tbuckley/cabot-search huggingface dataset:
Abstract 6756: Our RNA production platform and the associated tools facilitate the development of RNA-based vaccine
Authors: Célia Bosso-Lefèvre, Erica Cirri, Eric Mennesson, Dimitri Szymczak, Flavien Carpentier, Alexandra Foucher, Alzbeta Komarkova, Maxime Rochet, Armelle Vindrios, Romain Goulay
Journal: Cancer Research (2024)

Abstract mRNA vaccines have shown their full potential in the Covid-19 pandemic. The application of these technologies for the treatment of cancers represents significant hope, but clinical effectiveness remains to be demonstrated. For this purpose, researchers require high quality production of vaccine mRNA and accurate and cost-saving test tools that are adapted to oncology research. Since 2021, Tebubio has developed a miniscale RNA production platform for providing RNAs (from 100 µg to 1 mg) to researchers around the world. This service is completed by offers on RNA delivery solutions using lipid nanoparticles (LNPs) and cellular tests with biomarker analysis. Through an ingenious design, our DNA matrix for mRNA is easily transferable for GMP production for clinical studies. Recently, Tebubio has developed DNA matrices for circular RNA production. Indeed, circular RNA has many advantages by being less immunogenic and more stable than linear RNA. We compared the quality and the quantity of CAP1 capped linear RNA and circular RNA produced from our DNA templates. We also assessed the stability of both RNAs expressing GFP and the typical tumor antigen, p53, and their relative expression into antigen-presenting cells (APCs). Finally, we quantified the response of the APCs expressing p53 by using our biomarker multiplex analysis system. This new type of RNA and its efficiency testing in APCs will constitute a new addition to our pipeline of RNA production and testing for preclinical studies. Citation Format: Célia Bosso-Lefèvre, Erica Cirri, Eric Mennesson, Dimitri Szymczak, Flavien Carpentier, Alexandra Foucher, Alzbeta Komarkova, Maxime Rochet, Armelle Vindrios, Romain Goulay. Our RNA production platform and the associated tools facilitate the development of RNA-based vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6756.
Abstract 419: Evolutionary trajectories of complex genome rearrangements in osteosarcoma
Authors: Isidro Cortes Ciriano, Jose Espejo Valle-Inclán, Solange de Noon, Katherine Trevers, Hillary Elrick, Adrienne M. Flanagan
Journal: Cancer Research (2024)

Abstract Whole-genome sequencing (WGS) studies have revealed that osteosarcoma genomes are riddled by remarkably intricate forms of structural variants (SV), collectively known as complex genomic rearrangements (CGR). Yet, most CGR detected in osteosarcoma remain unexplained, hinting at the possibility of undiscovered mechanisms that might lead to novel therapeutic strategies. To elucidate the mechanisms underpinning cancer genome complexity in osteosarcomas and the downstream consequences of CGR during tumor evolution, we uniformly processed exiting osteosarcoma WGS data sets and performed high-depth (&amp;gt;120x) multi-regional short- and long-read WGS for hundreds of osteosarcomas. We found that whole genome doubling and diverse types of CGR are frequent clonal events in most osteosarcomas. Through the integration of multi-regional WGS data, we discovered that in tumors with whole-genome doubling, cancer genome evolution and oncogene amplification are the consequence of multi-generational CGR triggered by whole-genome doubling and involving multiple mechanisms, especially chromothripsis and breakage-fusion-bridge cycles. By contrast, in tumors without whole-genome doubling, biallelic inactivation of TP53 and oncogene amplification frequently occur as part of a cascade of genomic instability initiated by a single double-strand break upstream of the TP53 locus. This process results in clonal diversification and rapid tumor growth suggestive of punctuated evolution. In addition, we found that subclonal CGRs are also frequent events. Indeed, clonal expansions triggered by the acquisition of subclonal CGR often colonize distant tumor regions, suggesting that CGR act as subclonal driver events. Finally, we show that some recurrent genomic alterations are prognostic of poor survival, which we validate in independent cohorts. In sum, using WGS data, we have elucidated the mechanisms underpinning the complexity and evolution of osteosarcoma genomes. Our results indicate that diverse types of CGR, such as chromothripsis, are triggered by whole genome doubling and occur throughout tumor evolution, which primes the cancer genome for ongoing genomic instability, rapid karyotype evolution and clonal diversification. These results have implications for our understanding of the molecular basis of intra-tumor heterogeneity and drug resistance in osteosarcomas and other cancers driven by genomic instability. Citation Format: Isidro Cortes Ciriano, Jose Espejo Valle-Inclán, Solange de Noon, Katherine Trevers, Hillary Elrick, Adrienne M. Flanagan. Evolutionary trajectories of complex genome rearrangements in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 419.
Abstract 5541: The unique metabolite landscape of the aged microenvironment dictates melanoma migratory and invasive capacity
Authors: Gretchen Marie Alicea, Payal Patel, Meihan Wei, Vito Rebecca, Denis Wirtz
Journal: Cancer Research (2024)

Abstract Metastatic burden and organ failure are the root causes of mortality in patients with advanced melanoma; however, little is known of the metabolic drivers that enable organ colonization and the formation of overt metastases. Recent studies have drawn attention to the importance of metabolism in the survival and colonization of cancer cells. In melanoma, there have been studies focusing on the invasive capabilities of cells; however, not much is known regarding metabolic plasticity in melanoma migratory, invasive and ultimately metastatic capabilities.We have previously shown changes in the lipid landscape of the aged microenvironment promotes melanoma resistance to targeted therapy. Here, we find a distinct metabolite landscape in the aged microenvironment elevates melanoma metastatic capacity. We utilized a panel of well characterized melanoma models and tested their invasiveness and motility under different metabolite levels modeled after the aged microenvironment. Transcriptomic and proteomic analysis identifies distinct signatures that explain the migratory and invasive differences in cells cultured in varying metabolic environments. We hypothesize that different nutrient availabilities melanoma cells are exposed to during the metastatic phase affect the migratory and invasive capacity of the cell. We tested this by performing 3D migration assays, organoids and transwell assays of cells grown in media with varying nutrient levels. Further analysis is currently underway to better understand the mechanisms in which these metabolic differences facilitate cell migration, invasion and eventually colonization. This work has important implications for our understanding of the metabolic determinants of melanoma migration and metastatic colonization, and we hypothesize restraining tumor metabolic plasticity is vital to prevent and treat metastases in melanoma. Citation Format: Gretchen Marie Alicea, Payal Patel, Meihan Wei, Vito Rebecca, Denis Wirtz. The unique metabolite landscape of the aged microenvironment dictates melanoma migratory and invasive capacity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5541.
Abstract 4192: In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography
Authors: Mahn Jae Lee, Jaehyeok Lee, Weisun Park, Geon Kim, Hye-Jin Kim, YongKeun Park
Journal: Cancer Research (2024)

Abstract Intestinal mucositis is a prevalent adverse event associated with antineoplastic therapies, such as chemotherapy, which still lacks a targeted and effective treatment regimen. The difficulty in preclinical prediction and prevention of drug-induced intestinal mucositis is attributed to the intricate underlying mechanisms of its onset and the broad spectrum of patient-specific responses to chemotherapeutic agents. Advancements in regenerative medicine have enabled the generation of intestinal organoids from adult stem cells, serving as a personalized model to emulate disease pathology and simulate individual drug responses. Various imaging techniques are employed to evaluate the responses of the organoids to pharmacological agents, but the inherent complexity of their three-dimensional (3D) architecture poses significant challenges in organoid imaging. These challenges are exacerbated by the standard preparation processes for imaging, including fixation and staining, which do not allow for the observation of dynamic, real-time effects of drugs on living organoids. In this study, we focused on meticulously examining the histopathological alterations in small intestinal organoids subjected to chemotherapeutic agents that induce mucositis, specifically 5-fluorouracil and irinotecan. Employing holotomography, a label-free real-time 3D imaging technology, we were able to visualize the destructive processes affecting the intestinal organoids, including the breakdown of the epithelial lining, the exfoliation of dead cells, and the alteration of the villus/crypt structure. Furthermore, we propose a novel methodology for quantifying the viability of intestinal organoids. This quantification is essential for assessing the extent of damage caused by the chemotherapeutic agents and for determining the maximum drug concentrations that can be deemed safe for use, thereby minimizing the risk of inducing mucositis while maintaining therapeutic efficacy. These results provide new insights into the toxic mechanisms of chemotherapeutic drugs and highlight the importance of using organoid models in drug safety evaluation throughout the development phase. Citation Format: Mahn Jae Lee, Jaehyeok Lee, Weisun Park, Geon Kim, Hye-Jin Kim, YongKeun Park. In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4192.
Abstract 3576: CRISPR Cas9 mediated MADD deletion can induce autophagy via downregulation of MAPK and PI3K/AKT/mTOR signaling in anaplastic thyroid cancer
Authors: Velavan Bakthavachalam, Manikannan Madhayan, Mark Sanborn, Jalees Rehman, Prabhakar Bellur
Journal: Cancer Research (2024)

Abstract Thyroid cancer is a highly prevalent endocrine malignancy with one of the fastest growing incidences of all cancers in the United States. Anaplastic thyroid cancer (ATC) has an incidence of about 1.7% of all thyroid cancers, but it causes over 40% of thyroid cancer-related deaths with a median survival period of less than one year. This is why agents that inhibit the aberrant signaling pathways which drive ATC aggressiveness are of significant interest. MAPK-activating Death Domain-activating protein (MADD) plays a key role in cancer cell survival and proliferation. MADD is constitutively expressed at higher levels in most tumor tissues and cancer cells relative to normal tissues. Studies using shRNA suggest that MADD prevents apoptosis in ATC cells. For a more definitive and mechanistic analysis of MADD in ATC, we used conditional CRISPR-Cas9 gene editing to target MADD. We observed that MADD deletion in ATC cells induced spontaneous apoptosis and also activated the autophagy pathway in human ATC cells through downregulation of ERK and mTOR signals involving the MAPK and PI3K/Akt/mTOR signaling pathways. Transcriptomic analysis of publicly available TCGA data showed several PI3K/AKT/mTOR pathway genes were positively correlated with MADD levels. RNA sequencing data of ATC lines demonstrated that enhanced activity of the PI3K/AKT/mTOR signaling pathway was correlated with a worse prognosis in ATC. Targeted MADD deletion in ATC cells combined with treatment using ERK/PI3K/Akt/mTOR/autophagy inhibitors resulted in enhanced cell death compared with MADD deletion alone. Further, MADD deleted 8505C-ATC cells showed significantly delayed tumor formation in an orthotopic nude mouse model. These findings suggest that combining MADD deletion with inhibitors of PI3K/Akt/mTOR pathway could provide an attractive new therapeutic option for ATC. Citation Format: Velavan Bakthavachalam, Manikannan Madhayan, Mark Sanborn, Jalees Rehman, Prabhakar Bellur. CRISPR Cas9 mediated MADD deletion can induce autophagy via downregulation of MAPK and PI3K/AKT/mTOR signaling in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3576.
Abstract 4532: Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors
Authors: Dan Yan, Yao Zhang, Yan Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Xiaoling Lin, Jincong Zhuo, Kevin Zhou
Journal: Cancer Research (2024)

Abstract Cancers exhibiting homologous recombination (HR) repair deficiencies due to mutations in genes like BRCA1 or BRCA2 rely on alternative DNA damage response (DDR) pathways to uphold genomic integrity. This vulnerability allows for the targeted disruption of these pathways through synthetic lethality approaches. DNA polymerase theta (Polθ, encoded by POLQ) assumes a crucial role in mending DNA double-strand breaks (DSB) via microhomology-mediated end-joining (MMEJ), one of the principal pathways for repairing DNA DSB. Notably, Polθ expression is minimal in normal tissues but becomes upregulated in HR-deficient cancer cells, positioning Polθ as a prime target for synthetic lethality in HRD cancers. Reversion mutations in HR-related genes frequently employ micro-homology deletion mechanisms. Consequently, the inhibition of Polθ holds the potential to thwart the emergence of PARPi resistance, primarily driven by BRCA reversion mutations. In this context, we introduce DAT-1000A, a novel small-molecule Polθ inhibitor exhibiting potent activity with a single-digital nanomolar IC50 value. Its efficacy in MMEJ functional assays validates its on-target cellular activity. Assessments of cell viability in HR-deficient BRCA2-KO DLD-1 cells, compared to their parental counterparts, reveal a striking synthetic lethality window exceeding 500-fold. Additionally, DAT-1000A displays synergistic anti-proliferative effects when combined with PARP inhibitors in BRCA1/2-mutated cells. In BRCA1/2-mutated xenograft models, DAT-1000A demonstrates robust and sustained tumor regression, as evidenced by the level of γH2AX, a common marker for double-strand breaks, which closely correlates with anti-tumor efficacy. Importantly, high-dose DAT-1000A treatment in mice elicits no significant abnormalities, underscoring its excellent tolerability. Collectively, DAT-1000A emerges as a novel Polθ inhibitor, offering both potent activity and a favorable safety profile, and holds promise for advancing therapeutic options in the realm of HRD cancer treatment. Citation Format: Dan Yan, Yao Zhang, Yan Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Xiaoling Lin, Jincong Zhuo, Kevin Zhou. Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4532.
New prospective cohort study and Mendelian randomization analysis reveal a link between psoriasis and cardiovascular risk via elevated plasma triglycerides
Authors: Alexander V Sorokin, Joel M Gelfand
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript New Prospective Cohort Study and Mendelian Randomization Analysis Reveals a Link Between Psoriasis and Cardiovascular Risk Trough Elevated Plasma Triglycerides Get access Alexander V Sorokin, Alexander V Sorokin Section of Lipoprotein Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Correspondence: Alexander V. Sorokin, MD PhD, Email:sorokinav2@nhlbi.nih.gov https://orcid.org/0000-0002-2291-4888 Search for other works by this author on: Oxford Academic Google Scholar Joel M Gelfand Joel M Gelfand Department of Dermatology, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USADepartment of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA https://orcid.org/0000-0003-3480-2661 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae129, https://doi.org/10.1093/bjd/ljae129 Published: 22 March 2024 Article history Received: 14 March 2024 Accepted: 21 March 2024 Published: 22 March 2024
Abstract 4003: TBK1 inhibition enhances CAR-T cell efficacy against patient-derived organotypic tumor spheroids
Authors: Luke Maggs, Yi Sun, Giulia Cattaneo, Marco Ventin, Feng Chen, Martin Q. Rasmussen, Xinhui Wang, Cristina R. Ferrone, Soldano Ferrone, Russell W. Jenkins
Journal: Cancer Research (2024)

Abstract Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR)-T cells in the treatment of solid tumors. Here, we set out to evaluate novel therapeutic strategies to improve the efficacy of B7-H3 (CD276) directed (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS). PDOTS are generated from fresh patient tumor tissue and contain tumor cells, autologous immune cells and stromal cells, therefore recapitulating key features of the tumor microenvironment (TME), enabling the study of tumor-immune dynamics. We confirmed activity of B7-H3.CAR-T in PDOTS, although a strong correlation between B7-H3 expression and CAR-T efficacy was not observed. Mechanistic studies subsequently demonstrated dynamic upregulation of co-inhibitory receptors on CAR-T cells following target cell encounter leading to CAR-T cell dysfunction and limiting CAR-T efficacy in B7-H3 expressing tumors. PD-1 blockade restored CAR-T activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR-T efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR-T activity in monotypic and organotypic tumor spheroids, prevented CAR-T cell dysfunction, and enhanced T cell proliferation. Inhibition or deletion of TBK1 also enhanced sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR-T cells using PDOTS, and suggest that targeting TBK1 is a novel strategy to enhance CAR-T efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms. Citation Format: Luke Maggs, Yi Sun, Giulia Cattaneo, Marco Ventin, Feng Chen, Martin Q. Rasmussen, Xinhui Wang, Cristina R. Ferrone, Soldano Ferrone, Russell W. Jenkins. TBK1 inhibition enhances CAR-T cell efficacy against patient-derived organotypic tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4003.
Abstract 3961: Impact of CD8 resident memory T cells on antitumor immunity and response to cancer immunotherapy
Authors: Stephanie Corgnac, Isabelle DAMEI, Fathia Mami-Chouaib
Journal: Cancer Research (2024)

Abstract CD8+ resident memory T (TRM) cells expressing the CD103 integrin accumulate in human lung tumors and are associated with a favorable prognosis. We have previously demonstrated that a high density of CD103+CD8+ T cells in human lung tumors is a biomarker of response to immune checkpoint blockade (ICB) immunotherapy. However, a large fraction of human tumors is only weakly infiltrated by CD8+ TRM cells, and the reason of this TRM desert is not explained. Therefore, defining the molecular signals that give rise and maintain TRM cells within the tumor microenvironment (TME) and the mechanisms that potentiate antitumor TRM functions are important challenges. Data obtained in pre-clinical mouse colorectal cancer and melanoma models demonstrate that knocking-out CD103 impairs antitumor T-cell immunity and response to ICB and therapeutic peptide vaccine. Moreover, immunization of melanoma-bearing mice with the cancer vaccine results in a dramatic decrease in the percentage of CD103+ TRM cells among CD8+ tumor-infiltrating T lymphocytes (TIL). Algorithm analyses applied to spectral cytometry data of TIL support the conclusion that upon activation with the peptide vaccine a TRM subset gives rise to tumor-specific effector T cells. The mechanisms associated with the decrease in CD103 expression on CD8+ T cells and lead to a TRM differentiation shift will be presented as well as the key role of TGF-b in CD8+CD103+ TRM formation and persistence in the TME. Our data demonstrate that tumor CD8+CD103+ TRM are capable of mounting a potent antitumor immunity and suggest that a fine balance between diverse signals in the tumor ecosystem is required to induce their differentiation and thereby optimize response to cancer immunotherapy. Citation Format: Stephanie Corgnac, Isabelle DAMEI, Fathia Mami-Chouaib. Impact of CD8 resident memory T cells on antitumor immunity and response to cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3961.