tbuckley/cabot-search huggingface dataset:
Abstract LB043: A compressed genome-wide CROP-Seq screen to dissect the polarization of THP-1-derived macrophages
Authors: Daniela Flehberger, Katarina Lalatovic, Sumit Pawar, Henrik Schmidt, Lukas Badertscher, Tilmann Buerckstuemmer
Journal: Cancer Research (2025)

Abstract CRISPR screens are a powerful discovery engine for biological research and have been extensively used for drug target discovery and validation. Pooled screens are advantageous because they can easily be performed at genome-scale when linked to read-outs such as cellular fitness or viability. However, these types of screens often provide limited insights into complex molecular mechanisms. Arrayed screens, on the other hand, can be combined with information-rich read-outs, but tend to be challenging to scale and costly. Perturb-Seq/CROP-Seq screens, in which the effects of thousands of CRISPR perturbations can be studied using single-cell RNA sequencing (scRNA-Seq), offer an attractive alternative as they combine CRISPR perturbations in a pooled fashion with a high-content readout. Here, we present a genome-wide CROP-Seq screen to identify genes involved in the polarization of THP-1-derived macrophages. M0 macrophages were differentiated into the M1 subtype that secretes proinflammatory cytokines, phagocytizes microbes, and initiates an immune response. We used a compressed CROP-Seq paradigm in which cells were loaded with multiple sgRNAs to increase throughput, and the phenotypic outcomes were subsequently deconvolved. Macrophage polarization was assessed by scRNA-Seq, focusing on a pre-defined signature of 395 mRNAs. Our experiment identified key regulators of M1 polarization, including TLR4, INFGR1, JAK1 and TYK2. In addition, CITE-Seq was incorporated into the screening workflow as macrophages are known to orchestrate immune responses to microenvironmental stimuli sensed by a complex set of surface receptors. Overall, this experiment establishes the feasibility of genome-scale CROP-Seq screens and thus paves the way towards utilizing this technology for unbiased drug target discovery. Citation Format: Daniela Flehberger, Katarina Lalatovic, Sumit Pawar, Henrik Schmidt, Lukas Badertscher, Tilmann Buerckstuemmer. A compressed genome-wide CROP-Seq screen to dissect the polarization of THP-1-derived macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB043.
Abstract LB056: Metabolic adaptations under high glucose enhance lipid synthesis inhibitor efficacy in pancreatic cancer
Authors: Goutam Dey, Mehrdad Zarei, Omid Hajihassani, Priyashree Sunita, Hallie J Graor, Faith Nakazzi, Jordan M. Winter
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for over 90% of cases. Despite advances in treatment, the 5-year survival rate is less than 13% in the United States. The majority of PDAC cases do not display any symptoms and are diagnosed in the late stage, where Chemotherapies like gemcitabine or FOLFIRINOX offer limited benefits. Resistance to these treatments further underscores the need for novel strategies. Recently, lipid metabolism has emerged as a promising target for PDAC therapy. However, monotherapies targeting lipid synthesis pathways have shown limited efficacy. In the current study, we have presented a feasible and effective strategy to improve the therapeutic impact of lipid synthesis inhibitors. We demonstrated that high glucose conditions induce metabolic rewiring in PDAC cells, elevating the expression of lipid synthesizing enzymes, including Fatty Acid Synthase (FASN), ATP citrate lyase (ACLY), HMG-CoA reductase (HMGCR), and Stearoyl-CoA desaturase (SCD). This metabolic shift increases cancer cells dependency on lipid synthesis for survival and proliferation Furthermore, high glucose level inhibited nuclear enrichment of IDH1 protein whereas low glucose promoted nuclear enrichment of IDH1 in PDAC cells. We hypothesized that loss of nuclear IDH1 during high glucose condition may reprogram the chromatin states by modulating epigenetic marks. Our study showed that high glucose condition enhances histone acetylation (H3K9Ac, H3K14Ac) and methylation (H3K4Me3, H3K4Me and H3K36Me2) favoring transcriptional upregulation of lipid synthesizing genes. Additionally, high glucose activated mTOR and NADK that promote lipid biosynthesis. To assess therapeutic potential, we treated PDAC cell lines (PANC-1, BxPC3, and KPC8484) with FASN inhibitor TVB-2023 under low and high glucose conditions. Interestingly, high glucose significantly enhanced the efficacy of FASN inhibitor in in vitro model. In conclusion, our findings reveal that the hyperglycemic state drives a metabolic shift in PDAC cells depending on lipid synthesis pathway resulting sensitization to lipid synthesis inhibitors. Citation Format: Goutam Dey, Mehrdad Zarei, Omid Hajihassani, Priyashree Sunita, Hallie J Graor, Faith Nakazzi, Jordan M. Winter. Metabolic adaptations under high glucose enhance lipid synthesis inhibitor efficacy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB056.
Abstract LB474: Menin inhibition impairs metastatic colonization of Ewing sarcoma
Authors: Katherine Braun, Mohamed Ahmed, Nicolas Garcia, Elizabeth Lawlor
Journal: Cancer Research (2025)

Abstract Menin is a scaffolding protein that can act as either tumor suppressor or oncogene depending on cell context. In MLL rearranged (MLLr) leukemia, menin functions as an oncogene and a small molecule inhibitor of menin was recently FDA approved for MLLr leukemia therapy (Revumenib, Syndax). We previously showed than menin promotes tumorigenicity of Ewing sarcoma (EwS). In the current work we studied menin knockout (MEN1-KO) and VTP50469 (preclinical precursor to Revumenib) treated EwS cells to test the hypothesis that menin inhibition could be leveraged to impede metastatic progression of EwS. Tumorigenic and metastatic capacities of MEN1-KO A673 and TC32 cells were assessed in subcutaneous, tail vein, and/or spontaneous metastasis models. RNAseq of control and MEN1-KO tumors was performed to define mechanisms by which EwS cells escape deleterious effects of menin loss. To test the effect of pharmacologic inhibition of menin on colonization of disseminated EwS tumor cells (DTCs), mice were inoculated with 50,000 wild type A673 cells via tail vein and then fed control or 0.1% VTP50469 chow for up to 40 days. Results of our studies showed that MEN1-KO cells were reproducibly deficient in the capacity to initiate local and disseminated tumors following either subcutaneous or tail vein injection. Spontaneous metastasis of MEN1-KO tumors from subrenal capsules to livers was also impaired. Defects in metastasis were evident despite enhanced invasive capacity, suggesting that menin loss inhibited tumor colonization. Transcriptomic profiling revealed that EwS cells bypassed menin depletion to restore tumorigenicity by upregulating MYC, RNA transcription, and G2-M checkpoint gene programs and downregulating TGF-beta, NFkB, and apoptosis programs. Colonization of wild type DTCs was inhibited by pharmacologic menin inhibition, mimicking MEN1-KO. At 33 days post cell injection, 0/10 control mice and 12/20 VTP50469 treated mice were tumor free (p&amp;lt;0.0001). Two mice remained tumor free a month after withdrawing drug. Histology studies of VTP50469 mice are pending and will be presented at the meeting. These data reveal a critical role for menin in EwS tumor colonization and suggest that menin inhibitors could be repurposed as metastasis prevention agents in EwS patients who are at high risk of metastatic relapse. Citation Format: Katherine Braun, Mohamed Ahmed, Nicolas Garcia, Elizabeth Lawlor. Menin inhibition impairs metastatic colonization of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB474.
Abstract LB241: Development of a photoactivatable platform to optimize delivery of platinum chemotherapy in advanced women's cancers
Authors: Jycole Bush, Kanyashree Jana, Isai Ramos, Nancy Wilkinson, Kirk Schanze, April Risinger
Journal: Cancer Research (2025)

Abstract Patients with metastatic ovarian and triple-negative breast cancers have low overall survival. One limitation to the effective treatment of these cancers is that they don’t have targeted treatment options and therefore are highly dependent on cytotoxic chemotherapy, including highly toxic DNA damaging agents like oxaliplatin. A major limitation of these DNA-targeted drugs is that they have deleterious effects in both cancerous and non-cancerous cells. This toxicity leads to serious adverse side effects which can limit the duration of treatment and decrease a patient’s quality of life.We previously developed a water-soluble polymer functionalized with oxidized oxaliplatin that is released by photoactivation by blue-violet light at 400 nm to allow for the localized, temporal release of chemotherapy. Although this construct promoted the light-dependent cytotoxicity of ovarian cancer cells, this activation did not occur when the polymer was preloaded in the cancer cells and was only observed by activation in the extracellular environment. Herein we describe the development of an optimized platform, M1, that promotes photoactivatable cytotoxicity within breast and ovarian cancer cells. Photoactivation of M1 occurs at 600 nm, a wavelength of light with greater tissue penetration. We found that the photoactivation of M1 was sufficient to kill both ovarian and breast cancer cells independent of oxaliplatin delivery. Moreover, this cytotoxicity required preloading of M1 into cancer cells as extracellular photoactivation was not sufficient to kill cancer cells. These results highlight the potential of M1 to be a photoactivatable therapeutic agent in aggressive metastatic cancers. Future efforts will focus on strategies to enrich M1 uptake in cancer cells as compared to the surrounding normal tissue, which would allow for increased cytotoxic specificity necessary for in vivo and clinical applications. Funding supported by the San Antonio Medical Foundation and supported by NRSA T32 GM148752. Citation Format: Jycole Bush, Kanyashree Jana, Isai Ramos, Nancy Wilkinson, Kirk Schanze, April Risinger. Development of a photoactivatable platform to optimize delivery of platinum chemotherapy in advanced women's cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB241.
Abstract LB243: Secreted PTEN-long downregulates PI3K signaling and PD-L1 and promotes anti-tumor antigen-presenting cell functions to cause regressions of mouse tumors
Authors: Jia Xu, Tiphaine Martin, Daniel Lozano-Ojalvo, Andrew Baik, Bruno Giotti, Ashikur Rahaman, Andrew L. Wolfe, Natalie Suhy, Royce Zhou, Zhengxiang He, Kaitlyn Bosch, Madhuri Kalathur, Elias Stratikopoulos, Shen Yao, Ruifang Qiao, Sergio Lira, Emily Gallagher, Joshua Brody, Jordi Ochando, Alexander Tsankov, Katherine Cygnar, Aris Economides, Ramon E. Parsons
Journal: Cancer Research (2025)

Abstract PTEN is well known as a tumor suppressor that inhibits the PI3K/AKT pathway, but the role of its secreted isoform PTEN-Long (PTEN-L) is not fully understood. We developed tools to study PTEN-L independent of PTEN using cancer cell lines engineered to express PTEN-L, a mouse engineered to overexpress Pten-L, and Adeno-Associated Virus (AAV)-Pten-L treated xenograft models. AAV-Pten-L was engineered to be expressed in the liver, where it was efficiently secreted into blood using a strong signal peptide for the liver. Beyond its known ability to inhibit PI3K/AKT signaling, we showed that Pten-L entered tumor cells and macrophages and altered interferon-γ and TGF-β signaling as well as immune cell composition, which triggered the rapid regression of small mouse tumors. Pten-L treatment activated immune cells in the tumor microenvironment, including macrophages, T cells, and NK cells. These changes were associated with enhanced MHC-II and CD80 expression by macrophages and reduced expression of PD-L1 by tumor cells and macrophages. Depletion experiments using anti-CD8 or anti-CD80 antibodies revealed that CD8+ T-cells and antigen-presenting macrophage cells were required for AAV-Pten-L-induced tumor regression. These results demonstrate the capacity of secreted Pten-L to stimulate the innate immune system and attenuate the immune checkpoint ligand PD-L1 in the tumor, which likely together orchestrate an adaptive immune response to inhibit the growth of established tumors. The first and second authors are co-first authors. Citation Format: Jia Xu, Tiphaine Martin, Daniel Lozano-Ojalvo, Andrew Baik, Bruno Giotti, Ashikur Rahaman, Andrew L. Wolfe, Natalie Suhy, Royce Zhou, Zhengxiang He, Kaitlyn Bosch, Madhuri Kalathur, Elias Stratikopoulos, Shen Yao, Ruifang Qiao, Sergio Lira, Emily Gallagher, Joshua Brody, Jordi Ochando, Alexander Tsankov, Katherine Cygnar, Aris Economides, Ramon E. Parsons. Secreted PTEN-long downregulates PI3K signaling and PD-L1 and promotes anti-tumor antigen-presenting cell functions to cause regressions of mouse tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB243.
Abstract LB444: Disruption of oncogenic signaling by <i>Albizia julibrissin</i> leaf extract induces EGFR-mediated apoptosis in pancreatic cancer cells
Authors: Sung Min Bae, Sang-Chul Han, Sung Eun Bae, Seon-A Yoon, Hyejin Hyeon, Young-Min Ham, Ji-Gweon Park, Yong-Hwan Jung, Hye-Jin Boo
Journal: Cancer Research (2025)

Abstract Pancreatic cancer, characterized by its late-stage diagnosis, rapid progression, and poor prognosis, represents a significant global health burden as the seventh leading cause of cancer-related mortality. Current therapeutic options are limited by resistance and significant toxicity, underscoring the urgent need for novel, effective, and safer treatments. In this study, we investigated the anti-cancer potential of Albizia julibrissin leaf extract (AJLE), prepared as a hot water extract, using comprehensive in vitro and in vivo models. To evaluate the anti-cancer effects of Albizia julibrissin leaf extract (AJLE), we conducted a series of in vitro assays, including WST-1 cell viability, colony formation, cell cycle analysis via flow cytometry, and western blotting for apoptotic markers. Mechanistic insights were gained through receptor tyrosine kinase (RTK) array, while xenograft mouse models were employed to assess the in vivo therapeutic potential. Our findings revealed that AJLE significantly inhibits pancreatic cancer cell proliferation, reduces colony formation, and induces cell cycle arrest at the sub-G1 phase. Apoptosis was confirmed by increased levels of cleaved PARP and caspase-3, alongside nuclear morphological changes observed via fluorescence microscopy. Mechanistically, AJLE suppressed MAPK and PI3K/AKT signaling pathways while upregulating EGFR expression, highlighting EGFR-mediated apoptosis as a novel and significant mechanism underlying its anti-cancer effects. In vivo, AJLE treatment resulted in a dose-dependent reduction in tumor growth with no significant toxicity to the liver or kidney, as confirmed by histopathological and serum analyses. The increased expression of cleaved caspase-3 in AJLE-treated tumors further corroborated the apoptotic mechanism. Therefore, our findings highlight the therapeutic potential of AJLE as a natural product-based anti-cancer agent for pancreatic cancer, offering a promising, targeted, and less toxic complementary treatment option to conventional therapies. Citation Format: Sung Min Bae, Sang-Chul Han, Sung Eun Bae, Seon-A Yoon, Hyejin Hyeon, Young-Min Ham, Ji-Gweon Park, Yong-Hwan Jung, Hye-Jin Boo. Disruption of oncogenic signaling by Albizia julibrissin leaf extract induces EGFR-mediated apoptosis in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB444.
Abstract LB344: CertisOI Assistant™ - Accelerating Preclinical Cancer Model Selection with Generative AI
Authors: Luke Jervis, Yuan-Hung Chien, Warren Andrews, Raffaella Pippa, Long Do
Journal: Cancer Research (2025)

Abstract Pre-clinical oncology researchers face significant challenges when identifying suitable tumor models. Suboptimal model selection can impede the translational success of preclinical findings to clinical applications. Traditional online databases rely on rigid filtering systems that may not accommodate the complex and specific criteria researchers require. To address this critical need, Certis Oncology developed CertisOI, a Generative AI-powered platform that transforms how researchers discover and analyze cancer tumor models for their studies. CertisOI functions as an interactive research assistant, enabling users to articulate complex tumor selection criteria in natural language, generate dynamic queries, and retrieve actionable insights from a comprehensive database of pre-clinical models. The system integrates Certis Oncology's proprietary patient-derived xenograft (PDX) models with the Cancer Cell Line Encyclopedia (CCLE) database, providing information on tumor characteristics, patient demographics, growth dynamics, pharmacological studies, genetic analyses, and drug efficacy predictions. It also integrates with the company’s predictive AI platform, which uses a machine learning algorithm trained on experimental data to predict drug response based on chemical and biological features. This adds a level of sophistication to preclinical model selection, as it allows researchers to select models most likely to be responsive or resistant to FDA-approved therapies. What sets CertisOI apart is its ability to conduct sophisticated real-time analysis through an integrated coding environment, presenting insights through multiple modalities including visualizations, interactive charts, tables, and downloadable datasets. This dynamic approach allows researchers to iteratively refine their model selection criteria based on emerging insights, leading to more precise model identification and ultimately accelerating the path to clinical trials. By bridging the gap between complex research requirements and vast pre-clinical data, this platform represents a significant advancement in oncology research tools, enabling more efficient and effective pre-clinical model selection. Citation Format: Luke Jervis, Yuan-Hung Chien, Warren Andrews, Raffaella Pippa, Long Do. CertisOI Assistant™ - Accelerating Preclinical Cancer Model Selection with Generative AI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB344.
Abstract SY32-01: Beyond diagnosis: Survivorship research for people living with advanced and metastatic cancers
Authors: Michelle Mollica
Journal: Cancer Research (2025)

Abstract Targeted therapies, immunotherapy, and other advances in treatments and supportive care have revolutionized cancer care leading to a growing population of cancer survivors who live for many years with metastatic disease and have unique survivorship needs. People living with advanced cancer represent a distinct group whose needs remain understudied, especially compared with people diagnosed with early-stage disease. While the National Cancer Institute (NCI) has supported survivorship science for several decades, this has often been limited to those who are post-treatment and were treated with curative intent. The NCI identified survivorship needs for people living with advanced and metastatic cancer as a priority in 2021, with a specific focus on identifying unmet physical and psychosocial needs and care delivery challenges. A unique challenge facing patients living with advanced cancer is coping with the immense prognostic uncertainty and living well in the face of a life-limiting illness. Patients and caregivers often have substantial misperceptions about their prognosis and struggle with prognostic distress. Thus, it is critical for clinicians to understand patient needs and preferences for receiving prognostic information, even through great uncertainty about their disease. Furthermore, we need to integrate strategies to promote adaptive coping as patients learn to live with their uncertain prognosis. To this end, we share a review of the current landscape of advanced cancer survivorship research, the perspective of a survivor and caregiver, and a critical overview of prognostic understanding and coping with uncertainty for people living with advanced and metastatic cancer. Citation Format: Michelle Mollica. Beyond diagnosis: Survivorship research for people living with advanced and metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY32-01.