tbuckley/cabot-search huggingface dataset:
Abstract 2835: Comparison of xenograft and syngeneic cancer cachexia models for preclinical drug testing
Authors: Kyle Draheim, Diana Gietl, Karyn Shinn, William Durham, Fei Zhao, Caitlin Thompson, Alexis Baldwin, Glenn Harris, Chassidy Hall, Patrick Fadden, Anya Avrutskaya
Journal: Cancer Research (2024)

Abstract Cancer cachexia is a wasting syndrome characterized primarily by loss of skeletal muscle and adipose tissue mass and contributes greatly to overall cancer-related mortality (for recent review see Argiles 2023). An estimated 25-75% of cancer patients develop cachexia which leads to impacts on therapeutic tolerability, well-being, and eventually overall survival (Bossi 2021). Some preclinical mouse and rat cancer models manifest cachexia as they progress. In this study we established a syngeneic (immune competent) and a xenograft (immune incompetent) tumor model of cachexia with the intention of comparing the models with respect to typical study endpoints and to provide a platform for testing novel therapeutic agents aimed at inhibiting or reversing the effects of cachexia. The Colon26 syngeneic mouse colon adenocarcinoma model was reported as an experimental cancer cachexia model by Tanaka, et. al. in 1990. The model was developed in male BALB/c × DBA/2 F1 (first generation cross) mice. We typically implant Colon26 in female BALB/c mice for preclinical drug testing of anticancer agents and noticed a strong tendency for mice bearing Colon26 tumors to develop signs of cachexia on study, but not always consistently. A review of the literature showed there are clear gender differences with male cancer patients having higher prevalence of cachexia and greater muscle loss compared with female patients (Zhong 2020). Based on this we implanted Colon26 tumors in male BALB/c mice to establish the cachexia model. The HT1080 human fibrosarcoma model HT1080 was characterized as a cachexic model by Bernardo, et. al. in female severe combined immunodeficiency disease (SCID) mice. We developed the HT1080 model in male SCID mice based on the literature and previous experience. Both models were characterized by multiple endpoints including overall body weight loss, skeletal muscle weight loss, reduction of adipose tissue, and cardiac muscle loss, as well as tracking a broad panel of relevant cytokine levels at study endpoint. Both models generate robust wasting of skeletal muscle and adipose tissue providing an opportunity to assess novel anti-cachexia therapies. Citation Format: Kyle Draheim, Diana Gietl, Karyn Shinn, William Durham, Fei Zhao, Caitlin Thompson, Alexis Baldwin, Glenn Harris, Chassidy Hall, Patrick Fadden, Anya Avrutskaya. Comparison of xenograft and syngeneic cancer cachexia models for preclinical drug testing [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 2835.
Abstract 2446: Genomic landscape of longitudinally collected preinvasive airway lesions
Authors: Ahmed Alhendi, Lukas Kalinke, Adam Pennycuick, Kate Davies, Pascal Durrenberger, Kate Gowers, Kristiana Grigoriadis, Nicholas McGranahan, Sam Janes
Journal: Cancer Research (2024)

Abstract Lung carcinoma in situ (CIS) lesions, as precursors to squamous cell carcinoma, exhibit microscopic uniformity while displaying diverse clinical trajectories. Half of these lesions progress to invasive cancer, while the remaining half either regress or remain indolent. Previous genomic profiling efforts have elucidated progression-specific genomic changes against a backdrop of inherent heterogeneity and notable chromosomal instability signatures. Here, we present a novel approach by analyzing longitudinally collected samples of preinvasive airway lesions, encompassing both progressive and indolent trajectories. Our findings reveal that genomic integrity and cell cycle dynamics constitute key distinctions between progressive and indolent lesions. Notably, a decrease in clonal diversity and an inverse correlation between TCRA-Tcell fraction and genomic instability are observed as lesions approach invasion. Somatic mutations in cancer driver genes BRAC2, CSMD3, and MUC16 are found significantly associated with lesion progression. Furthermore, progressive lesions exhibit a higher frequency of copy number changes compared to indolent lesions. Copy number loss in 1p, 3p, 9p, and 17p are found to be significantly associated with lesion progression. Phylogenetic analysis further confirms positive selection for copy number loss in these specific genomic regions, providing insights into the evolutionary trajectory of alterations in progressive lesions. The comprehensive understanding derived from these genomic analyses is anticipated to advance early detection strategies, mitigate overtreatment, and facilitate the development of preventative therapies targeting early clonal events in lung cancer. Citation Format: Ahmed Alhendi, Lukas Kalinke, Adam Pennycuick, Kate Davies, Pascal Durrenberger, Kate Gowers, Kristiana Grigoriadis, Nicholas McGranahan, Sam Janes. Genomic landscape of longitudinally collected preinvasive airway lesions [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 2446.
Abstract 5371: Multimodal CRISPR activation screens reveal new mechanisms to sensitize cancer cells to targeted T cell mediated elimination
Authors: Reece V. Akana, Chang Sun, YoungMin Kim, Yuxin Cai, Subin Kim, Jeehyun Yoe, Olivia Laveroni, Livnat Jerby-Arnon
Journal: Cancer Research (2024)

Abstract Cell autonomous resistance mechanisms can protect cancer cells from targeted T cell elimination, resulting in resistance to a broad range of immunotherapies. High-throughput gene knockout and gene inhibition screens have been instrumental in identifying key drivers of such mechanisms, yet often uncovering gene activity that is essential but not sufficient for response. Here we set out to leverage gene activation as an orthogonal approach to identify novel regulators of the cancer-immune interface. First, we performed CRISPR activation screens in melanoma cells co-cultured with antigen-specific primary CD8+ T cells. Our findings revealed a collection of novel genes that substantially sensitize melanoma cells to targeted T cell-driven elimination when activated, including DNA damage and unfolded protein response genes (e.g., ETS1, TSPYL2), Wnt ligands (e.g., WNT3A, WNT1), and others that are deleterious only in combination with targeting T cells. Among the resistance genes we found regulators of insulin signaling (e.g., HGF, TCF7L2) and numerous glycoproteins (e.g., PDPN, CD44). Second, we validated top novel hits in 2D and in 3D spheroid models, using optical readouts to investigate their impact on cancer cell elimination and cancer-T-cell spatial dynamics. Third, we performed a Perturb-seq screen to stratify dozens of hits into functional groups based on the transcriptional readouts in the cancer cells. Lastly, we developed an in situ Perturb-Seq method, where we combine high-plex spatial transcriptomic readouts at subcellular resolution with in situ detection of genetically modified cells, and applied it to track the impact of the (de)sensitizing perturbations not only on the cancer cells themselves, but also on T cell recruitment and suppression. Taken together, our study provides a catalog of immune evasion mechanisms and an array of novel targets, demonstrating that synthetic gene activation can diminish immune evasion and open novel avenues for development of agonist-based and RNA-based interventions. Citation Format: Reece V. Akana, Chang Sun, YoungMin Kim, Yuxin Cai, Subin Kim, Jeehyun Yoe, Olivia Laveroni, Livnat Jerby-Arnon. Multimodal CRISPR activation screens reveal new mechanisms to sensitize cancer cells to targeted T cell mediated elimination [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 5371.
Abstract 4049: The beta-carboline Harmine sensitives microsatellite stable colorectal cancer mouse model to anti-PD-1 through upregulating MHC-I dependent antigen presentation machinery and improving the infiltration of CD8 T cells into the tumor microenvironment
Authors: Ruize Gao, Kris Van Moer, Coralie Pulido, Anaïs Oudin, Diane Murera, Teresa L. Ramos, Margaux Poussard, Andreas Schläpfer, Annette Ives, Christian Auclair, Bassam Janji
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the most common gastrointestinal cancer and the third leading cause of cancer-related death in both sexes. Mismatch repair deficient/microsatellite instability-high (MSI) colorectal cancer patients benefit from immune checkpoint blockades (ICBs)-based immunotherapy; however, this benefit has not been translated into microsatellite stable (MSS) colorectal cancer. It has been proposed that the loss of major histocompatibility complex class I (MHC-I) in tumor cells limits the use of ICB in colorectal cancer. Harmine displays a number of biological and pharmacological properties affecting the immune response and tumor phenotype. Here, we assessed the impact of combining harmine, also referred to as ACB1801 molecule, on improving the responsiveness of ICB in the mouse MSS CRC model. Our results showed that combining ACB1801 significantly improves the therapeutic benefit of anti-PD-1 in the CT26 CRC mouse model by decreasing tumor growth and improving the survival of tumor-bearing mice. The improvement of anti-PD-1-based therapy by combining ACB-1801 was associated with a modification of the immune landscape of tumors as evidenced by an increase in the CD8+ T cells and a decrease in the Treg infiltrations into the tumor microenvironment. By profiling the cytokine/chemokine network, we showed that ACB1801 induced the expression and the release of the proinflammatory chemokine CXCL10 by CRC tumor cells in vitro, which could be responsible for driving CD8+ T cells to the tumor microenvironment. Mechanistically, we showed that ACB1801 increased the expression of MHC-I genes, including TAP1 and TAPASIN, and improved the antigen loading on MHC-I in CRC cells in vitro. Overall, our study highlights the value of combining ACB1801 and anti-PD-1 as a therapeutic opportunity to convert MSS colorectal cancer into an “immune hot” cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need. Citation Format: Ruize Gao, Kris Van Moer, Coralie Pulido, Anaïs Oudin, Diane Murera, Teresa L. Ramos, Margaux Poussard, Andreas Schläpfer, Annette Ives, Christian Auclair, Bassam Janji. The beta-carboline Harmine sensitives microsatellite stable colorectal cancer mouse model to anti-PD-1 through upregulating MHC-I dependent antigen presentation machinery and improving the infiltration of CD8 T cells into the tumor microenvironment [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 4049.
Abstract 3685: Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm
Authors: Hua Bao, Wanxiangfu Tang, Ningyou Li, Min Wu, Jinfeng Zhang, Baihan Zhu, Xue Wu, Yang Shao
Journal: Cancer Research (2024)

Abstract Objective: Existing methods for detecting circulating-tumor DNA (ctDNA) through fixed panels exhibit constrained sensitivity, while customized panels are time-consuming and rely on prerequisite tumor mutation profiles. Here, we aimed to introduce an adaptive noise cancellation approach for efficient Minimal Residuals Disease (MRD) detection in colorectal cancer patients employing a fixed panel under both tumor-informed and tumor-naïve situations. Methods: 108 plasma samples were collected from 52 colorectal cancer patients (11 relapse, 41 non-relapse) at various post-surgical timepoints. Comprehensive mutational profiling of plasma samples was conducted using a fixed MRD panel (SHIELDINGTM ULTRA) that encompasses hotspots in 2365 cancer-related genes. Background errors were removed by an adaptive noise cancellation algorithm relying on DNA fragment profiling, normal pool, and white blood cell background and intra-run plasma sampling. Variants were called both with (tumor-informed) and without (tumor-naïve) the present of tumor tissue. Results: Our longitudinal analysis of 108 plasma samples yielded 90.9% sensitivity, 97.6% specificity and 97.6% negative predictive value in the tumor-informed scenario. The ctDNA positive patients exhibited significantly higher risk than those with negative ctDNA status (Hazard Ratio = 87.2, p = 3.5 × 10^(-5)). For landmark analysis, 33 plasma samples (≤7 days post-operation) were assessed, yielding a remarkable performance of 66.7% sensitivity and 100% specificity. Our approach showed robustness under tumor-naïve scenario, illustrating 90.9% sensitivity, 92.7% specificity and 97.4% NPV for the longitudinal analysis. This corresponded to an increased risk of 49 times in the ctDNA positive patients (HR = 49.0, p = 2.2 × 10^(-4)). Notably, the results of tumor-naïve samples closely aligned with those of tumor-informed samples, showing a concordance of 92.6% and substantial agreement (Cohen’s Kappa = 0.691). Conclusion: Our method stands as an ultra-sensitive tool for identifying colorectal patients at high risk of recurrence. By employing an adaptive noise cancellation algorithm, our fixed panel approach demonstrates superiority over existing fixed panels in accuracy and proves to be a cost-effective alternative to personalized panels. Significantly, it extends potential clinical utilization towards tumor-naïve patients, which is not feasible for personalized panels. Citation Format: Hua Bao, Wanxiangfu Tang, Ningyou Li, Min Wu, Jinfeng Zhang, Baihan Zhu, Xue Wu, Yang Shao. Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm [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 3685.
Abstract 5073: Advancing precision oncology: Insights from pan-cancer proteogenomic signatures
Authors: Yize Li, Nadezhda V. Terekhanova, Michael C. Wendl, Feng Chen, Li Ding
Journal: Cancer Research (2024)

Abstract Somatic mutations in cancer genomes arise from diverse mutational processes, leaving distinct mutational signatures. However, the proteogenomic implications of these signatures and their connections to environmental influences and immune interactions remain largely unexplored. In this study, we comprehensively investigated these signatures from a broader proteogenomic perspective to further discern their genetic, proteomic, phosphoproteomic, and environmental ramifications. The harmonized dataset of 1064 samples across ten cancer types from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) pan-cancer resource was utilized for this investigation. Beyond genetic alterations and mutational signatures, we harnessed high-throughput multi-omics data to detect critical changes and infer expression signatures associated with the transitions to seven tumor-linked phenotypes: aging, Apolipoprotein B mRNA Editing Catalytic Polypeptide (APOBEC), Homologous Recombination Deficiency (HRD), Microsatellite Instability (MSI), Polymerase Epsilon (POLE), smoking, and ultraviolet (UV) light exposure at the pan-cancer level. We prioritized the top differentially expressed markers uniquely found at the protein and phosphoprotein levels and developed a quantitative score predicting each phenotype status, such as MSI. Respectively, we pinpointed potential candidates as actionable therapeutic targets by linking the identified markers to druggable databases. This offers additional cues to optimize therapeutic options for patients. Specifically, directing attention to genes up-regulated in HRD tumors treated with PARP1 inhibitors shows potential promise in overcoming resistance. Moreover, we explored environmental exposure-related tumor proteogenomic signatures and their association with immune infiltration levels and phenotypes. Notably, smoking strongly influenced the tumor microenvironment (TME) and prognosis in lung cancer. In summary, our identification of expression signatures facilitates phenotype prediction and unveils their molecular mechanisms. We anticipate clinical utility in classifying samples using proteogenomics, particularly in cases where a solely genomic assessment is inconclusive. Citation Format: Yize Li, Nadezhda V. Terekhanova, Michael C. Wendl, Feng Chen, Li Ding. Advancing precision oncology: Insights from pan-cancer proteogenomic signatures [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 5073.
Abstract 479: Enhanced payload delivery for acute myeloid leukemia treatment through CD37-targeting DNA nanobots
Authors: Nicholas Vantangoli, Patrick D. Halley, Jeffrey R. Spitzner, John C. Byrd, Karilyn T. Larkin, Carlos E. Castro, Christopher R. Lucas
Journal: Cancer Research (2024)

Abstract Acute Myeloid Leukemia (AML) treatment faces considerable challenges, in particular the delivery of therapeutics with sufficient potency and specificity. Traditional Antibody-Drug Conjugates (ADCs) offer a strategic approach to cancer therapy by combining the targeting capabilities of monoclonal antibodies with the cell-killing effect of cytotoxic drugs. However, the limitations in drug-to-antibody ratio (DAR) and the challenges in controlling the release kinetics have often hindered their therapeutic window suggesting novel approaches are necessary. Our approach integrates DNA nanobot technology to facilitate targeted delivery of anthracycline agents directly to CD37-expressing leukemic cells. CD37, a tetraspanin superfamily antigen, has shown promise as a target for AML due to its selective expression on immune cells and favorable internalization properties. By harnessing DNA origami assembly techniques, we developed a customizable platform capable of accommodating a significantly higher payload of chemotherapeutic agents than traditional ADCs. This increased payload potential, paired with the precision targeting of CD37, presents a potent therapeutic strategy with the possibility of reduced systemic toxicity. Here we present preclinical evidence demonstrating targeted delivery of our DNA nanobot drug delivery device and anthracycline payload to CD37+ AML target cells in vitro. In addition, we show targeted efficacy in vitro and in vivo of our anthracycline-loaded DNA nanobot-enabled delivery system, which significantly outperformed free anthracycline in AML target cells. Collectively, our findings suggest an improvement in the therapeutic index of anthracycline and antimitotic agents as well as the ability to combine multiple drug pathways in a single delivery device. The implications of this work extend beyond AML, offering a versatile platform that could revolutionize ADC chemistry and targeted drug delivery. We propose that our DNA nanobot delivery system signifies a pivotal advancement in the field of targeted cancer therapy, with the potential to overcome longstanding barriers in the treatment of AML and potentially other malignancies. Citation Format: Nicholas Vantangoli, Patrick D. Halley, Jeffrey R. Spitzner, John C. Byrd, Karilyn T. Larkin, Carlos E. Castro, Christopher R. Lucas. Enhanced payload delivery for acute myeloid leukemia treatment through CD37-targeting DNA nanobots [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 479.
Abstract 5497: Towards a drag and drop spatial biology workflow: Introducing sample reinterrogation as a conduit for the progressive development and on-line analysis of high parameter spatial biology data
Authors: Matthew H. Ingalls, Xenia Meshik, Charles E. Jackson, Kayla E. Cashion, Arne Christians, Anke Brix, Marcus Boettcher, J Spencer Schwarz, Oliver Braubach
Journal: Cancer Research (2024)

Abstract The potential for spatial biology in cancer research is understood and edified. With it we can understand the tumor microenvironment, unravel responsiveness to drug treatments and cell therapies, and ultimately stratify patients for targeted treatment and clinical trial enrollment. Yet, researchers exploring spatial biology may be discouraged by what can be a resource intensive exercise, and most importantly, a commitment of high value patient samples. Furthermore, the design of reagent panels used to study samples is not trivial, and a specimen’s unique biomarker expression profile may require adjustments. Here we present a novel solution that permits sample re-interrogation and in-flight adjustments of reagent panels in our spatial biology workflow. The CellScape™ platform for Precise Spatial Multiplexing paired with VistaPlex™ Assay Kits provide a ready-to-use cyclic multiplex immunofluorescence (IF) solution to interrogate fresh frozen and FFPE tissue samples. Tissues are mounted in enclosed fluidic chambers, while staining and imaging are conducted on the CellScape instrument. The experiment requires no additional autostainer equipment and is divided into separate staining and imaging rounds. The end user may therefore pause between rounds and conduct inter-round analyses, which can then guide decisions of whether and how to continue the experiment. To illustrate the benefit of this approach, we present a use case in which we applied VistaPlex antibody panels to reveal the spatial distribution of major immune cell populations. Inter-round analysis and conclusions were then drawn from this preliminary phenotype map before successive rounds of rationally planned staining were conducted to further deepen the depth and breadth of spatial phenotyping. The CellScape sample reinterrogation feature is a pragmatic spatial biology solution that optimizes the use of precious resources, whilst allowing researchers to generate informed decisions about antibody panel designs almost in real time. This enhanced utility may reduce the resistance to spatial biology among researchers working with samples that are limited or irreplaceable. Citation Format: Matthew H. Ingalls, Xenia Meshik, Charles E. Jackson, Kayla E. Cashion, Arne Christians, Anke Brix, Marcus Boettcher, J Spencer Schwarz, Oliver Braubach. Towards a drag and drop spatial biology workflow: Introducing sample reinterrogation as a conduit for the progressive development and on-line analysis of high parameter spatial biology data [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 5497.