. GenSci139 exhibited stronger in vitro tumor cell binding and internalization activities than DS-8201 and potent direct cytotoxicity and bystander killing effect in tumor cell lines. The parental bispecific antibody of GenSci139 inhibited EGF-induced signaling and cell proliferation in tumor cell culture. GenSci139 demonstrated superior in vivo anti-tumor efficacy versus DS-8201 in a number of CDX models in mice. In addition, GenSci139 was shown to induce hallmarks of ICD in tumor cells, providing a complementary anti-tumor mechanism when in a combination therapy regimen with immune checkpoint inhibitors. Conclusion: These data suggest the potential of GenSci139 as a novel and effective therapy across a variety of tumor types, including urothelial cancer, lung cancer, gastric cancer, colorectal cancer, ovarian cancer, breast cancer, etc., and support its further evaluation in IND-enabling studies. Citation Format: Xiaojuan Chai, Fu Li, Hongmei Xie, Yuting Lu, Nan Li, Hanxi Yu, Li Tong, Weiming He, Wenqiang Zhai, Fanglong Yang, John L. Xu. GenSci139, a highly differentiated EGFR×HER2 bispecific ADC, for the treatment of multiple solid tumors [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 340.