tbuckley/cabot-search huggingface dataset:
Abstract 3820: Impact of primary site in early-stage follicular lymphoma on patient outcomes: Analysis of a large national database
Authors: Olivia Davis, Rana Kasht, Andrew Cohoon, Silas Day, Sami Ibrahimi, Adam Asch, Taha Al-Juhaishi
Journal: Cancer Research (2024)

Abstract Introduction: Follicular lymphoma (FL) is the most common indolent Non-Hodgkin lymphoma and is associated with better outcomes compared to other types of lymphoma. Despite this, cure is usually elusive and most patients experience multiple relapses within their lifetime. Previous studies have identified risk factors associated with worse outcomes, but little is known about the role of primary disease site in FL. We sought to investigate the outcomes of patients with extranodal early-stage FL compared to nodal disease using a large national cancer database. Methods: The Surveillance, Epidemiology, and End Results (SEER) public database was used to identify and extract data for patients with FL. Early-stage disease was defined as stage I or II by the Ann Arbor staging system. Most patients in the database were diagnosed after 2000 so this was used as the diagnosis year cutoff and also to reflect the impact of recent management strategies on outcomes. Patients were divided into two groups based on their primary disease site. These two groups were nodal (includes spleen) and extranodal. Treatment effect (surgery, radiation, or chemotherapy) was analyzed when available. Survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards models were used for adjusted survival analyses. Results: A total of 13,400 patients with FL of all histologic grades diagnosed between 2000 and 2015 were identified in the SEER database. The median age at diagnosis was 65 years (2-100). A majority of patients were Caucasian (81%), had stage I disease (62%), and belonged to the nodal FL group (79%). Median overall survival (OS) for patients with nodal FL was 181 months [95% CI (175-187)]. Median OS for extranodal FL was 189 months [95% CI (179-195)]. Extranodal FL was associated with better OS compared to the nodal group [HR=0.89, 95% CI (0.84-0.96); p-value =0.00012] even after adjusting for age and race [HR=0.84, 95% CI (0.79-0.90); p-value &amp;lt;0.0001]. Conclusions: In this analysis of a large national cancer database, early-stage FL presenting as extranodal disease can be seen in about 20% of patients and is associated with slightly better outcomes. Citation Format: Olivia Davis, Rana Kasht, Andrew Cohoon, Silas Day, Sami Ibrahimi, Adam Asch, Taha Al-Juhaishi. Impact of primary site in early-stage follicular lymphoma on patient outcomes: Analysis of a large national database [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 3820.
Abstract 4989: Targeting IL-1β mitigates radiation induced MDSC expansion &amp; improves survival in glioblastoma
Authors: Subhajit Ghosh, Jiayi Huang, David DeNardo, Dennis Hallahan, Jerry Jaboin, Dinesh Thotala
Journal: Cancer Research (2024)

Abstract Background: Our previous research demonstrated that radiation therapy (RT) for glioblastoma (GBM) induces aberrant myelopoiesis, increasing production of myeloid derived suppressor cells (MDSCs) and exacerbating T-cell suppression. However, the precise biological mechanisms underlying this phenomenon remain unclear. This study aims to elucidate the role of the pro-inflammatory cytokine interleukin-1beta (IL-1β) in RT-induced myelopoiesis and its correlation with poor prognosis in GBM patients. Methods: We conducted an extensive analysis of circulatory immune cells and pro-inflammatory cytokines in GBM patients treated with chemoradiotherapy. Using an orthotopic mouse model of GBM, we investigated the impact of IL-1β on myelopoiesis and survival. Functional assays were employed to examine MDSC expansion. Multi-color flow cytometry was used for immune profiling. Results: We found that RT elevated the plasma IL-1β concentration in both GBM patients and GBM-bearing mice, which also corresponded with an increase of MDSC in blood. In the murine GBM model, RT appeared to promote hematopoietic stem (HSPC) differentiation towards myelopoiesis. This led to increased MDSC precursor cells in the bone marrow, elevated circulating MDSCs in blood, and more infiltration of MDSCs in the tumor microenvironment (TME). Similar effects were observed in GBM-bearing mice following the administration of exogenous IL-1β. In contrast, inhibition of IL-1β using anti-IL-1β antibody during RT led to reduced myelopoiesis. When anti-IL-1β antibody was combined with functional inhibition of MDSCs using phosphodiesterase-5 inhibitor-tadalafil during RT, we observed decreased MDSC infiltration and increased CD8+ T cell infiltration in the TME. The combination approach also extended the survival of GBM-bearing mice after RT longer than either drug alone. Conclusions: Irradiation of GBM appears to induce IL-1β to promote aberrant myelopoiesis and MDSC expansion. A multi-pronged approach to inhibit MDSC production using IL-1β inhibitor and MDSC function using tadalafil during RT may be a promising approach to overcome the immune-suppressive TME of GBM. Citation Format: Subhajit Ghosh, Jiayi Huang, David DeNardo, Dennis Hallahan, Jerry Jaboin, Dinesh Thotala. Targeting IL-1β mitigates radiation induced MDSC expansion &amp; improves survival in glioblastoma [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 4989.
Abstract 4995: Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer
Authors: Chisom J. Uzendu, Yohan Kim, Roxane R. Lavoie, Haidong Dong, Sean Park, Fabrice Lucien-Matteoni
Journal: Cancer Research (2024)

Abstract Metastasis-ablative radiotherapy is a new therapeutic approach that prolongs survival in patients with advanced cancers. Tumour irradiation can elicit an immunogenic cell death resulting in the expansion of tumour-reactive T cells and eradication of both irradiated and distant non-irradiated metastases, referred to as the “abscopal effect”. This abscopal response, nevertheless, is observed in a minority of patients suggesting uncharacterized mechanisms that prevent robust systemic anti-tumor immune response. Tumour-derived extracellular vesicles (TdEVs) have recently emerged as mediators of antitumor immunity but their immunomodulatory role in response to radiotherapy remains largely unknown. Recent clinical studies by our lab have demonstrated that circulating levels of tumour-derived extracellular vesicles (tdEVs) are elevated in response to radiotherapy and high tdEV concentrations are associated with reduced levels of peripheral cytotoxic CD8+ T cells and higher risk of disease recurrence in advanced prostate cancer. Based on our findings, we hypothesize that radiotherapy induces the release of tumor-derived EVs that suppress anti-tumor immunity. Prostate cancer cells (PC3 and DU145) were irradiated with clinically used doses of ionizing radiation (20Gy x 1 or 10Gy x 3 fractions) and tdEVs were co-cultured with human CD8+ T cells to measure their proliferation and cytotoxic activity. Increased levels of tdEVs were released by tumour cells treated with radiotherapy. A higher frequency of impaired T cell cytotoxic activity and a reduction in CD8 T cell proliferation was found in the 10Gy x 3 radiation regimen. Proteomic analysis and western blot showed an increased expression of the immune checkpoint molecule B7-H3 on the tumour cell surface and tdEVs in response to radiotherapy. While coculture of CD8 T cells with B7-H3 depleted tdEVs led to recovery of T-cell cytotoxic ability, overexpression of the B7-H3 in tdEVs inhibited cytotoxic activity. This study provides a rationale for future studies in which we will test the immune-mediated effects of radiotherapy-induced tdEVs in immunocompetent mouse models and investigate B7-H3 blockade as a therapeutic approach to boost abscopal response in the treatment of advanced prostate cancer. Citation Format: Chisom J. Uzendu, Yohan Kim, Roxane R. Lavoie, Haidong Dong, Sean Park, Fabrice Lucien-Matteoni. Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate 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 4995.
Abstract 3006: Morphogen-driven regulation of nuclear shape and its implication for colorectal cancer
Authors: Mona A. El Gendi, Solène Hervé, Sudeep Gautam, Yekaterina A. Miroshnikova
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide despite improved rates of early detection and development of targeted treatments. Dysregulation of nuclear shape and the emergence of aberrant chromatin architecture correlate with cancer onset and progression, including CRC. Both extrinsic and intrinsic factors, most critically cytoskeletal and nucleoskeletal organization, chromatin architecture, and metabolic signaling, impact nuclear shape. Yet, what precisely determines nuclear shape in health and disease and how it is linked to cell fate and function remains a fundamental open question. In the case of over 75% of CRC cases, the first transformative genetic event is the loss of function in the tumor suppressor gene, adenomatous polyposis coli (APC). Mechanistically, perturbed APC signaling leads to aberrant activation of Wnt/beta-catenin signaling. This pathway is essential for intestinal homeostasis, as is the regulation of proper nuclear shape and function. Here, we aim to decipher the crosstalk between Wnt gradients and nuclear shape regulation in non-transformed and APC-mutated epithelial cells in vitro, as well as in WT and APC-mutant mouse colon tissues. The long-term goal of this work is to test whether a mechanistic link exists between Wnt-driven cellular transformation and the emergence of aberrant nuclear shape and function. Citation Format: Mona A. El Gendi, Solène Hervé, Sudeep Gautam, Yekaterina A. Miroshnikova. Morphogen-driven regulation of nuclear shape and its implication for colorectal 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 3006.
Abstract 278: Investigating the functional role of cancer-associated fibroblasts in the emergence of drug-tolerant persisters in ovarian cancer
Authors: Angel S. Ng, Ngoc Bui, Laurie Ailles
Journal: Cancer Research (2024)

Abstract Chemoresistance remains a major clinical challenge for the treatment of high-grade serous ovarian cancer (HGSC), the most lethal gynecologic malignancy. The majority of patients who initially respond to first-line platinum/taxane-based chemotherapy eventually relapse with chemoresistant disease, leading to poor survival outcomes. It is increasingly recognized that cancer cells can enter a reversible drug-tolerant persister (DTP) state through non-genetic mechanisms to evade chemotherapy-induced cytotoxicity prior to the development of chemoresistance. However, how environmental signals and extracellular factors from the tumor microenvironment drive the process remains poorly understood. Cancer-associated fibroblasts (CAFs) are a functionally heterogeneous population of activated fibroblasts. CAFs play a critical role in shaping the tumor microenvironment and tumor behaviors, including promoting tumor growth and mediating therapy resistance. Here, we demonstrated that HGSC cell lines co-cultured with patient-derived FAP-high CAFs, a subpopulation of CAFs previously identified in our lab to be tumor-promoting, significantly increase the formation of DTPs upon prolonged carboplatin treatment compared to the mono-cultured condition. Interestingly, the extracellular matrix (ECM) organization signature is enriched in FAP-high CAFs compared to their FAP-low counterparts, and we found that ECM deposited by FAP-high CAFs also facilitates the emergence of DTPs in HGSC cells. Future work will focus on elucidating the mechanisms by which FAP-high CAFs and the associated ECM promote DTP formation in HGSC cells through transcriptomic and proteomic profiling. This will aid the identification of potential therapeutic vulnerabilities to target cancer cells in the DTP state in FAP-high HGSC patients. Citation Format: Angel S. Ng, Ngoc Bui, Laurie Ailles. Investigating the functional role of cancer-associated fibroblasts in the emergence of drug-tolerant persisters in ovarian 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 278.
Abstract 7623: Biomarker study to personalized neoadjuvant chemotherapy using preoperative gastric cancer specimens of biopsy from the COMPASS trial, a phase II randmazed controlled trial
Authors: Takashi Oshima
Journal: Cancer Research (2024)

Abstract Background and Aim: The results of COMPASS, a randomized phase II trial, suggest that preoperative adjuvant chemotherapy (NAC) regimen or course for locally advanced gastric cancer (GC) does not affect overall survival (OS). However, we hypothesized that some NAC regimens may be more effective for OS on a case-by-case basis. Furthermore, we searched for biomarkers, assuming that further improvement in the outcome of locally advanced GC could be expected if appropriate NAC regimens could be selected using biomarkers before treatment initiation. Materials and Methods: RNA was extracted from endoscopic biopsy specimens of primary tumors collected prior to NAC administration in COMPASS patients, and real-time polymerase chain reaction (PCR) of 127 genes was performed to identify genes with significant (P &amp;lt; 0.05) interaction P values for survival with each regimen and stratified OS with each regimen. Genes were identified and biomarkers were searched at the protein level using immunohistochemical analysis. Results: The THBS1, MSI1, and IGF2BP3 genes were identified as genes whose expression levels significantly (P &amp;lt; 0.05) stratified survival for each regimen and had significant (P &amp;lt; 0.05) interaction P values. Furthermore, a strong correlation was observed between each gene and THBS1, MSI1, and IGF2BP protein expression by immunohistochemical analysis, confirming that protein expression levels by immunohistochemical analysis are also useful as biomarkers. Conclusion: Using endoscopic biopsy specimens prior to NAC for locally advanced GC, biomarkers were identified to select NAC regimens over predicted OS. The results of this study may guide the conduct of clinical trials of individualized treatment of NAC using biomarkers. Citation Format: Takashi Oshima. Biomarker study to personalized neoadjuvant chemotherapy using preoperative gastric cancer specimens of biopsy from the COMPASS trial, a phase II randmazed controlled trial [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 7623.
Abstract 4463: Metabolic reprogramming through Notch1 signaling promotes a survival advantage in pancreatic neuroendocrine tumor cells
Authors: Rachael Guenter, Weisheng Chen, Brendon Herring, Yuvasri Golivi, Melissa Sammy, Jason Whitt, Renata Jaskula-Sztul, Herbert Chen, J. Bart Rose
Journal: Cancer Research (2024)

Abstract Background: Cancer cells utilize both oxidative phosphorylation (OXPHOS) and glycolysis to generate energy. Switching between OXPHOS and glycolysis can promote tumor progression. The mechanisms governing oncogenic metabolic reprogramming are largely unknown, but recent data has suggested that Notch1 dysregulation in cancer cells can contribute to altered metabolic phenotypes. We hypothesized that Notch1 signaling supports metabolic reprogramming in pancreatic neuroendocrine tumor (pNET) cells. Methods: We established a Notch1-knockout pNET cell line (BON-N1-KO) by deleting Notch1 at exon 3 in a pNET cell line (BON) using CRISPR/Cas9. Proliferation over time was measured using a trypan blue exclusion test. Seahorse Glycolytic Rate Assay and Mitochondria Stress Test were used to measure the glycolytic and mitochondrial activities of cells. A glycolysis deprivation assay was employed to determine cell viability at varying glucose concentrations. Single end RNAseq was performed using the Illumina NGS platform, to a read depth of 50M. Results: Over time, pNET cells lacking Notch1 (BON-N1-KO) proliferated slower than wildtype (WT) cells (p=0.034). Compared to WT BON, the BON-N1-KO cells had reduced basal oxygen consumption rate (28.2 ± 1.3 vs. 40.7 ± 1.4; p=0.02, ATP production (21.9 ± 1.0 vs. 29.6 ± 0.98; p=0.04), and maximal respiration (39.4 ± 1.7 vs. 63.7 ± 2.1; p=0.004). BON-N1-KO cells also had a reduction in basal glycolysis, as measured by proton efflux rate, compared to WT (48.7 ± 2.6 vs. 57.7 ± 6.2; p=0.2). To further test metabolic reprogramming, WT and BON-N1-KO cells were starved of glucose (0mM), compared to normal glucose (17.5mM) and viability was measured over time. By day 5, the BON-N1-KO group had a viability of 0%, whereas 12.8% of WT cells were alive (p=0.038). To determine if Notch1 loss was associated with altered expression of established metabolic genes, we performed RNAseq. Differential gene expression analysis found that OXPHOS-related genes (UQCC2, COX15, COX20) and glycolysis-related genes (Slc1a1, Slc2a4, Hk1, Hk2) were significantly down-regulated in BON-N1-KO cells. Conclusions: Our study shows that Notch1 signaling facilitates metabolic reprogramming as a survival advantage in pNET cells. Targeting Notch1 signaling to mediate cellular metabolism may be a novel therapeutic strategy in pNETs. Citation Format: Rachael Guenter, Weisheng Chen, Brendon Herring, Yuvasri Golivi, Melissa Sammy, Jason Whitt, Renata Jaskula-Sztul, Herbert Chen, J. Bart Rose. Metabolic reprogramming through Notch1 signaling promotes a survival advantage in pancreatic neuroendocrine tumor cells [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 4463.
Abstract 7473: Flotillin-2 ablation in T cells enhances antigen sensitivity and functionality
Authors: Sookjin Moon, Peer W. Karmaus, Michael B. Fessler
Journal: Cancer Research (2024)

Abstract The membrane scaffolding protein flotillin-2 (Flot2) has been proposed to support receptor signaling, but its involvement in T cell receptor (TCR) signaling and T cell responses remains unclear. Here, we show that the deletion of Flot2 increases antigen sensitivity along with changes in surface TCR clustering, resulting in enhanced TCR signaling and effector function to weak TCR stimulation. T cell-specific Flot2-deficient mice showed enhanced proliferation and effector cytokine production in both CD4+ and CD8+ T cells, resulting in better control of tumor growth and infection. However, in vitro TCR stimulation with plate-bound anti-CD3 and soluble anti-CD28 showed increased TCR signaling and early activation of CD4+, but not CD8+ Flot2-deficient T cells upon weak stimulation. In addition, Flot2-deficient CD4+ T cells showed better in vitro polarization toward T helper 1 cells upon weak TCR stimulation, likely due to increased sensitivity of the TCR-triggering threshold. Changes in TCR clustering on the membrane have been suggested to influence the early detection of foreign stimuli and the formation of immune synapses. Flot2 ablation indeed increased the number of membrane TCR nanoclusters on naïve CD4+ T cells. Collectively, this study suggests a mechanism for increasing T cell functionality to weak TCR stimulation by modulating the membrane protein Flot2, which affects surface TCR clustering. These results may have important implications for improving T cell reactivity in diseases with poor antigenicity, such as anti-tumor immune responses. Citation Format: Sookjin Moon, Peer W. Karmaus, Michael B. Fessler. Flotillin-2 ablation in T cells enhances antigen sensitivity and functionality [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 7473.
Abstract 1760: Mutational landscape of the canine acute myeloid leukemia exome
Authors: Robert Harris, Evan Conaway, Anne Avery
Journal: Cancer Research (2024)

Abstract Over 21,000 newly diagnosed cases of human acute myeloid leukemia (hAML) and 10,000 hAML-related deaths are reported in the United States every year. hAML is considered a highly diverse aggressive hematopoietic malignancy, with over 16 recurrent gene rearrangements, 60 recurrent point mutations, and hundreds of rarely mutated genes. There are large ongoing multi-institutional studies devoted to advancing medical management for hAML by providing targeted therapeutics to patients based on their molecular characteristics. A preclinical spontaneous large animal model for testing novel therapies could accelerate the development of better treatments in people. Dogs spontaneously develop AML with similar clinical features and outcomes. As such, the dog may be a useful pre-clinical model, but little is known about the molecular landscape and/or drivers of canine AML (cAML). The goal of this work was to identify somatic mutation candidates in cAML and determine the overlapping features with hAML. We utilized whole exome sequencing at 300x coverage to identify candidate mutations in 51 cAML samples. Somatic variant calling was performed per the GATK best practice recommendations using Mutect2 and a reference panel of normals (n=77) and a variant call file of canine germline variants. We focused our analysis on novel variants predicted to have a moderate to high impact and that occurred in genes implicated in cancer. At least one variant was identified in genes involved in the RTK/RAS pathway (e.g. NRAS, KRAS, PTPN11, FLT3, KIT) in over 75% of cAML samples, a trend that is also found in people. Additionally, recurrent point mutations were predicted in NRAS and KRAS, and some of which, such as the codon changes G13R and Q61R/H in NRAS, were noted to be shared between hAML and cAML. Mutations in DNMT3A were uncommon (n=3/44) and NPM1 mutations were not identified in our cohort, both of which are common hAML-associated genes. However, mutations in other epigenetic modifiers, such as KDM5C and KDM6A, occurred at a high frequency. This data provides insight into the candidate mutations potentially driving cAML pathogenesis and highlights the overlapping molecular features with hAML. Citation Format: Robert Harris, Evan Conaway, Anne Avery. Mutational landscape of the canine acute myeloid leukemia exome [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 1760.