tbuckley/cabot-search huggingface dataset:
Abstract 3991: A neural organoid glioblastoma model to assess tumor microenvironment interactions and tumor associated microglia and macrophage responses
Authors: Connie S. Lebakken, William Richards, Sophia Clark, Kailyn Parham, Lei Zhao, Jack Shireman, Mahua Dey
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is a treatment resistant brain tumor with a median survival post-diagnosis of only 18-20 months. One significant limitation in the development of effective therapeutics for GBM is the lack of suitable pre-clinical models that accurately replicate human GBM and the surrounding tumor microenvironment (TME) cell interactions. Tumor Associated Microglia and Myeloid-derived Macrophages, collectively TAMs, are of particular interest due to their essential role in tumor immunosuppression. We have adapted Stem Pharm’s neural organoid technology by incorporating GBM cell lines and PDX models to develop a GBM organoid model which enables interrogation of these complex, multicellular interactions within a 3D tumor organoid. Stem Pharm’s cerebral organoids contain neurons, astrocytes, endothelial cells, and microglia and leverage our proprietary synthetic hydrogel matrix to form highly reproducible organoids in a 96 well plate format. We have previously applied these organoids as a general model of neuroinflammation and developmental neurotoxicity. Microglia integrated into Stem Pharm’s neural organoids exhibit appropriate gene signatures, ramified morphology, tile, and are uniformly distributed throughout the organoid. Here we demonstrate that GBM cells integrate into and proliferate within the neural organoids and activate tumor associated microglia to an immunosuppressive phenotype. Using single cell RNA Sequencing (10X Genomics) we have characterized microglia gene expression in our model in the presence or absence of integrated GBM cells. We find microglia form distinct clusters based on the presence or absence of GBM cells in the organoids. Differentially expressed genes (DEGs) of microglia between GBM and control organoids were used for Gene Set Enrichment Analysis (GSEA). Gene sets related to migration, response to growth factors, and oxygen levels were upregulated in microglia exposed to GBM cells while sets related to inflammatory responses, cytokine production, and antigen presentation were downregulated, consistent with an anti-inflammatory, tumor-supportive microglia phenotype found within glioblastoma. This model will be useful to explore cellular interactions and modulation of the immunosuppressive tumor microenvironment of GBM in pursuit of improved therapeutics. Citation Format: Connie S. Lebakken, William Richards, Sophia Clark, Kailyn Parham, Lei Zhao, Jack Shireman, Mahua Dey. A neural organoid glioblastoma model to assess tumor microenvironment interactions and tumor associated microglia and macrophage 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 3991.
Abstract 184: PHF6-LEO1 axis depletion drives aggressive colorectal cancer through WNT activation and metabolic reprogramming with therapeutic implications
Authors: Su Chan Park, Shinae Park, Ji-Yeon Lee, Taehan Yoon, So Hyun Kwon, Jung-Shin Lee, Eun Jung Park, Ji Min Lee
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) progression is closely linked to alterations in key signaling pathways and metabolic reprogramming. The WNT signaling pathway plays a critical role in regulating cell development and proliferation, and its abnormal activation is a hallmark of CRC. Plant Homeodomain 6 (PHF6), a chromatin-associated factor, is known for its roles in clonal hematopoiesis, ribosome biogenesis, DNA repair, and aging, and is frequently mutated in lymphoid cancers and leukemia. In this study, RNA-seq and ATAC-seq were conducted to investigate the function of PHF6, we identified PHF6 as a novel regulator of the WNT signaling pathway. We found that PHF6 depletion activate WNT signaling and proliferation of colon cancer cells. In the AOM/DSS model, PHF6 knockout mice exhibited larger polyp formation compared to wild type mice, with polyps extending into the proximal region. Proximal CRC is more prevalent and aggressive and has distinct genetic features compared to distal CRC. Alterations in proximal CRC include the PIK3CA mutation and CpG island methylator phenotype (CIMP)-high frequency, the development of CIMP is followed by global gene expression alteration and metabolic changes. However, the molecular mechanisms of this type of cancer are not fully understood. We observed a reduced levels of LEO1, the transcriptional elongation partner of PHF6 within the PAF1 complex, in the proximal region of PHF6 KO mice. We identified LEO1 and SETD1A as epigenetic regulators of lipid homeostasis in colon cancer cells and patient samples with matched normal. Dysregulation of lipid metabolism in cancer cells impacts tumor initiation, progression, and metastasis. LEO1 KO cells exhibited reduced expression and activation of SREBP1, a master regulator of lipid metabolism, under glucose starvation. These effects were further enhanced by SETD1A knockdown. LEO1 was found to localize to the nucleus and is required for the nuclear localization of SETD1A under nutrient stress. These cells showed an altered cell cycle, resulting in reduced proliferation but increased metastatic potential. These findings suggest that the PHF6-LEO1 axis plays a crucial role in the regional development and metastasis, underscoring its importance in advancing our understanding of tumor biology and guiding targeted therapy development. Citation Format: Su Chan Park, Shinae Park, Ji-Yeon Lee, Taehan Yoon, So Hyun Kwon, Jung-Shin Lee, Eun Jung Park, Ji Min Lee. PHF6-LEO1 axis depletion drives aggressive colorectal cancer through WNT activation and metabolic reprogramming with therapeutic implications [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 184.
Abstract 6376: KRASmultidegrader BPI-585725 displays potent anti-tumor activity in KRAS-driven preclinical models
Authors: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Xiaoqiang Kong, Ying Zhao, Tao Zhang, Yanju Liu, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Haibo Chen, Lieming Ding, Hong Lan, Quan Zhou
Journal: Cancer Research (2025)

Abstract As a prominent oncogenic driver, KRAS mutation is prevalent in approximately 20-30% of cancer patients, particularly in colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), where it accounts for roughly 45%, 90% and 35%, respectively. Although several KRAS G12C inhibitors are already on the market, they suffer from limited efficacy and short duration of response. Thus, eliminating the KRAS protein, rather than inhibiting KRAS holds hope for the long lasting clinical efficacy. Here, we introduce BPI-585725, a novel multiple KRAS (KRASmulti) proteolysis targeting chimera (PROTAC) molecular with a DC50 in nanomolar range. In cell-based KRAS degradation assays, BPI-585725 exhibited remarkable KRAS degradation property in KRAS G12C, G12D, G12V, G13D, and WT-Amplification (WTAmp) cell lines via a ubiquitin-proteasome system (UPS) dependent mechanism. BPI-585725 suppressed the proliferation of multiple KRAS driven cancer cell lines with an IC50 &amp;lt;10 nM, including those with G12X, G13D and WTAmp mutations. Additionally, binding assay revealed that BPI-585725 has &amp;gt;300-fold selectivity for KRAS compared to N/HRAS. In vivo, a single intravenous (IV) injection of 30 mg/kg BPI-585725 maintained drug concentration in tumor for up to 6 days, accompanied by sustained KRAS degradation and downstream DUSP6 inhibition. In multiple KRAS driven CDX models, weekly dosing of BPI-585725 dose dependently inhibited the tumor growth. In conclusion BPI-585725 is a highly potent and selective KRASmulti degrader with favorable pharmacokinetic properties, demonstrating a promising safety in preclinical studies. Citation Format: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Xiaoqiang Kong, Ying Zhao, Tao Zhang, Yanju Liu, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Haibo Chen, Lieming Ding, Hong Lan, Quan Zhou. KRASmultidegrader BPI-585725 displays potent anti-tumor activity in KRAS-driven 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 6376.
Abstract 6390: Identification of novel pan-KRAS mutation inhibitor shows significant efficacy in pancreatic cancer with no toxicity, offering hope beyond current therapies
Authors: Pinar Atalay, Asli Ture, Nermin Kahraman, Izabela Fokt, Waldemar Priebe, Erdem Buyukbingol, Bulent Ozpolat
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers to treat, with current therapies providing a median survival of just six months. The intrinsic chemoresistance and genetic heterogeneity of PDAC tumors complicate the development of effective targeted therapies. Approximately 90% of PDAC cases harbor KRAS mutations, which drive tumor initiation and progression, making KRAS a critical therapeutic target. Although the FDA has approved two KRAS inhibitors (Sotorasib and Adagrasib) for lung cancer, these drugs specifically target the KRAS-G12C mutation, found in only 2% of PDAC cases. Most PDAC tumors carry other KRAS mutations, particularly KRAS-G12D, leaving patients with limited targeted treatment options. To address this, we synthesized 21 compounds and identified 3E as a novel pan-KRAS inhibitor targeting KRAS-G12D, KRAS-G12C, and KRAS-G12S. Kaplan-Meier analysis of the TCGA PDAC database (n=177, p=0.00036) showed that elevated KRAS expression correlates with shorter survival, highlighting KRAS's role in PDAC progression. In vitro, treatment with 3E inhibited KRAS signaling in PDAC cells (PANC1, Miapaca-2) and KPC transgenic cells, as indicated by p-ERK suppression. 3E significantly reduced cell proliferation, migration, and invasion. Clonogenic assays demonstrated that 3E was more effective than Adagrasib and Salirasib (a non-specific RAS inhibitor in Phase II trials) at inhibiting PDAC cell growth. Moreover, 3E showed synergy with gemcitabine, a first-line chemotherapeutic agent for PDAC, enhancing its antiproliferative effects. In vivo, systemic delivery of 3E encapsulated in single lipid nanoparticles (SLNP) delayed tumor growth in PDAC xenograft and KPC transgenic mouse models without toxicity, as shown by blood chemistry markers. Tumor analysis after 3E treatment revealed reduced intra-tumoral proliferation (Ki-67 by IHC) and increased apoptosis (TUNEL assay). These findings suggest that 3E is a promising therapeutic candidate for KRAS-driven PDAC and other cancers. Its superior efficacy over FDA-approved KRAS inhibitors and synergy with gemcitabine support its clinical potential as a novel treatment approach for this aggressive cancer. Citation Format: Pinar Atalay, Asli Ture, Nermin Kahraman, Izabela Fokt, Waldemar Priebe, Erdem Buyukbingol, Bulent Ozpolat. Identification of novel pan-KRAS mutation inhibitor shows significant efficacy in pancreatic cancer with no toxicity, offering hope beyond current therapies [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 6390.
Abstract 6371: KLIPP: Precision targeting of fusions and amplified oncogenes using CRISPR
Authors: Huibin Yang, Radhika Suhas Hulbatte, Natalie Gratsch, Ashley Sutter, Anne Urzynicok, Mayer Cusnir, Mario Ashaka, Aadi Shiv Malhotra, Ishwarya Venkata Narayanan, Michelle Paulsen, Anna Schwendeman, Tom Wilson, Mats Ljungman
Journal: Cancer Research (2025)

Abstract Oncogenic fusion genes and amplified oncogenes are common drivers of cancer but there are currently no therapeutic approaches available that directly target these cancer-specific genomic features. Amplified oncogenes in cancer can be found on chromosomes as homologous staining regions (HSRs) or on extrachromosomal DNA (ecDNA). Presence of oncogenes on ecDNA poses a particular challenge because they are under strong positive selection in response to anti-cancer therapies leading to treatment resistance as their copy number can rapidly change due to uncontrolled segregation during cell division. To specifically target cells with fusions or amplified oncogenes, we have developed a CRISPR-based therapeutic approach, “KLIPP, ” which is designed to target structural variants junctions (SVJs) specific to cancer genomes, with few, or no off-target effects expected in normal cell. KLIPP uses a “split enzyme” approach consisting of a dead Cas9 endonuclease (dCas9) fused to the endonuclease Fok1 where two Fok1 endonucleases need to homodimerize to become active. To “nucleate” and activate these complexes, sgRNAs are designed to bind sequences flanking cancer-specific SVJs, bringing two Fok1-dCas9 complexes together to induce double-strand breaks (DSBs). Using the KLIPP approach, we have obtained strong proof-of-concept that it can specifically target cancer-unique SVJs and induce DSBs leading to cell death in cancer cells both in culture and in vivo. We have shown this for SVJs throughout cancer genomes as well as in oncogenic fusion genes such as EWS-FLI1 in Ewing sarcoma. Furthermore, we show that we can use KLIPP to target unique SVJs on amplified oncogenes resulting in strong induction of γH2AX and loss of cell survival. We are currently investigating the efficacy of KLIPP in targeting ecDNA in cancer cells. We believe that KLIPP could be a safe and cancer-specific precision therapy for targeting cancer cells driven by fusions and amplified oncogenes. Citation Format: Huibin Yang, Radhika Suhas Hulbatte, Natalie Gratsch, Ashley Sutter, Anne Urzynicok, Mayer Cusnir, Mario Ashaka, Aadi Shiv Malhotra, Ishwarya Venkata Narayanan, Michelle Paulsen, Anna Schwendeman, Tom Wilson, Mats Ljungman. KLIPP: Precision targeting of fusions and amplified oncogenes using CRISPR [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 6371.
Abstract 3357: Identification of outcome-associated tumor perivascular features in renal cell carcinoma
Authors: Alfonso Martín-Bernabé, Víctor Sánchez-Miñarro, Philipp Schmucker, Magnus Lindskog, Ulrika Harmenberg, Martin Johansson, Lars Egevad, Arne Östman
Journal: Cancer Research (2025)

Abstract Background: One third of patients with clear cell renal cell carcinoma (CCRCC) eventually develop metastasis. The introduction of anti-angiogenic therapy and immunotherapy in metastatic CCRCC (mCCRCC) has significantly improved outcomes for many patients. Among vascular endothelial growth factor tyrosine kinase inhibitors (TKIs), sunitinib is the most commonly used first-line drug. However, treatment is administered without specific patient selection criteria and relapse occurs in approximately 40% of cases. Given the lack of clinical stratification of these patients, predictive and prognostic biomarkers are needed to improve their clinical outcome. Methods: This work explored the clinical impact of perivascular (PV) characteristics in RCC by performing multiplex-based tissue profiling in a population-based cohort (N = 70) and a sunitinib-treated mCCRCC cohort (N = 61). Vessel features and tumor PV cell subsets were characterized based on multimarker (CD34, PDGFRα, PDGFRβ, αSMA and pSMAD2) expression combinations. In both cohorts, patients were categorized using a tertile-based dichotomization of the variables, with the upper tertile compared against the combined lower and middle tertiles to explore associations. Results: Two PV cell subsets, PER4 (PDGFRB+/ASMA+/PDGFRA-/pSMASD2-) and PER5 (PDGFRB+/ASMA-/PDGFRA-/pSMASD2-), showed statistically significant survival associations using multiple endpoints in both cohorts. In the sunitinib-treated cohort (OS from treatment), PER4 (log-rank p &amp;lt; 0.001) and PER5 (log-rank p = 0.002) were associated with poor survival. Similarly, in the population-based cohort (OS), PER4 (log-rank p = 0.043) and PER5 (log-rank p = 0.001) were also linked to worse survival. Univariate and multivariate analyses confirmed robust survival associations for the identified PV cell subsets PER4 and PER5. Conclusions: Collectively, this study identified candidate prognostic or TKI predictive response markers in RCC. These data provided in-depth characterization of PV cell subsets associated with clinical outcome in RCC. These data could be further explored to find clinically useful patient selection to improve the accuracy of anti-angiogenic therapy administration in RCC. Citation Format: Alfonso Martín-Bernabé, Víctor Sánchez-Miñarro, Philipp Schmucker, Magnus Lindskog, Ulrika Harmenberg, Martin Johansson, Lars Egevad, Arne Östman. Identification of outcome-associated tumor perivascular features in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3357.
Abstract 7036: Co-targeting AR, mTOR, and PI3K inhibitors in DSRCT as a novel therapeutic approach
Authors: Roberto Cardenas-Zuniga, Asmaa G. Ahmed, Kien Ryan Cao, Abid Raza, Clement Agyemang, Danh Truong, Joseph Ludwig
Journal: Cancer Research (2025)

Abstract DSRCT (Desmoplastic Small Round Cell Tumor) is a rare soft tissue sarcoma that appears in the abdominal and pelvic area of mainly young males. There is little information about the molecular mechanisms involved in its pathology. Despite existing treatment options such as surgery, chemotherapy, and radiation, the NIH estimates that the five-year survival rate is only 15%, with frequent recurrence. Thus, new molecular targets and more effective therapeutic strategies are needed. Due to the high prevalence in males during puberty and the fact that AR (Androgen Receptor) is expressed in DSRCT, we hypothesized that AR plays an essential role in DSRCT development. We evaluated sensitivity to DHT (Dihydrotestosterone) and its effect on proliferation in the presence of different FBS (Fetal Bovine Serum) concentrations. For this approach, the LNCaP (prostate cancer) cell line was used as control. Our results indicated that DSRCTs responded differently to DHT at different FBS concentrations. We observed that DHT stimulates AR phosphorylation and increases total AR, pS6, and total S6 protein levels. Next, we explored the sensitivity of DSRCT cell lines to Enzalutamide and Darolutamide inhibitors; Temsirolimus (an mTOR inhibitor); Alpelisib (a PI3K inhibitor); and Gedatolisib (a dual mTOR and pan-PI3K inhibitor). Individual drug sensitivity was evaluated using in vitro exposure via the classic dose-response curve assays, measuring viability with CellTiterGlo2.0 reagent to calculate IC50 values. DSRCTs were more sensitive to Darolutamide than Enzalutamide, two different AR inhibitors. Dual targeting PI3K and mTOR with Gedatolisib was more effective than Alpelisib or Temsirolimus alone. Taking lessons learned from prostate cancer, we studied combination assays of AR antagonists combined with PI3K/mTOR inhibitors. Those assays suggested that Darolutamide and Gedatolisib effects were mainly additive, with a slight synergy. We conclude that DSRCT cell lines are responsive to AR blocking and highly sensitive to PI3K/mTOR inhibitors. A co-targeting strategy that jointly inhibits the AR and PI3K/mTOR pathways is being investigated in murine models and might be considered for future studies if the regimens have non-overlapping toxicity profiles. Citation Format: Roberto Cardenas-Zuniga, Asmaa G. Ahmed, Kien Ryan Cao, Abid Raza, Clement Agyemang, Danh Truong, Joseph Ludwig. Co-targeting AR, mTOR, and PI3K inhibitors in DSRCT as a novel therapeutic approach [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 7036.
Abstract 3923: Lung cancer autochthonous model gene expression database
Authors: Ling Cai
Journal: Cancer Research (2025)

Abstract Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models remain disparate, siloed, and difficult to compare centrally. To address this, we established the Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB), an extensive repository encompassing 1, 354 samples from 77 transcriptomic datasets, including 974 from genetically engineered mouse models (GEMMs), 368 from carcinogen-induced models, and 12 from a spontaneous model. Importantly, 85% of the data were reprocessed through standardized pipelines tailored to each platform, including RNA-seq and five microarray platforms, enhancing comparability across studies. LCAMGDB aligns 859 GEMM tumors with human lung cancer mutations, revealing the need to expand the diversity of genetic aberrations modeled. Our analysis highlights underrepresentation of key alterations such as ROS1, RET, and MET, which are pivotal in human cancers. Furthermore, we are actively updating LCAMGDB to include 989 additional samples from 44 studies, augmenting the current collection of RNA-seq data by nearly 80%. Complementing the database, we developed a web application at https://lccl.shinyapps.io/LCAMGDB/ offering researchers data review and download, as well as intuitive tools for dynamic gene expression analysis and cross-study comparisons. Future iterations aim to integrate pathology data through engagement with the lung cancer mouse model community, potentially complementing transcriptomic insights. LCAMGDB bridges gaps between mouse models and human lung cancer, laying the groundwork for translational research and collaborative advancements. By standardizing and expanding this resource, we aim to improve the fidelity and relevance of preclinical studies for understanding lung cancer biology and developing therapies. Citation Format: Ling Cai. Lung cancer autochthonous model gene expression database [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 3923.