tbuckley/cabot-search huggingface dataset:
Abstract 6331: Prevention of lung cancer growth by an edible mushroom-derived p-terphenyl antioxidant, Vialinin-A
Authors: Neha Ratna, Aleeza Namit, Kota A. Ramana
Journal: Cancer Research (2025)

Lung cancer remains the leading cause of cancer-related deaths in the United States, surpassing the combined fatalities from colon, breast, and prostate cancer. In 2024, approximately 234,580 individuals were diagnosed with lung cancer, with projections indicating an increase in 2025. A history of smoking, both first and secondhand, the use of other combustible tobacco products, and hereditary risk factors have been strongly associated with lung cancer. Environmental exposures to radon, asbestos, arsenic, air pollution, and other occupational exposures exacerbate the likelihood of developing the disease. Novel treatment approaches are required to improve outcomes in lung cancer prognosis. Vialinin-A, a ubiquitin-specific peptidase inhibitor derived from Chinese edible mushrooms, T. terrestris and T. vialis, has potent antioxidant and anti-inflammatory properties. However, its potential anti-carcinogenic effects remain unexplored. Therefore, we hypothesize that Vialinin-A, with its potent anti-oxidative and anti-inflammatory effects, could prevent lung cancer growth. Human Non-Small Cell Lung Cancer (NSCLC) cell lines (A549) were used to investigate the potential chemopreventive role of Vialinin-A on lung cancer. An MTT assay was conducted to evaluate EGF-induced cell viability without or with Vialinin-A. The expression of pro-, anti-inflammatory, and apoptotic proteins was then assessed via multiplex antibody arrays. Mitochondrial reactive oxygen species (ROS) and a scratch array were then used to calculate cell migration. Cell death was observed using a live and death assay. Our results suggest that Vialinin-A could prevent EGF-induced lung cancer growth in a dose- and time-dependent manner. The expression of apoptotic proteins such as Catalase, Cleaved Caspase-3, cIAP-1, Claspin, SMAC/Diablo, and Clusterin was significantly upregulated in A549 cells treated with EGF+Vialinin-A. EGF-induced cell migration and invasion were prevented with Vialinin-A treatment. Vialinin-A also decreased the EGF-induced ROS and elevated caspase-3 levels. Thus, our data suggests that by increasing the caspase-3-mediated apoptotic pathway, Vialinin-A could prevent lung cancer growth and migration. Next, we will examine how Vialinin-A prevents lung cancer growth using nude mice xenograft models. Citation Format: Neha Ratna, Aleeza Namit, Kota A. Ramana. Prevention of lung cancer growth by an edible mushroom-derived p-terphenyl antioxidant, Vialinin-A [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 6331.
Abstract 4102: N6-methyladenosine modification of FZR1 mRNA promotes gemcitabine resistance in pancreatic cancer
Authors: Ziming Chen
Journal: Cancer Research (2025)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of less than 10% and limited treatment options. Gemcitabine, a pyrimidine nucleoside analogue, is the standard first-line treatment for pancreatic cancer. However, drug resistance to gemcitabine remains a major challenge in PDAC. Dysregulation of N6-methyladenosine (m6A) modification has been linked to human disease regulation, and targeting aberrant m6A modifications or their key regulators may be beneficial to overcome drug resistance. However, the potential role and precise mechanism of m6A modification in the development of gemcitabine resistance in PDAC have not been fully elucidated. Methods: In this study, we screened gemcitabine-insensitive and -sensitive PDAC cells through exposure to time- and dose-gradient gemcitabine. We then performed m6A-sequencing analysis on these cells and identified the hyper-m6A modification of FZR1 as a key molecular event contributing to gemcitabine insensitivity in PDAC. Additionally, we examined human PDAC samples using m6A-qPCR assays and reaved that FZR1 m6A modification had a significant clinical PDAC diagnosis and therapeutic value for PDAC. Results: We found that PDAC cells with distinct gemcitabine sensitivity showed different m6A profiles and that FZR1 had the most upregulated m6A modification in gemcitabine-insensitive cells compared with gemcitabine-sensitive cells. Mechanistically, we discovered that RNA m6A modification enhanced FZR1 translation in a GEMIN5-dependent manner, leading to a gemcitabine-insensitive phenotype by inducing a quiescent state. Importantly, targeting the m6A modification of FZR1 increased the sensitivity of PDAC cells to gemcitabine both in vitro and in vivo. Conclusions: This study identified the m6A-FZR1 axis as an underlying mechanism contributing to gemcitabine treatment resistance in pancreatic cancer. The m6A-FZR1 axis may serve as a predictor of gemcitabine treatment response in patients with PDAC. Overall, our discoveries interestingly link the dysregulated m6A modification to gemcitabine insensitivity in PDAC, and provide new insights into the molecular mechanisms of gemcitabine resistance in this cancer type. Citation Format: Ziming Chen. N6-methyladenosine modification of FZR1 mRNA promotes gemcitabine resistance 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 4102.
Abstract 1386: The HSP90 Co-chaperone UNC45A is essential for prostate cancer cell proliferation in vitro and tumor growth in vivo
Authors: Taoufik LLBIYI, Asif Elahi, Digvijay Singh, Nada Eisa, Yasmeen Jilani, Ahmed Chadli
Journal: Cancer Research (2025)

Abstract UNC45A is a key co-chaperone supporting cancer cell proliferation and tumorigenesis. Interestingly, UNC45A is essential for cancer cells but not for normal cell proliferation. However, the mechanism underlying UNC45A regulatory function is not well studied. We have previously shown that UNC45A functions as a glucocorticoid receptor (GR) co-activator to drive the mitotic kinase NEK7 gene transcription. NEK7 is essential for centrosome separation, mitotic spindle formation, and cytokinesis. GR has been implicated in promoting aggressive prostate tumor growth and resistance to therapy. Indeed, GR upregulation is an established mechanism to bypass the androgen receptor blockade therapy in metastatic-resistant prostate tumors. Here, we tested the hypothesis that UNC45A promotes GR-mediated resistance to hormonal therapy. To this end, we used shRNA-mediated gene silencing to evaluate the impact of UNC45A loss on PC3 prostate tumor progression. Our results show that silencing UNC45A reduces cell proliferation in vitro and tumor growth in vivo. TUNEL analysis and Ki67 staining show that loss of UNC45A triggers DNA damage, reduced cell proliferation, and apoptosis in PC3 tumors grown in the NOD SCID mice model. Immunofluorescence analysis shows a remarkable disorganization of centrosomes in tumor cells expressing UNC45A shRNA. The importance of UNC45A in promoting enzalutamide resistance is being tested in tridimensional spheroid culture and in vivo and will be discussed in this meeting. Overall, our results support the hypothesis that UNC45A is a promising cancer therapeutic target and highlight the need for developing UNC45A small molecule inhibitors to treat aggressive diseases such as prostate and breast cancers. Citation Format: Taoufik LLBIYI, Asif Elahi, Digvijay Singh, Nada Eisa, Yasmeen Jilani, Ahmed Chadli. The HSP90 Co-chaperone UNC45A is essential for prostate cancer cell proliferation in vitro and tumor growth in vivo [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 1386.
Abstract 5033: Secondary findings from genome sequencing are prevalent in pediatric cancer patients
Authors: Safa Majeed Grant, Brianne Laverty, Stephenie Prokopec, Christian Marshall, Trevor Pugh, Adam Shlien, Anita Villani, Stephen Scherer, Yvonne Bombard, David Malkin
Journal: Cancer Research (2025)

Abstract Purpose: Genome sequencing in cancer care can reveal secondary findings (SFs) - genetic variations unrelated to the primary condition - yielding potential impacts on patient health and reproductive decision-making. While the American College of Medical Genetics (ACMG) recommends investigating a specific list of actionable SFs during clinical diagnostic sequencing, the prevalence of these findings in pediatric patients with cancer remains unknown. Germline genome sequencing is becoming standard in cancer care, yet no evidence exists to guide providers on the frequency and clinical relevance of SFs in pediatrics. Methods: To understand the landscape of SFs in pediatric cancer, we analyzed germline variants from genome sequencing across pediatric patients from the SickKids Cancer Sequencing Program (KiCS) and the Canadian COVID-19 Genomics Network (HostSeq). Germline pathogenic (P) and likely-pathogenic (LP) variants with allele frequencies &amp;lt;0.03 in gnomAD populations were considered SFs (including carrier status). Variants associated with primary clinical indications were removed. We compared the prevalence of SFs (including ACMG SF v3.2) across cancer and non-cancer populations of diverse genetic ancestry to inform clinical decision-making in pediatrics. Results: The median age of KiCS participants (n=396) was 15 years (SD=10.6), compared to 7 years for HostSeq participants (SD=5.3, n=158), with 55% and 56% male participants respectively. Cancer diagnoses for KiCS participants included 51 different tumor types. On average, KiCS patients had 3.96 P or LP SFs from germline genome sequencing, similar to the HostSeq COVID-19 cohort (3.73). Across the combined cohort (n=454), P and LP variants were most common in CFTR (n=39), ABCA4 (n=32), NPHS2 (n=32), FLG (n=31) and BCHE (n=21) genes. Moreover, 5.7% of participants across cohorts had ≥1 clinically actionable ACMG SF (36 patients, n=454). Hereditary breast and ovarian cancer were the most common ACMG conditions identified from ACMG SFs in the Hostseq cohort. Citation Format: Safa Majeed Grant, Brianne Laverty, Stephenie Prokopec, Christian Marshall, Trevor Pugh, Adam Shlien, Anita Villani, Stephen Scherer, Yvonne Bombard, David Malkin. Secondary findings from genome sequencing are prevalent in pediatric cancer patients [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 5033.
Abstract 4145: TRIM21 functions as an oncogene in glioblastoma by transactivating FOSL1 and promoting the ubiquitination of p27 transactivating FOSL1 and promoting the ubiquitination of p27
Authors: Vanajothi Ramar, Rajveer Sidhu, Osei Pako, Cheyenne R. Cisse, Shanchun Guo, Mingli Liu
Journal: Cancer Research (2025)

Abstract Background: Our previous studies demonstrated that FOSL1 promotes glioblastoma (GBM) progression and stemness through multiple pathways such as STAT3 and NF-κB signaling. Recently, we identified that FOSL1 physically interacts with the E3 ligaseTRIM21, which is localized in the nucleus of glioma cells. This study investigates the role of TRIM21 in GBM, its relationship with FOSL1, and its regulation of the TRIM21 ubiquitination target gene p27. Methods: 1) Protein interaction: Immunoprecipitation assays were conducted to examine the physical interaction between TRIM21, FOSL1, and p27. 2) Regulation of p27: TRIM21 overexpression and knockdown (via siRNA) were used to analyze the effects on p27 protein levels. 3) Ubiquitination assay: TRIM21 knockdown followed by p27 immunoprecipitation and anti-ubiquitin probing was performed to assess ubiquitination. 4) Clinical data analysis: TCGA datasets were analyzed to correlate TRIM21 expression with glioma subtype and patient survival. 5) Functional assays: Glioma cell growth (MTT, colony formation) and invasion (transwell assay) were measured following TRIM21manipulation. 6) Histopathology: IHC was performed to evaluate TRIM21 expression in glioma patient tissues and its relationship with FOSL1 expression. 7) Nuclear TRIM21: The effects of nuclear-localized TRIM21 in regulating FOSL1 was assessed, including its ability to stimulate FOSL1 promoter activity via AP-1 binding sites. Results: 1) TRIM21 physically interacts with FOSL1 and p27. 2) TRIM21 promotes p27 degradation through ubiquitination in a dose-dependent manner. 3) TCGA analysis reveals high TRIM21 expression in GBM patients, particularly in the mesenchymal subtypes. 4) TRIM21 enhances glioma growth and invasion in short-term and long-term assays. 5) IHC data show elevated TRIM21 levels in grade IV GBM tissues, correlating with FOSL1 expression. 6) nuclear-localized TRIM21 promotes FOSL1 transactivation via AP-1 sites and simultaneously mediates p27 degradation. Conclusion: TRIM21 functions as an oncogene in GBM by driving FOSL1 transactivation and degrading the tumor suppressor gene of p27, thereby promoting GBM progression and aggressiveness. Citation Format: Vanajothi Ramar, Rajveer Sidhu, Osei Pako, Cheyenne R. Cisse, Shanchun Guo, Mingli Liu. TRIM21 functions as an oncogene in glioblastoma by transactivating FOSL1 and promoting the ubiquitination of p27 transactivating FOSL1 and promoting the ubiquitination of p27 [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 4145.
Abstract 4137: Investigating VRK1 inhibition as an anti-cancer therapy for pancreatic ductal adenocarcinoma
Authors: Kun Yuan Chu, Yaning Xi, Shelby Schwarz, Kevin T. Vaughan
Journal: Cancer Research (2025)

Pancreatic ductal adenocarcinoma (PDAC) is a aggressive and often a lethal form of exocrine pancreatic cancer with a 5-year survival rate of 12%. Current PDAC therapeutics are ineffective and highly toxic, leading to a variety of harsh side effects that greatly reduce patient quality of life. This low quality of life highlights the need for new approaches. This study investigates the potential of inducing nuclear envelope instability in PDAC cells through inhibition of Vaccinia-Related Kinase 1 (VRK1). Previous studies in the Vaughan lab have demonstrated that the knock down of VRK1 reduces BAF phosphorylation, reduces BAF/Lamin A interaction, and leads to nuclear blebbing. Evidence also suggests that nuclear blebbing leads to DNA leakage and activation of the cGAS-STING pathway and cellular senescence. However, it remains unclear what stage of the cell cycle is inhibited by VRK1 inhibition. To determine when this phenomenon occurs, we synchronized Cos7 cells using a thymidine and nocodazole block and treated with VRK1-IN-1, a potent VRK1 inhibitor. To determine if VRK1 inhibition affects a certain stage of mitosis, cells were synchronized and stained for tubulin and Lamin A. We observed that VRK1-IN-1 does not affect a specific stage of the cell cycle. Here we developed a protocol for measuring the effect of VRK1 inhibitors on mitosis and the cell cycle. This protocol will serve as a launching point to validate the discovery of VRK1 inhibitors from a 12,000-compound kinase assay screen. Elucidation and understanding of when VRK1 inhibition activate/induces the cGAS-STING pathway and cellular senescence, may provide the rational for to pursuing of VRK1 inhibitors as novel therapeutics for the treatment of PDAC. Citation Format: Kun Yuan Chu, Yaning Xi, Shelby Schwarz, Kevin T. Vaughan. Investigating VRK1 inhibition as an anti-cancer therapy for pancreatic ductal adenocarcinoma [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 4137.
Abstract 5052: Large-scale genomic analysis of mutation signatures reveals pathway alternations linked to breast cancer prognosis
Authors: Mate Posta, Balazs Gyorffy
Journal: Cancer Research (2025)

Abstract Introduction: Advancing breast cancer treatment demands a thorough understanding of the genetic and molecular mechanisms that drive disease progression. Our study aims to explore pathway-wide mutational patterns to uncover molecular interactions that influence survival outcomes. Methods: We integrated mutation data from three major breast cancer databases, comprising a total of 4,586 samples and over 25,000 genes. We considered disruptive mutations for survival analysis. We applied Cox proportional hazard regression to link gene mutations and altered molecular pathways with patient outcomes. Results: Our analysis identified 17 genes with significant associations with relapse-free survival, with the most impactful genes being TP53 (HR: 2.04, p: 4.65×10-33), CARD11 (HR: 2.59, p: 1.54×10-5), and PIK3R1 (HR: 2.27, p: 3.66×10-5). The most significant KEGG pathways affecting relapse-free survival were MicroRNAs in cancer (hsa05206, HR:2.48, p: 2.69×10-32), Hepatocellular carcinoma (hsa05225, HR: 2.39, p: 8.88×10-30), and Breast cancer (hsa05224, HR:2.38, p: 1.78×10-28). We also identified significant patterns of mutual exclusivity and co-mutation. Pairs such as GATA3-TP53 (OR: 0.201, p: 1.42×10-37), CDH1-TP53 (OR: 0.336, p: 3.66×10-21), and AKT1-PIK3CA (OR: 0.199, p: 4.97×10-13) were mutually exclusive, while MAP3K1-PIK3CA (OR: 2.83, p: 4.62×10-23), CBFB-GATA3 (OR: 4.67, p: 3.37×10-18), and AHNAK2-MUC16 (OR: 3.39, p: 1.35×10-15) emerged as co-mutated gene pairs. Finally, an online platform (https://server2.kmplot.com/breast) has been developed to facilitate future studies designed to validate pathway-specific results. Conclusions: In summary, by compiling a large-scale breast cancer database, we identified disruptive mutation patterns associated with altered survival outcomes. Out new tool provides a valuable resource for future research and treatment development. Citation Format: Mate Posta, Balazs Gyorffy. Large-scale genomic analysis of mutation signatures reveals pathway alternations linked to breast cancer prognosis [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 5052.
Abstract 4472: Self-assembly of CD38-binding peptides into nanofibers for imaging multiple myeloma
Authors: Jacqueline Godbe, Amit Kumar Sharma, Rui Tang, Han Jing, Alexander Zheleznyak, Monica Shokeen
Journal: Cancer Research (2025)

Abstract CD38 is overexpressed in multiple myeloma (MM) and the target of clinically approved therapeutic antibodies daratumumab and isatuximab. Our lab has previously developed a peptide-based radiotracer (LS1209) that targets CD38 for specific and sensitive imaging in MM. In this study, we demonstrate that the addition of lipid tails to LS1209 templates self-assembly of this peptide into multivalent nanofibers with morphology controlled by the length of the lipid tail. Morphology of the nanofibers was assessed via conventional and cryo-electron microscopy. Internal packing of the peptides was assessed via fluorescence. As the length of the lipid tail increases, the average spacing between residues increases. Additionally, there is a distinct morphologic change between cylindrical nanofibers and helical nanofibers as the lipid tail increases in length from a hexanoic acid tail to an octanoic acid tail. These nanofibers effectively multimerize LS1209 in order to take advantage of multivalent and cooperative binding to CD38, which was assessed via surface plasmon resonance (SPR) and cell surface binding. We demonstrate that binding activity is related to nanofiber morphology and the packing density/availability of peptides for binding interactions. Additionally, the nanofiber design co-localizes radiotracers to the site of interest without CD38 binding events, leading to additional increases in signal. The nanofibers demonstrate high efficiency radiolabeling with 64Cu and are stable at 24h in serum when assessed by radio thin layer chromatography. Preliminary animal experiments demonstrate no toxicity at expected imaging and high concentration (20x) doses. Citation Format: Jacqueline Godbe, Amit Kumar Sharma, Rui Tang, Han Jing, Alexander Zheleznyak, Monica Shokeen. Self-assembly of CD38-binding peptides into nanofibers for imaging 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 4472.
Abstract 6167: Defining the role of transcriptional coregulator MED15 in immune adaptation in cancer
Authors: Sara Cristiano, Xuanjin Cheng, Stefan Taubert
Journal: Cancer Research (2025)

Abstract The immune system is widely recognized as an important regulator of cancer progression and metastasis, where immune cells can actively promote or inhibit tumor growth. Initially, immune cells act to eradicate cells with emerging cancerous properties, but cancer cells reprogram these immune cells to instead help promote growth of the cancer. Modulating the immune system is therefore an important approach in cancer therapy, however, the identification of new molecular targets is still needed. A potential target includes MED15, a subunit of the transcriptional coregulator complex Mediator, which interacts with transcription factors (TFs) bound to gene regulatory elements. MED15 upregulation occurs in several cancers and is associated with aggressive clinical presentation and shorter patient survival. The precise role that MED15 plays in immune responses in cancer, however, is not known. To investigate this, MED15KO A549 lung adenocarcinoma cells were used to analyze the expression and secretion of various pro-inflammatory immune response genes. The MED15KO cells displayed downregulated expression of the immune genes CXCL3, CXCL5, and PTGS2, and the immune receptor TLR4, indicated by qPCR. Decreased expression of the pro-inflammatory modulator COX2 (the product of PTGS2) was also observed using immunoblot analysis and decreased secretion of CXCL chemokines and PGE2 (the proinflammatory mediator synthesized by COX2) was observed using ELISA and multiplex assays. The functional effects resulting from this lower expression/secretion of pro-inflammatory mediators were examined, specifically the migration of immune cells towards the cancer cells. A decrease in the migration of THP-1 differentiated macrophages was observed towards the MED15KO cells in comparison to WT A549 cells, using a transwell migration assay. To determine how MED15 regulates the expression/secretion of these pro-inflammatory genes a Cut&amp;Run protocol was optimized. This will reveal if MED15 binds chromatin near TFs known to regulate these immune genes, identifying candidate TFs that may cooperate with MED15. In sum, this data suggests that MED15 is required for the expression and secretion of these immune genes and their ligands, while highlighting an important role for MED15 in pro-inflammatory immune responses in cancer. Citation Format: Sara Cristiano, Xuanjin Cheng, Stefan Taubert. Defining the role of transcriptional coregulator MED15 in immune adaptation 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 6167.