tbuckley/cabot-search huggingface dataset:
Abstract 1682: Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E)
Authors: Md Mohiuddin, Vanda Póvoa, Rita Fior, Frank A. Sinicrope
Journal: Cancer Research (2025)

Abstract Background: Mutant BRAF(V600E) is present in 8-12% of human colorectal cancers (CRCs) and is associated with treatment resistance and poor survival. Targeted therapy with inhibitors of BRAF and EGFR is associated with only an incremental survival benefit. Methods: We studied the novel CDK2/CDK9 inhibitor, fadraciclib, alone and in combination with the BRAF inhibitor encorafenib on isogenic CRC cells with two, one, or no BRAFV600E alleles (RKO+/+, A19+/-, T29-/-). Analysis of apoptosis, colony formation, and the cell cycle was performed. The effect of drug treatment on growth of tumor xenografts was determined in a zebrafish model. Results: Fadraciclib induced apoptosis and inhibited colony formation in a gene dose-dependent manner. Its growth inhibitory effect when combined with encorafenib was synergistic. Mechanistically, fadraciclib suppressed the expression of pro-survival MCL-1 and decreased the phosphorylation of RNA polymerase II indicating suppression of RNA transcription. Fadraciclib also impaired Rb phosphorylation and promoted a DNA damage response indicated by the cleavage of PARP, pH2AX (ser139), and activation of p53. Drug treatment was associated with a greater suppression of Rb phosphorylation, cell cycle inhibition, and apoptosis in RKO+/+ versus A19+/- and T29-/- cells. In a zebrafish tumor xenograft model, fadraciclib plus encorafenib significantly reduced the tumor xenograft size concurrent with increased caspase-3 activation. Conclusion: Fadraciclib plus encorafenib potently induced apoptosis and synergistically suppressed tumor cell growth in a gene dose-dependent manner in BRAFV600E CRC cells, and exerted anti-tumor effects in a tumor xenograft model. These data suggest a novel therapeutic strategy in this CRC subtype. Citation Format: Md Mohiuddin, Vanda Póvoa, Rita Fior, Frank A. Sinicrope. Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E). [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 1682.
Abstract 2799: SNORD80-guided 2'-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses
Authors: Liang Xu, Xiao hong Zhao, Yuan yuan Zhang, Lei Jin, Xu Dong Zhang
Journal: Cancer Research (2025)

Abstract The introns of the gene encoding the long noncoding RNA (lncRNA) GAS5 host up to 10 C/D box small nucleolar RNAs (snoRNAs). However, whether there is a regulatory and functional relationship between these snoRNAs and GAS5 is unknown. Here, we show that the expression of SNORD80, but not the other snoRNAs, parallels GAS5 expression and is regulated alongside GAS5 in response to cellular stress. The 2′-O-methylation at the A496 site, located within a segment of GAS5 complementing the conserved RNA binding region on SNORD80, promotes GAS5 stability and consequent upregulation. This methylation requires SNORD80, as it is diminished by knockdown of SNORD80 and increased by SNORD80 overexpression, similar to the effects of manipulating the expression of fibrillarin, the methyltransferase of the box C/D small nucleolar ribonucleoprotein particle (snoRNP). The upregulation of SNORD80 in response to cellular stress is due to an enhancement in its stability, which is associated with an increase in its interaction with fibrillarin. Collectively, these results identify a novel role for SNORD80 in guiding 2′-O-methylation to stabilize GAS5. This uncovers a feedforward regulatory loop at the GAS5 gene locus in response to cellular stress and sheds new light on posttranscriptional mechanisms governing lncRNA expression. Citation Format: Liang Xu, Xiao hong Zhao, Yuan yuan Zhang, Lei Jin, Xu Dong Zhang. SNORD80-guided 2'-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses. [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 2799.
Abstract 1523: Discovery and Validation of a novel small molecule metabolic inhibitor targeting glioblastoma growth
Authors: Maheedhara R. Guda, Andrew J. Tsung, Swapna Asuthkar, Kiran Velpula
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis and limited treatment options. Pyruvate dehydrogenase kinase 1 (PDK1) plays a critical role in the metabolic reprogramming of GBM cells, making it an attractive therapeutic target. In this study, we investigated the efficacy of a novel PDK1 inhibitor, in inhibiting GBM progression. Using U87 glioblastoma cells, we demonstrated that the UIC novel inhibitor significantly reduced cell viability, induced G2/M cell cycle arrest, inhibited glycolysis, and promoted oxidative phosphorylation. In vitro assays revealed that the UIC novel inhibitor effectively suppressed U87 cell migration and invasion compared to dichloroacetate (DCA), another PDK1 inhibitor. Wound healing and transwell invasion assays showed that the UIC novel inhibitor reduced wound closure and cell invasion by 83%, outperforming DCA. Furthermore, the UIC novel inhibitor treatment increased reactive oxygen species (ROS) production and decreased lactate release, indicating a shift from glycolysis to oxidative metabolism. In vivo, intracranial implantation of U87 cells into mice followed by the UIC novel inhibitor treatment resulted in prolonged survival, delayed tumor-associated weight loss, and reduced tumor burden compared to vehicle controls. Hematoxylin and eosin (H&amp;E) staining confirmed smaller tumor sizes in treated mice, while immunohistochemistry (IHC) revealed decreased expression of PDK1 and phosphorylated EGFR (pEGFR), key oncogenic markers in GBM. These findings suggest that the UIC novel inhibitor is a potent inhibitor of PDK1 with significant anti-tumor activity in GBM models, offering a promising therapeutic strategy for targeting metabolic vulnerabilities in GBM. Further clinical evaluation of the UIC novel inhibitor is warranted to explore its potential as a novel treatment option for glioblastoma patients. Citation Format: Maheedhara R. Guda, Andrew J. Tsung, Swapna Asuthkar, Kiran Velpula. Discovery and Validation of a novel small molecule metabolic inhibitor targeting glioblastoma growth [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 1523.
Abstract 2719: Decoding role of KMT5C-H4K20me3 in EGFRi resistance in non-small cell lung cancer
Authors: Jihye Son, Alexandra Glaws, Christina Davidson, Ching-Hua Shih, Paula Vertino, Andrea Kasinski
Journal: Cancer Research (2025)

Abstract Epigenetic dysregulation has recently been recognized as a new hallmark of cancer, with dysregulation of chromatin remodelers estimated to affect 10-20% of cancer. Thus, understanding how epigenetic-based mechanisms contribute to cancer initiation and progression is critical. KMT5C is a histone methyltransferase that catalyzes histone H4 lysine 20 trimethylation (H4K20me3), which has historically been associated with formation and maintenance of constitutive heterochromatin regions. Perturbations in KMT5C-H4K20me3 in cancer has been extensively characterized, including our own work in which we discovered that loss of KMT5C promotes development of resistance to EGFR inhibitor (EGFRi) in EGFR-mutant non-small cell lung cancer (NSCLC) cells. Patient data further supports that the KMT5C transcript level is downregulated following resistance to osimertinib, a third-generation EGFRi. Here, we present data to support a non-canonical role for H4K20me3 where it regulates genes outside of heterochromatin. Notably, deposition of H4K20me3 in these regions occurs without the need for H3K9me3, which was thought to be a prerequisite for H4K20me3 deposition. This uniquely deposited H4K20me3 is associated with pathways such as DNA replication and cell cycle transition. H4K20me3 also co-localizes with activating histone modifications including H3K4me3, requiring additional studies to evaluate how dysregulation of H4K20me3 is involved in transcriptional programming in NSCLC to promote EGFRi resistance. Finally, we identifed the KMT5C interactome, which reveals novel interacting partners of KMT5C, potentially uncovering mediators of KMT5C dysregulation. Taken together, our findings unveil novel roles of KMT5C-H4K20me3 in regulating chromatin architecture and suggest etiological mechanism of KMT5C-driven EGFRi resistance in NSCLC. Citation Format: Jihye Son, Alexandra Glaws, Christina Davidson, Ching-Hua Shih, Paula Vertino, Andrea Kasinski. Decoding role of KMT5C-H4K20me3 in EGFRi resistance in non-small cell lung 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 2719.
Abstract 2698: Altered collagen morphology in pancreatic cancer treated with the iRGD tumor-penetrating peptide
Authors: Yoon Ho Choi, Minji Kim, Hotaka Kawai, Yukihito Kuroda, Norio Miyamura, Seock-Jin Chung, Kazuki N. Sugahara, Tae Hyun Hwang
Journal: Cancer Research (2025)

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, collagen-rich stroma that impedes drug delivery. We investigated how iRGD-mediated nanoparticle delivery modifies collagen architecture using humanized mouse models. Computational analysis of Picro-Sirius Red-stained whole-slide images (WSIs) using curvelet transform-based fiber extraction method (CT-FIRE) was performed to quantitatively examine changes in collagen features, thereby understanding treatment-induced alterations in the tumor microenvironment (TME). Methods: Humanized PDAC mice were prepared with either the human PANC-1 cell line or 0779 primary human PDAC cells and treated with or without iRGD monotherapy for two months (n=12). Primary tumors were sectioned and stained with Picro-Sirius Red to visualize collagen structures. WSIs of Picro-Sirius Red-stained tissues were analyzed with CT-FIRE to extract six morphological features of collagen, including average fiber length, waviness, and density to capture structural changes. WSIs were divided into 256×256 pixel tiles with consistent sampling through bootstrapping, followed by permutation testing for statistical validation (1,000 permutations, p&amp;lt;0.01). Results: Computational analysis revealed significant iRGD-induced collagen remodeling with quantifiable changes in key structural and morphological features. Permutation testing showed that, compared to controls, average fiber length decreased by 3.27% (p&amp;lt;0.01), waviness reduced by 3.25% (p&amp;lt;0.01), and density diminished by 36.3% (p&amp;lt;0.01), compared to controls. The structural changes were more notable in 0779-derived tumors compared to PANC-1, with reductions in average fiber length (1.03%, p&amp;lt;0.01), waviness (8.78%, p&amp;lt;0.01), and collagen density (24.27%, p&amp;lt;0.01), demonstrating cell-line dependent stromal remodeling. Conclusions: Our findings suggest that long-term iRGD therapy alters collagen morphology in PDAC. Further investigation is warranted to understand how these alterations contribute to enhanced penetration of drugs and immune cells observed in iRGD-treated PDAC tumors. The observed cell-line dependent variations in stromal remodeling suggest tumor heterogeneity influences treatment response, highlighting the potential for personalized therapeutic approaches in stromal-rich tumors like PDAC. Citation Format: Yoon Ho Choi, Minji Kim, Hotaka Kawai, Yukihito Kuroda, Norio Miyamura, Seock-Jin Chung, Kazuki N. Sugahara, Tae Hyun Hwang. Altered collagen morphology in pancreatic cancer treated with the iRGD tumor-penetrating peptide [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 2698.
Abstract 1821: <i>In vivo</i> synergy is observed with AMG-232 and radiotherapy in endometrial cancer
Authors: Aaron P. Petty, Yvonne Parker, Daniel Lindner, Roberto Vargas
Journal: Cancer Research (2025)

Abstract Background: Approximately 15% of high-grade TP53-mutated endometrial cancers (EC) are heterozygous and retain wild-type (WT) signaling. Our previous in vitro findings nominated MDM2 inhibitors as potential radio-sensitizing strategies that leverage TP53 WT signaling. Here, we further explore this radio-sensitizing role for one particular inhibitor, AMG-232, in an in vivo xenograft model with a TP53 WT EC cell line. Methods: To evaluate the radio-sensitizing potential of AMG-232 in vivo, we utilized a xenograft tumor model with the JHUEM-2 (TP53 WT) cell line. Cells (2x106) were injected subcutaneously in the bilateral flanks of 6-8 week old female NSG mice. Mice were separated into 4 treatment groups and 6 mice (n= 12 tumors) were included in each group: Vehicle, Radiation (RT), AMG-232, and Combination. Once the largest tumors were 200-300mm3 in size, mice were given either Vehicle or AMG-232 (30 mg/kg) by gavage for 9 days. In the RT and Combination groups, a single dose of 1 Gy of radiation was given 24 hours following first drug dose. Assessment of treatment synergy was carried out using both the Highest Single Agent (HSA) and Bliss Independence models with bootstrap analysis at either single timepoints, or over the entire growth curve based on area under the curve (AUC). Synergy scores were calculated as a measure of deviation from additivity, with positive values indicating synergy. Synergy analyses were carried out using the invivoSyn package in R software. Results: AMG-232 and RT together significantly suppressed tumor growth at treatment days 7 and 9 compared to either RT alone (P= 0.004 and P= 0.0014, respectively) or AMG-232 alone (P= 0.003 and P= 0.0061, respectively). Synergy analysis of growth inhibition at treatment day 9 using both the HSA and Bliss models showed significant synergy in the combination group, with mean synergy scores of 27 (P= 0) and 25 (P= 0.003), respectively. Entire growth curve AUC analysis also showed synergy only in the less stringent HSA model, with synergy score of 37.5 (P= 0.033). Conclusions: Overall, these findings further support the use of MDM2 inhibitors to improve radiotherapy response in EC. The improved tumor response that we observed at clinically relevant doses further highlights the potential of these agents to either enhance responses to current therapeutic strategies, or to lower the radiotherapy dose necessary for complete response. Citation Format: Aaron P. Petty, Yvonne Parker, Daniel Lindner, Roberto Vargas. In vivo synergy is observed with AMG-232 and radiotherapy in endometrial 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 1821.
Abstract 234: Gαi2 induces cell migration in prostate cancer cells in the absence of rac1 activation
Authors: Rarnice Johnson, Silvia Caggia, Shafiq Khan
Journal: Cancer Research (2025)

Abstract Prostate cancers can grow slowly and are confined to the prostate gland; However, metastatic prostate cancers are aggressive and can spread quickly. Gαi2 is a heterotrimeric G protein subunit and its essential for cell migration in prostate cancer cells, in response to both oxytocin and EGF, acting via GPCR and PTKR, respectively. The Rho family of GTPases includes RhoA, Rac1 and Cdc42, these are intracellular protein that regulate cell migration. In the previous studies we seen that the knockdown of Gαi2 reduces cell migration and lamellipodia formation at leading edge of PC3 cell overexpressing constitutively active Rac1, therefore Gαi2 may be involved in the regulation of cell motility and lamellipodia formation at a step which is independent or downstream of Rac1 activation. We hypothesize that Gαi2 is required for the activation of the downstream proteins of Rac1 leading to lamellipodia formation at the leading edge of migrating cells. We overexpressed constitutively active form of Gαi2 (Gαi2-Q205L) in PC3 parental cell lines. The result showed that when PC3 cells are transfected with Gαi2-Q205L the migration rate in these cells is significantly increased. In the parallel experiment we used a specific Gαi2 inhibitor, which resulted in attenuation of Giα2-Q205L effects on cell migration in PC3 cells. Furthermore, Rac1 inhibitor did not block increased cell migration in PC3 cells overexpressing constitutively active Gαi2. We studied Gαi2 effects on proteins activated by Rac1, specifically Wave2 and Arp 2/3. We transfected PC3 empty vector and PC3 Rac1 constitutively active stable cells with control siRNA or Gαi2 siRNA to knockdown endogenous Gαi2 expression. The western blot analysis showed Rac1 dependent activation of Wave2 and Arp 2/3 are impaired in the absence of Gαi2. We conclude activated Gαi2 plays a crucial role in cell migration in prostate cancer cells which is independent of Rac1 activation. Acknowledgement: These studies were supported by the NIH/NIMHD/RCMI under Award Number U54MD007590. Citation Format: Rarnice Johnson,Silvia Caggia,Shafiq Khan. Gαi2 induces cell migration in prostate cancer cells in the absence of rac1 activation [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 234.
Abstract 2696: Targeting SLC7A11 creates a favorable immune microenvironment in colorectal cancer
Authors: Jichang Li, Xiaoxue Pan, Kang Xia, Zeruo Yang, Xiaojing Yang, Pengyuan Wang, Shanwen Chen
Journal: Cancer Research (2025)

Abstract Background: Cysteine is a key immunoregulatory nutrient in colorectal cancer (CRC). Cystine uptake is primarily mediated by the cystine/glutamate transporter SLC7A11, which consists of 12 transmembrane α-helices that forming a channel through the cell membrane. Given SLC7A11’s role in both metabolic competition and resistance to ferroptosis, we aim to explore whether SLC7A11 can be effectively targeted with monoclonal antibodies as a therapeutic strategy for colorectal cancer. Methods: Using a cell-based in vivo immunoassay and standard hybridoma technology, we generated a human SLC7A11-specific murine monoclonal antibody, designated 1A4. Subcutaneous and orthotopic colorectal cancer models in mice, as well as an AOM/DSS-induced colitis-associated colorectal cancer model was established. We evaluated the effects of the SLC7A11 antibody on the immune microenvironment of colorectal cancer by multicolor immunofluorescence and flow cytometry. Furthermore, single-cell sequencing was employed to analyze alterations in immune cell subpopulations and to investigate the impact of the SLC7A11 antibody on immune cell metabolism and intercellular interactions within the tumor microenvironment. Flow cytometry was further utilized to validate the differential effects of the SLC7A11 antibody on CD4+ and CD8+ T cells. Results: Subcutaneous and orthotopic cancer model of colon cancer showed that treatment with 1A4 significantly reduced tumor volume. Multiplex immunofluorescence analysis showed that both duel immune checkpoint blockade and 1A4 increased the number of infiltrating CD8+ T cells and the CD8+T/Treg ratio in tumor tissues, with a more pronounced increase observed in tumors treated with 1A4. Single-cell sequencing results demonstrated that 1A4 modulated the tumor immune microenvironment by increasing the infiltration of T cells, B cells, and NK cells within the tumor tissue. RNA sequencing on CD4+ T cells exhibited more pronounced alterations in metabolic pathways. The flow cytometry results showed that treatment of CD8+ T cells with 1A4 enhanced stemness and a reduction in the proportion of exhausted CD8+ T cells. Conclusions: This study developed an antibody targeting the SLC7A11 and validated its anti-tumor effects in colorectal cancer. Targeting SLC7A11 potently creates a favorable immune microenvironment through inhibiting the activation of Tregs and increasing the stemness of CD8+ T cells. Citation Format: Jichang Li, Xiaoxue Pan, Kang Xia, Zeruo Yang, Xiaojing Yang, Pengyuan Wang, Shanwen Chen. Targeting SLC7A11 creates a favorable immune microenvironment in colorectal 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 2696.
Abstract 694: Brush biopsy miRNA based oral squamous cell carcinoma detection and localization-overcoming barriers to classifier development
Authors: Madeleine W. Fine, Samira Cheruku, Antonia Kolokythas, Ashleigh Weyh, Joel Schwartz, Beth Miloro, Guy R. Adami
Journal: Cancer Research (2025)

Abstract Cancers of the oral cavity arise from the surface tissues and, despite prominence of these sites, over 50% are not diagnosed until they are in advanced stage. Unfortunately, patients with advanced stage oral cancer have high mortality rates because treatments are usually not successful, complex and have high complication rates. Among the main reasons for delays in diagnosis of squamous cell carcinoma, which make up over 90% of oral cancers, is the resemblance of these lesions to benign lesions. Specifically, oral squamous cell carcinoma (OSCC) is often misdiagnosed as a benign process, most commonly benign leukoplakia (BL) or oral lichen planus (OLP) and is not interrogated for diagnosis confirmation. On the other extreme, patients with BL or OLP that have no malignant potential are subjected to unnecessary stress and surgical interventions when these lesions are mistaken as cancers. Unlike cancers of other organs, no screening protocols or non-invasive diagnostic tests are currently available to reliably detect these cancers early when treatments can save lives. We have developed a noninvasive brush-based tissue collection and miRNA (and not mRNA) analysis method that can differentiate OSCC from other mucosal lesions. This brush based sampling method showed 93% accuracy in differentiating OLP from OSCC based on the expression of as few as 6 miRNAs. We will report on the validation of this classifier with a set of 40 OSCC and OLP samples, and the training of a classifier to differentiate BL from OSCC with over 35 additional samples. We will also discuss the role of technical replicates and clinician calibration in efficient miRNA based classifier development. Citation Format: Madeleine W. Fine, Samira Cheruku, Antonia Kolokythas, Ashleigh Weyh, Joel Schwartz, Beth Miloro, Guy R. Adami. Brush biopsy miRNA based oral squamous cell carcinoma detection and localization-overcoming barriers to classifier development [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 694.