tbuckley/cabot-search huggingface dataset:
Abstract 1439: Gene expression profiling of canine diffuse large B-cell lymphoma: Insights from RNA sequencing
Authors: Nelly Elshafie, Ekramy SayedAhmed, Michael O. Childress, Andrea Pires dos Santos
Journal: Cancer Research (2025)

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive form of lymphoma in dogs, closely resembling human DLBCL in its clinical behavior and molecular features. While CHOP chemotherapy is the standard treatment, many dogs experience poor responses or early relapse, underscoring the need for a more comprehensive understanding of the disease’s molecular underpinnings. This study aimed to investigate the gene expression profiles in canine DLBCL to identify potential biomarkers and therapeutic targets. Materials and Methods: Fresh frozen lymph node samples were collected from six dogs diagnosed with DLBCL and four healthy controls. Total RNA was extracted, and RNA sequencing (RNA-seq) was performed to profile global gene expression. Differentially expressed genes were identified using DESeq2, and principal component analysis (PCA) was used to distinguish expression patterns between groups. Key findings were validated using quantitative PCR (qPCR) to confirm the dysregulation of selected genes. Results: RNA-seq analysis revealed 3, 156 differentially expressed genes, including 1, 418 upregulated and 1, 738 downregulated in DLBCL samples. PCA showed distinct clustering between DLBCL and healthy groups, confirming significant gene expression divergence. qPCR analysis validated these results, highlighting the upregulation of genes such as NIT2 (fold change: 3.145; FDR: 0.0074), MYC (fold change: 3.086; FDR: 0.0494), and CDK4 (fold change: 2.151; FDR: 0.0331), suggesting their involvement in tumorigenesis and disease progression. Conversely, genes such as AICDA (fold change: -4.338; FDR: 0.0284), BCL6 (fold change: -2.352; FDR: 0.0469) and CDH1 (fold change: -1.699; FDR: 0.0469) were significantly downregulated, indicating potential suppression of tumor-suppressive pathways. Conclusion: This study provides valuable insights into the molecular mechanisms underlying canine DLBCL. The identification of differentially expressed genes and pathways highlights novel biomarkers and potential therapeutic targets. Moreover, the findings demonstrate the translational relevance of canine DLBCL as a comparative model for human lymphoma, advancing our understanding of both veterinary and human oncology. This abstract was edited and formatted with the assistance of generative artificial intelligence (Chatgpt) to enhance clarity and presentation. Citation Format: Nelly Elshafie, Ekramy SayedAhmed, Michael O. Childress, Andrea Pires dos Santos. Gene expression profiling of canine diffuse large B-cell lymphoma: Insights from RNA sequencing [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 1439.
Abstract 2996: TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models
Authors: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Alan Huang, Jannik N. Andersen, Adam S. Crystal, Kimberly J. Briggs
Journal: Cancer Research (2025)

Abstract TNG462 is a clinical-stage, MTA-cooperative PRMT5 inhibitor currently being evaluated in an ongoing phase I/II clinical trial for solid tumors with MTAP loss. Approximately 10-15% of all human cancers exhibit MTAP deletions, including 10-15% of lung cancer and more than 20% of pancreatic adenocarcinomas. MTAP deletion frequently co-occurs with other genetic alterations: ∼30% of MTAP-deleted lung adenocarcinomas and ∼92% of MTAP-deleted pancreatic ductal adenocarcinomas (PDAC) also harbor KRAS mutations, while ∼20% of MTAP-deleted lung adenocarcinomas are also EGFR mutant. Although TNG462 monotherapy drives deep and durable tumor regressions in MTAP-null preclinical models, we investigated its potential in combination with therapies targeting actionable genetic alterations. In relevant models, the combination of TNG462 with either KRAS or EGFR inhibitors led to significant tumor regressions, surpassing the effects of either agent alone. This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca. Additionally, nearly all MTAP-deleted cancers are also CDKN2A-deleted due to the proximity of the two genes on chromosome 9p, resulting in de-repression of the cyclin D-dependent CDK4/6 complexes, which creates a susceptibility to CDK4/6 inhibition. Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib. Lastly, MTAP loss also sensitizes cells to MAT2A inhibition, providing strong rationale for combining PRMT5 inhibitors with MAT2A inhibitors. Preclinical data demonstrated significant efficacy when subtherapeutic doses of both agents are combined. However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss. Citation Format: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Alan Huang, Jannik N. Andersen, Adam S. Crystal, Kimberly J. Briggs. TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models [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 2996.
Abstract 1332: Major histocompatibility complex class I chain-related gene A and B expression induced by heavy ion beam irradiation in cervical cancer cells
Authors: Sumitaka Hasegawa, Nakako Nakajima
Journal: Cancer Research (2025)

Major histocompatibility complex class I chain-related gene A and B (MIC) are transmembrane glycoproteins to function as a ligand for human NKG2D that is a main activating receptor of NK cells. MIC is minimally expressed on normal cells, but frequently upregulated via viral infection, cellular stress signals, and malignant transformation. NKG2D recognizes MIC, resulting in the activation of NK cells. Recent progress on radiation biophysics has shown that photon or particle radiation can modulate anti-tumor immunity in host irradiated via regulation of immune recognition protein expression on cancer cells. The aim of this study is to investigate the effects of heavy ions beam irradiation on membrane MIC expression in human cervical cancer cells. We used HEK293 cells stably overexpressing HPV-E6 or E7 oncoproteins and 5 human cervical cancer cell lines in this study. Carbon ions beam irradiation (CIR, 290 MeV/n; LET, ∼70 keV/μm, mono peak), a beam of heavy ion beams, was performed at the in-house synchrotron accelerator that is able to produce carbon ion beams. Irradiated doses ranged from 0 to 10 Gy of carbon-ions. Cell membrane MIC expression was evaluated by flowcytometry using an anti-MIC antibody. MIC expression was upregulated in HPV-E6 or E7 overexpressing HEK293 cells and 5 human cervical cancer cells in a dose-dependent manner. HPV16-positive human cervical cancer Caski cells showed a remarkable upregulation of MIC expression after CIR. Other cervical cell lines (ME-180, HeLa, SiHa, and C33A) showed a modest MIC upregulation. E6- or E7-overexpressing HEK293 cells exhibited a considerable induction of MIC expression after CIR. We investigated the impact of DNA damage responses on HIR-mediated MIC upregulation using drug inhibitors of proteins that are involved in DNA damage responses. Both pharmacological Chk1 inhibition and ATM inhibition cancelled CIR-mediated MIC upregulation in HPV oncoprotein-positive HEK293 cells. The results indicated that ATM/ATR-Chk1 pathways were involved in MIC upregulation on HPV-positive cells including cervical cancer cells. These findings support the favorable combination of MIC-targeted therapy with heavy ion therapy against cervical cancers. Citation Format: Sumitaka Hasegawa, Nakako Nakajima. Major histocompatibility complex class I chain-related gene A and B expression induced by heavy ion beam irradiation in cervical cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1332.
Abstract 4696: Targeting CSF1R+ macrophages to synergize immune checkpoint therapy in SCCA-mediated radioresistant cervical cancer
Authors: Liyun Chen, Eric Liu, Victoria Shi, Marlene L. Campos Guerrero, Jasmin Yang, Abhay Singh, Matthew Inkman, Jin Zhang, Julie Schwarz, Stephanie Markovina
Journal: Cancer Research (2025)

Abstract Tumor-associated factors released by cancer cells can promote immune suppression and tolerance to radiation or immune therapy. Squamous cell carcinoma antigen (SCCA) is a tumor-associated antigen released by cancer cells. In cervical cancer, elevated pre-treatment SCCA in the serum is seen in 28-88% of patients and these patients are more likely to experience treatment resistance and recurrence. The poor prognosis for patients with elevated SCCA shows the need for improve treatment strategies. Here, we aim to understand the mechanism of action of circulating SCCA to tumor progression and response to radiotherapy. Using sequencing analysis of paired pre- versus on-treatment biopsies, we found that patients with elevated serum SCCA had increased macrophages expressing immunosuppressive features and T-cell immune checkpoints, inversely correlated with inflammatory signaling and radiation-induced interferon-stimulated gene expression. The supplement of SCCA protein (rSCCA) to the media during in vitro macrophage differentiation promotes anti-inflammatory cytokines and gene expression. Peritoneal macrophages isolated from mice treated with intra-peritoneal rSCCA expressed high M2-associated markers and functional inhibition of T cell activation. Moreover, we found that mouse tumors engineered to express SCCA with a signal peptide promoting extracellular secretion displayed increased CSF1R+ TAM infiltration and decreased T cell activation, associated with reduced response to combined radiation and anti-PDL1 treatment. Giving the findings, we hypothesized that targeting TAMs in tumors with elevated SCCA is imperative. We further demonstrated that tumor-bearing mice showed improved response to radiation and immune checkpoint therapy when receiving concurrent CSF1R blockade, abolishing the protective effect of high circulating SCCA. Our results suggest that blockade of CSF1R signaling or other myeloid-targeting therapeutics will optimize response to radiation and PD-L1 blockade in cervical cancer, particularly those with high circulating SCCA. Citation Format: Liyun Chen, Eric Liu, Victoria Shi, Marlene L. Campos Guerrero, Jasmin Yang, Abhay Singh, Matthew Inkman, Jin Zhang, Julie Schwarz, Stephanie Markovina. Targeting CSF1R+ macrophages to synergize immune checkpoint therapy in SCCA-mediated radioresistant cervical 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 4696.
Abstract 4710: Heterogeneous efficacy patterns of KRAS inhibitors in digestive cancers
Authors: Gustave Ronteix, Jérôme Caron, Rafal Pietrzak, Gizem Altay, Fabiana Graziosi, Lélia Polit, Anna-Rose Gryspeert, Jacques RR Mathieu, Jérôme Cartry, Sabrina Bedja, Alice Boilève, Michel Ducreux, Sophie Postel-Vinay, Fanny Jaulin
Journal: Cancer Research (2025)

Abstract Introduction: KRAS is a well-studied oncogenic driver in a variety of solid tumors, playing a pivotal role in cell proliferation and survival. Its involvement in digestive cancers, including colorectal cancer (CRC) has made it an attractive target for therapeutic development. However, efforts to expand KRAS-targeted assets in these cancers are hindered by the complex and heterogeneous expression patterns of KRAS in solid tumors, which complicate effective targeting and the translation of therapeutic efficacy across patient populations. Furthermore, clinical studies have shown that resistance mechanisms compensate KRAS inhibition and require the development of efficient combination therapies. Methods: To address these challenges, we collected 24 patient-derived organoids (PDO) representing the molecular diversity of KRAS-driven CRC and PDAC with 5 KRAS G12C variants, 8 KRAS G12D variants and 6 KRAS G12R variants. In-depth molecular and transcriptomic characterization was performed with a particular focus on co-mutation patterns for each KRAS variant. Then the PDOs were screened against a KRAS drugs with and without combination with an EGFR inhibitor. The efficacy of the drugs were systematically compared among different variant populations. Results: Our findings demonstrate that the PDO models faithfully recapitulate the KRAS heterogeneity observed in primary tumors, providing a robust preclinical platform for testing KRAS-targeted therapies. Strong synergistic effects were identified when using KRAS and EGFR inhibitors simultaneously, matching prior clinical trial results. This model system allows us to dissect the impact of KRAS expression patterns on therapeutic response and resistance mechanisms. Conclusion: Our study emphasizes the utility of PDOs as a precision tool for advancing KRAS-targeted strategies in complex solid tumors and highlights the potential for individualized approaches in the treatment of KRAS-driven digestive cancers. Citation Format: Gustave Ronteix, Jérôme Caron, Rafal Pietrzak, Gizem Altay, Fabiana Graziosi, Lélia Polit, Anna-Rose Gryspeert, Jacques RR Mathieu, Jérôme Cartry, Sabrina Bedja, Alice Boilève, Michel Ducreux, Sophie Postel-Vinay, Fanny Jaulin. Heterogeneous efficacy patterns of KRAS inhibitors in digestive cancers [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 4710.
Abstract 6321: Vialinin-A, an antioxidant isolated from edible mushroom <i>thelephora vialis</i>, inhibits colorectal cancer growth
Authors: Divya Lahori, Dallin Thornton, Kota V. Ramana
Journal: Cancer Research (2025)

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. While CRC screening typically begins at age 45-50, its incidence is rising in younger populations, highlighting the need for diversified treatment options. Genetic predisposition, oxidative stress, and inflammation are recognized as major contributors to the pathogenesis of this disease. Current treatments, such as chemotherapy and surgical resection, often lead to unwanted side effects and risks, including potential cardiotoxicity from chemotherapeutics like anthracyclines. Vialinin-A, a compound isolated from the edible Chinese mushroom Thelephora Vialis, has demonstrated antioxidant and anti-inflammatory properties. However, its anti-carcinogenic mechanisms are not well known. Human colon cancer cells such as SW480 and CaCO-2 were treated with varying concentrations of Vialinin-A for 24 and 48 h. Cell viability was determined by MTT assay. Apoptosis was evaluated through the activation of caspase-3 and the use of a human apoptosis array to analyze the expression of key apoptotic markers. Additionally, a multiplex array was used to identify oncogenic, inflammatory, and apoptotic markers in treated cells. Next, we plan to use nude mice xenografts to examine the chemopreventive role of Vialinin-A in vivo. So far, our results indicate that Vialinin-A inhibits CRC cell growth in a dose-dependent manner and suppresses the generation of reactive oxygen species (ROS). Vialinin-A activates caspase-3 in growth factor-treated cancer cells. Furthermore, Vialinin-A modulates the expression of various apoptotic and inflammatory markers in CRC cells, supporting its potential role in anti-carcinogenic pathways. Ongoing experiments aim to further elucidate the molecular mechanisms through which Vialinin-A inhibits CRC growth. Citation Format: Divya Lahori, Dallin Thornton, Kota V. Ramana. Vialinin-A, an antioxidant isolated from edible mushroom thelephora vialis, inhibits colorectal cancer 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 6321.
Abstract 6329: Edible Chinese mushroom-derived antioxidant, vialinin A, prevents breast cancer cell growth
Authors: Malak Rafik, Afnan Khan, Kota V. Ramana
Journal: Cancer Research (2025)

Abstract Breast cancer ranks as the second most prevalent cancer worldwide, impacting millions annually, and stands as the leading cancer affecting women. Neoplasia occurs when free radicals, antioxidants, and reactive oxygen species increase in the cell, which can alter protein function and cause mutations and genomic instability. Current breast cancer treatments typically include chemotherapy and radiation. However, different breast cancer cell types have different antioxidative capacities, which allow them to resist these treatments, thereby reducing the efficacy of these expensive treatments. Several vitamins, antioxidants, and anti-inflammatory compounds have been tested for their effectiveness in preventing breast cancer. However, the role of vialinin A, an antioxidant and ubiquitin-specific peptidase inhibitor derived from edible Chinese mushrooms, is unknown. Therefore, in this study, we examined the chemopreventive effect of vialinin A in preventing breast cancer cell growth and migration. Human breast cancer cells (MCF-7) were treated with vialinin A in a time- and dose-dependent manner. Cell viability assay indicates that vialinin A prevents the growth of breast cancer cells in a dose-dependent manner. Further, vialinin also prevented the EGF-induced invasion of MCF-7 cells in a scratch assay. Vialinin A also prevented the EGF-induced trans-well migration of breast cancer cells. Vialinin A also regulated the growth factor-induced expression of various pro- and anti-apoptotic factors in breast cancer cells. Vialinin A also increased the activation of caspase-3 and cleavage of PARP in growth factor-treated breast cancer cells. Next, we plan to examine the chemopreventive efficacy of vialinin A in a nude mouse xenograft model. In conclusion, our results indicate that vialinin A could prevent breast cancer cell growth and invasion, suggesting its potential development as a chemopreventive drug. Citation Format: Malak Rafik, Afnan Khan, Kota V. Ramana. Edible Chinese mushroom-derived antioxidant, vialinin A, prevents breast cancer cell 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 6329.
Abstract 4138: Investigating the relationship between DUSP12 and ZPR9 in cell division and death
Authors: Mai Abdusamad, Xiao Guo, Ivan Ramirez, Whitaker Cohn, Erick Velasquez, Ankur Gholkar, Julian P. Whitelegge, Jorge Z. Torres
Journal: Cancer Research (2025)

Abstract Protein phosphatases regulate essential processes in human cells and have critical roles in many human diseases, including cancer. The dual-specific phosphatases (DUSPs) are a subset of protein phosphatases that have become increasingly implicated in human cancers over the past decade. DUSP12 is a poorly characterized atypical DUSP widely conserved throughout evolution. While DUSP12 has been shown to possess pro-survival attributes, it is unclear if this is related to its potential role in cell division. Specifically, DUSP12 has been shown to play a role in both cell death and proliferation, acting in a protective capacity against stressful conditions in both hepatic and myocardial ischemic-reperfusion injury. Interestingly, several studies have also linked aberrant expression of DUSP12 to the development of a wide range of cancers, highlighting the importance of investigating the biological activities of DUSP12 as it appears that dissecting its functions in detail can provide insight into new mechanisms supporting uncontrolled cell growth. More recent evidence further suggests that DUSP12 affects cell cycle progression by regulating DNA content at the G1/S and G2/M checkpoints, likely through its unique zinc binding domain. However, the lack of known DUSP12 targets has hindered our understanding of the biological significance of this unique enzyme. From preliminary proteomic analyses of DUSP12 using affinity- and proximity-based approaches coupled to mass spectrometry, we identified ZPR9 as a potential interactor of DUSP12 which has been validated by in-cell and in-vitro immunoprecipitation assays. Previous studies have shown that ZPR9 may play a role in apoptosis, but it is unclear if and how ZPR9 participates in cell division and, more so, how it promotes cell death. Using cancer cell lines as a model system and leveraging advanced imaging techniques, I am performing follow-up functional studies to determine if and how ZPR9 is modified by DUSP12 and, further, if modification of ZPR9 by DUSP12 is important in influencing improper cell division. Collectively, this work will provide insights into the mechanism and regulatory role of the phosphatase DUSP12 during cell division as well as form the basis for designing novel therapeutic approaches to address diseases associated with abnormal proliferation. Citation Format: Mai Abdusamad, Xiao Guo, Ivan Ramirez, Whitaker Cohn, Erick Velasquez, Ankur Gholkar, Julian P. Whitelegge, Jorge Z. Torres. Investigating the relationship between DUSP12 and ZPR9 in cell division and death [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 4138.