tbuckley/cabot-search huggingface dataset:
Abstract SY02-03: Stochastic modeling of clonal evolution in carcinogenesis
Authors: Kit Curtius
Journal: Cancer Research (2024)

Abstract In order to develop strategies that can detect cancer earlier, we need to better understand the dynamics of cancer evolution during the human lifetime. Starting from gestation, this includes measuring both the timing of early somatic mutations that lead to clonal mosaicism as well as the growth rates of mutated clones that carry higher potential for malignant transformation. Continuous observation of this evolving clonal composition across a lifetime is not feasible, therefore mathematical models are needed to integrate data from longitudinal and cross-sectional samples and infer these dynamics. Stochastic models of clonal evolution offer such a framework and provide a means for predicting individual clone trajectories into the future. Furthermore, if measurements of evolution are to be utilized clinically for early detection and patient risk stratification, faster methods to apply these models to data are required. To this end, we derived methods using coalescent theory for single-cell DNA sequencing data that enable instantaneous estimation of the growth rate of a clone along with its confidence intervals. Our tool is available in an open source R package, cloneRate, and provides the first method for constructing valid confidence intervals of growth rates analytically without having to rely on Bayesian inference techniques and complex simulations. When applying our methods to recent datasets derived from normal and neoplastic human blood cells, we quantified increased fitness effects of multi-hit driver mutations and found that higher initial clone growth rates led to decreased time to cancer diagnosis in patients. We can also use these models to estimate other important biological parameters that are difficult to measure in vivo such as bounds for total number of hematopoietic stem cells and expansion rates in early development. Ultimately, the ability to easily and quickly parameterize clonal dynamics in individual patients will benefit future early detection efforts and screening strategies for many cancer types. Citation Format: Kit Curtius. Stochastic modeling of clonal evolution in carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY02-03.
Abstract LB318: Exploring early precursor lesions of ovarian cancer: Insights from an in vitro model
Authors: Yan E. Wang, Vera Levina, Deborah L. Galson, Anna E. Lokshin
Journal: Cancer Research (2024)

Abstract Ovarian cancer ranks as the fifth leading cause of cancer-related deaths in women, surpassing other cancers of the female reproductive system. Recent epidemiological and molecular studies highlight the significance of high-grade serous carcinoma (HGSC), the most aggressive subtype of ovarian cancer, constituting nearly 96% of cases with mutations in p53. HGSC originates from fallopian tube secretory epithelial (FTSEC) cells through a progression of precursor lesions, ranging from p53 signatures to serous tubal intraepithelial carcinoma (STIC). The p53 signature involves a linear expansion of over 12 TP53 mutant FTSECs, morphologically normal and displaying no increase in proliferative activity. In this study, we established a model system for P53 signature by either overexpressing p53 mutations (R175H and R273H) or knocking down P53 expression in normal FTSECs maintained as 2D, 3D, or organoid cultures. We have characterized the cells using RNA seq, mass spectroscopy and functional assays. Functional assays revealed increased migration and proliferation, along with decreased apoptosis in response to the cytotoxic stimulus (cisplatin). Despite the inability of p53 signature cells to proliferate or migrate in vivo, our hypothesis posited that clonal expansion of progenitor cell with a p53 mutation maintains plasticity by preserving the stemness of one or more cells capable of responding to cues from the microenvironment. Our experiments revealed heterogeneity in the model system, reflecting the composition of p53 signature in vivo. We also observed that stem-like cells tend to organize into clusters. Notably, stem-like cluster cells bearing a p53 signature exhibit migratory behavior, whereas clusters lacking p53 do not demonstrate such mobility. Given that most high-grade serous carcinoma (HGSC) cases occur in postmenopausal women, we demonstrated induction of proliferation and migration of p53 mutant stem cells in response to stimuli from aging stromal cells (fibroblasts and autologous immune cells) and to changes in hormonal background in our model. Conclusion: This study illuminates a novel aspect of ovarian cancer development, underscoring the role of a distinct population of fallopian tube epithelial cells with stem-like properties within p53 signatures. Further investigations into the tumorigenicity of these cells hold promise for providing valuable insights into future therapeutic strategies. Citation Format: Yan E. Wang, Vera Levina, Deborah L. Galson, Anna E. Lokshin. Exploring early precursor lesions of ovarian cancer: Insights from an in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB318.
Abstract LB020: Extracellular vesicle-mediated intrinsic induction of ferroptosis causes reversal of chemoresistance in lung cancer
Authors: Akhil Srivastava, Anjugam Paramananantham, Rahmat Asfiya
Journal: Cancer Research (2024)

Abstract Introduction: Resistance to chemotherapeutic drugs is the major cause of treatment failures and high mortality in lung cancer(LC). Thus, strategies to overcome chemoresistance is the major thrust area of cancer research. Ciplatin (CDDP) is the first line of chemotherapeutic interventions in lung cancer however, the treatment benefit diminishes due to develop resistance against the drug. Dysregulation of apoptosis is the major reason for developing chemoresistance. Ferroptosis is a recently discovered form of non-apoptotic regulated cell death (RCD) that can overcome the apoptosis mediated resistance. To exploit this our laboratory has developed a novel Extracellular Vesicle (EV)-iron oxide nanoparticle (IONP) hybrid system- 'ExoFeR,' that can induce ferroptosis. Experiments conducted on LC cells and patient derived tumoroids (PDTs) have shown reversal of CDDP resistance after ExoFeR treatment. Our study demonstrates the utility of ferroptosis as alternate treatment intervention for treating chemoresistant LC tumors. Materials and methods: EVs derived from normal lung fibroblast cells (MRC9) were loaded with IONPs. The complex was characterized by Transmission electron microscopy (TEM), Inductively coupled plasma mass spectrometry (ICP-MS) and through Zeta potential measurements. The induction ferroptosis by ExoFeR was confirmed in Non-Small Cell Lung Cancer (NSCLC) A549 cells and NSCLC PDTs by Prussian blue, FerroOrange, and Mito-FerroGreen staining. Further, ferroptosis markers like GPX4 and SCL7A11/xCT were evaluated to examine the induction of ferroptosis. Finally, A549 cells and resistant NSCLC PDTs were tested for sensitivity to chemo drugs. Results: Physicochemical characterization indicated the successful formulation of ExoFeR. Reduction in the expression level of SLC7A11/xCT- and GPX4 proteins in ExoFeR-treated NSCLC cells and PDTs suggested induction of ferroptosis which also showed sensitization of chemo drug (cisplatin). Summary/Conclusion: We report here the synthesis of a novel EV-IONP-based system that can intrinsically induce ferroptosis and overcome chemoresistance by circumventing the conventional apoptosis-based resistance. Our finding is expected to develop a potent cancer treatment strategy for efficiently treating resistant NSCLC tumors. Citation Format: Akhil Srivastava, Anjugam Paramananantham, Rahmat Asfiya. Extracellular vesicle-mediated intrinsic induction of ferroptosis causes reversal of chemoresistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB020.
Abstract LB313: Immunosuppressive effect of tumor-infiltrating IL-22 receptor-expressing myeloid cells in early-stage pancreatic ductal adenocarcinoma
Authors: Yoolim Sung, Ji-Eun Kim, Hyo-Jin Min, Soo-Hyun Chung, Seong Who Kim, Eun-Ju Chang
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor survival rate, largely due to the lack of diagnostic biomarker for early detection. Here, we found enriched IL-10R2+/IL-22R1+ myeloid cells in peripheral blood and specifically PDAC tissues respectively using xenograft/orthotropic PDAC mouse models. The subcutaneous injection of PDAC cell line in mouse showed a positive correlation of pancreatic tumor growth with increased IL-10R2+/IL-22R1+ myeloid cells by flow cytometry. We also verified that IL-10R2+CD45+ and IL-22R1+CD45+ myeloid cells were infiltrated in tumor tissues after 2 weeks and 3 weeks of injection in orthotropic murine PDAC model. Notably, the IL-10R2+IL-22R1+ cells were highly detected in tumor tissues after 7 days of injection, an earlier time point of PDAC progression. To define whether these cells have immunosuppressive functions to contribute further PDAC progression, IL-10R2+/IL-22R1+ myeloid cells were sorted from splenocytes after 3 days of tumor implantation and co-cultured with T cells in the presence of T cell receptor triggering. The proliferation and cytotoxicity of CD8+ T cells were alleviated by co-culture with IL-10R2+, IL-22R1+, or IL-10R2+IL-22R1+ myeloid cells, compared to that with IL-10R2-IL-22R1- cells. In addition, the population of regulatory T cells was increased when they were co-cultured with IL-22R1+ myeloid cells. Furthermore, the proliferation of human T cells in vitro was also inhibited by co-culture with IL-10R2+/IL-22R1+ myeloid cells from human peripheral blood, indicating the immunosuppressive function of IL-10R2+/IL-22R1+ cell population. Therefore, IL-10R2+/IL-22R1+ myeloid cell population could be a possible promising early detection marker for PDAC, contributing to the non-immunogenic features of tumor microenvironment during PDAC progression. Citation Format: Yoolim Sung, Ji-Eun Kim, Hyo-Jin Min, Soo-Hyun Chung, Seong Who Kim, Eun-Ju Chang. Immunosuppressive effect of tumor-infiltrating IL-22 receptor-expressing myeloid cells in early-stage pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB313.
Abstract LB389: Highly potent and selective RET inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations
Authors: Li Xing, Wei Zhu, Jingbing Wang
Journal: Cancer Research (2024)

Abstract RET gene mutations and fusions are the driving events for the generation and deterioration of many cancer types. The first generation RET inhibitors, selpercatinib (Loxo-292) and pralsetinib (Blu-667), demonstrated clinically acquired resistance (e.g., solvent frontier mutations G810X, double mutations V804X-G810X etc.). Novel treatment that overcomes multiple resistance mutations is needed to improve patient outcomes. Leveraging our in-house AI technology platform, we have discovered the next generation RET inhibitors that overcome multiple resistance mutations including solvent front, gatekeeper and various double mutations. We employ the synergistic advantages of domain expertise and modern technology to accelerate early stage drug discovery. On our deep learning (DL) centric AI platform, extensive scientific computing supports large scale virtual screening, generative design, drug property prediction and multi-objective lead optimization. Only the optimized candidate compounds are passed along for synthesis and testing to save time and cost. In cell proliferation assays, our compound effectively inhibited KIF5B-RET Ba/F3 WT, V804M, G810S, G810R, V804M-G810S with IC50 values of 0.4 nM, 1.3 nM, 1.1 nM, 3.4 nM, 6.3 nM, respectively, demonstrating significant improvement over selpercatinib in the range of several hundred fold in activities. Importantly, the compound is highly selective against VEGFR2, an off-target responsible for cardiovascular adverse effects in the approved RET inhibitors. The superior cellular potencies translated consistently into animal models. In Ba/F3 KIF5B-RET-G810R xenograft model, treatment of 25 mg/kg bid resulted in &amp;gt;90% TGI with a100% survival rate. The compound showed favorable pharmacokinetic properties, lack of drug-drug interaction (DDI), and devoid of hERG liability (IC50 &amp;gt; 10uM). Preclinical safety evaluations in rats exhibited good tolerance margin. We have discovered the second generation compound that potently inhibits a diverse range of RET alterations. The compound exhibits preferable pharmaceutical profiles and is advancing toward IND application. Citation Format: Li Xing, Wei Zhu, Jingbing Wang. Highly potent and selective RET inhibitor with robust anti-tumor activities against wild-type and acquired drug-resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB389.
Abstract LB319: Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth
Authors: Baotong Zhang, Mingcheng Liu, Fengyi Mai, Siyuan Xia, Jin-Tang Dong
Journal: Cancer Research (2024)

Abstract Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in the United States. PTEN deficiency is prevalent in patients with prostate cancer. As a tumor suppressor, PTEN is mutated in approximately 20% of primary prostate cancers, and up to 50% of metastatic castration resistant prostate cancer. PTEN inactivation results in high-grade adenocarcinoma with a long latency. The limited tumor progression induced by PTEN deficiency suggests that additional molecular events are activated to constrain tumor progression, and second hits are required. Understanding these secondary genetic hits will provide the rationale for combined therapies in prostate cancer treatment. In this study, we employed a unique genetically knockin mouse model and found that PTEN deficiency induces a KLF5 K369 acetylation-dependent barrier that attenuates FGFR1 signaling and constrains prostate tumor growth. More importantly, we discovered novel microenvironmental crosstalk between prostate cancer cells and cancer associated fibroblasts (CAFs). As suggested by RNA-seq and bioinformatic analyses and further validated by molecular and cellular experiments, we found that interruption of KLF5 acetylation in cancer cells stimulates CAFs to release FGF9 via TNF-α, and FGF9 activating FGFR1 signaling in cancer cells. In addition to this paracrine crosstalk, deacetylated KLF5 induces CX3CR1 and facilitates FGFR1 activation. Our findings provide a proof of concept for posttranslational modifications as essential molecular events induced by PTEN inactivation to stall prostate cancer progression and demonstrate KLF5 acetylation as a key component in a negative feedback loop by which FGFR1 was suppressed by AKT activation. This study reveals a paracrine reciprocal communication between cancer cells and fibroblasts and provides a clinical rationale for combined therapies using FGFR1 inhibitors (or CX3CR1 inhibitors) and p-AKT inhibitors in PTEN-deficient prostate cancer. Citation Format: Baotong Zhang, Mingcheng Liu, Fengyi Mai, Siyuan Xia, Jin-Tang Dong. Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB319.
Abstract LB192: AGR2 knockdown reduces cell proliferation and increases endoplasmic reticulum proteotoxic stress in pancreatic cancer
Authors: Philip Salu, Katie Reindl
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal solid malignancy with low survival rates due to a dense stroma, abnormal gene expression patterns, and limited treatment options. Anterior gradient 2 (AGR2) is often overexpressed in many cancers, including PDAC. AGR2 belongs to the protein disulfide isomerase family of proteins and is located in the endoplasmic reticulum, where it helps with protein-disulfide isomerase reactions to ensure proper protein folding. However, the molecular mechanisms underpinning AGR2 overexpression in PDAC pathophysiology are not well understood. Gene expression data obtained from the pancreatic adenocarcinoma (PAAD) dataset shows that AGR2 is overexpressed in PDAC tumors compared to normal tissues. We confirmed this gene over-expression in PDAC tumors and multiple pancreatic cancer cell lines using fluorescent microscopy, RT-qPCR, and western blotting. Using stable inducible short hairpin (shRNA) technology, we showed that AGR2 knockdown significantly decreases the viability and colony-forming ability of HPAF-II and PANC-1 cells. Gene Ontology (GO) enrichment analysis revealed that AGR2 knockdown suppresses a host of protein biosynthesis pathways, including protein targeting and localization to the endoplasmic reticulum (ER). Significantly, ER stress was induced in knockdown cells, shown by the activation of unfolded protein response, suggesting an accumulation of unfolded proteins. To determine the effects of unfolded protein accumulation on the ER, we performed transmission electron microscopy. Here, the results show an increase in the ER lumen size of knockdown cells compared to controls. Interestingly, we observed a decrease in mitochondria size and confirmed the increased expression of mitochondria fission proteins DRP1 and MFF. Finally, flow cytometry analysis revealed increased apoptosis in AGR2 knockdown cells compared to controls. Overall, our data provide insights into the role of AGR2 in PDAC tumorigenesis. However, more research is warranted to determine if AGR2 could be a potential therapeutic target. Citation Format: Philip Salu, Katie Reindl. AGR2 knockdown reduces cell proliferation and increases endoplasmic reticulum proteotoxic stress in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB192.
Abstract LB293: O-GlcNAc transferase drives the proliferative state in adaptive drug tolerance
Authors: Dinoop Ravindran Menon, Heinz Hammerlindl, Gregory Gimenez, Elmar Zuegner, Christoph Magens, Michael Eccles, Mayumi Fujita, Helmut Schaider
Journal: Cancer Research (2024)

Abstract Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs in melanoma. Deploying a model of adaptive cancer drug tolerance H3K4me3 ChIP-seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo. H3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in vivo. Our findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes. Citation Format: Dinoop Ravindran Menon, Heinz Hammerlindl, Gregory Gimenez, Elmar Zuegner, Christoph Magens, Michael Eccles, Mayumi Fujita, Helmut Schaider. O-GlcNAc transferase drives the proliferative state in adaptive drug tolerance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB293.