bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2116: VPS34 inhibitor SB02024 activates cGAS-STING signaling and sensitizes tumors to STING agonist
Authors: Yu Yasmin , Noman Muhammad Z. , Parpal Santiago , Kleinendorst Simone C. , Saether Kristine B. , Alexeyenko Andrey , Viklund Jenny , Andersson Martin , Martinsson Jessica , Tamm Katja P. , De Milito Angelo , Janji Bassam 
Published: June 2022

Abstract
Novel approaches to reduce tumor immunosuppression and improve responses to anti-cancer immunotherapies based on immune-checkpoint inhibitors are needed. Emerging evidence demonstrates that autophagy inhibition enhances anti-tumor immunity by tumor cell-intrinsic and extrinsic mechanisms. Recently, we reported that pharmacological inhibition of VPS34 (PIK3C3), a lipid kinase regulating autophagy initiation, decreases tumor growth and improve the efficacy of anti-PD-1/PD-L1 therapy in melanoma and colorectal cancer mouse models. This effect was dependent on increasing T and NK cell infiltration as well as the expression of CCL5 and CXCL10 chemokines in the tumor microenvironment. Here, we explored the signaling mechanisms underlying the chemokine release following treatment with VPS34 inhibitor SB02024. We found that both pharmacological and RNAi-mediated inhibition of VPS34 activated a cGAS-STING-dependent type I interferon response in renal cell carcinoma (RCC) and melanoma cell lines. Furthermore, combination treatment of VPS34 inhibitor SB02024 with STING agonist ADU-S100 or cGAMP increased the mRNA expression and release of proinflammatory cytokines in human and murine RCC and melanoma cancer cell lines. Oral administration of SB02024 in combination with intratumoral injections of ADU-S100 significantly decreased tumor growth and weight and improved mice survival of B16-F10 tumor-bearing mice. Taken together, our data demonstrates that targeting of VPS34 results in a cGAS/STING-mediated increase of pro-inflammatory cytokine secretion and synergizes with a STING agonist. We believe that systemic VPS34 inhibition using SB02024 would be of major interest in combination or as an alternative to STING agonists to improve anti-tumor immune responses.
Citation Format: Yasmin Yu, Muhammad Z. Noman, Santiago Parpal, Simone C. Kleinendorst, Kristine B. Saether, Andrey Alexeyenko, Jenny Viklund, Martin Andersson, Jessica Martinsson, Katja P. Tamm, Angelo De Milito, Bassam Janji. VPS34 inhibitor SB02024 activates cGAS-STING signaling and sensitizes tumors to STING agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2116.
Abstract 2166: Ibuprofen induces ferroptosis to potentiate antitumor immunity
Authors: Talty Ronan , Ferreira Michelle , Krykbaeva Irina , Bosenberg Marcus 
Published: June 2022

Abstract
Ferroptosis is an iron-dependent regulated cell death pathway that has recently emerged as a promising target for cancer therapy. PTGS2 has been identified as a marker of ferroptosis due to its upregulation in cells after treatment with ferroptosis inducers. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the protein product of PTGS2 and have been shown to enhance antitumor immunity. We hypothesized that NSAIDs induce ferroptosis and that this mechanism is essential for their effect on antitumor immunity. To test this, we first determined that ibuprofen and other NSAIDs induce cell death in YUMMER-1.7 melanoma and MC38 colorectal cancer cells in vitro. Cell death occurred progressively over 24 hours and could be blocked by multiple ferroptosis inhibitors. Treatment with NSAIDs also increased intracellular lipid peroxides and decreased levels of reduced glutathione and ferrous iron. This indicated that ibuprofen and other NSAIDs induce ferroptosis in vitro, so we next evaluated whether ibuprofen also induces ferroptosis in vivo. Analysis of ibuprofen-treated YUMMER-1.7 or MC38 tumors showed increased levels of lipid peroxides and lipid peroxide intermediates, 4-hydroxynonenal and malondialdehyde, compared to untreated tumors. Treatment of tumor-bearing mice with ibuprofen alone resulted in approximately 60% tumor clearance and survival, whereas a combination of multiple ferroptosis inhibitors with ibuprofen completely abrogated this effect. Since it has been demonstrated by that CD8+ T cells can release IFN-γ to induce ferroptosis in tumor cells, we next tested the dependence of the antitumor effect of ibuprofen on CD4+ T cells, CD8+ T cells, and IFN-γ using depleting antibodies. Depletion of any of these was sufficient to prevent the antitumor effect of ibuprofen. Given the need to identify pathways that enhance responses to existing immunotherapies, we determined whether treatment with ibuprofen synergizes with PD-1 checkpoint blockade. The combination of α-PD-1 with ibuprofen resulted in a 100% tumor clearance and survival rate, whereas α-PD-1 or ibuprofen alone resulted in 40% and 60% tumor clearance and survival rates, respectively. Furthermore, treatment with ibuprofen also sensitized α-PD-1-resistant tumors to PD-1 in two distinct models of α-PD-1 resistance. Overall, these findings establish ibuprofen and other NSAIDs as inducers of ferroptosis and underscore the potential for ferroptosis inducers to be used in combination with existing immunotherapy regimens.
Citation Format: Ronan Talty, Michelle Ferreira, Irina Krykbaeva, Marcus Bosenberg. Ibuprofen induces ferroptosis to potentiate antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2166.
Abstract 245: Interleukin-4 receptor-targeted Abraxane inhibits tumor growth by enhancing drug delivery and reprogramming of M2-type macrophages into M1 phenotype
Authors: Murugan Poongkavithai Vadevoo Sri , Rangaswamy Gunassekaran Gowri , Lee Byungheon 
Published: June 2022

Abstract
Abraxane, an albumin-bound paclitaxel nanoparticle, is widely used in treating patients with cancer such as breast cancer. The present study aims at a targeted delivery of Abraxane to tumors by conjugating it with IL4RPep-1, an interleukin-4 receptor (IL4R)-binding peptide. IL4R is up-regulated in many tumor cells and M2-polarized macrophages. IL4R-targeted Abraxane (IL4RPep-1-Abx) showed more efficient binding and internalization into IL4R-high tumor cells and M2-type macrophages than untargeted Abraxane, which was inhibited in part by an inhibitor of macropinocytotsis and receptor-mediated endocytosis, respectively, while being completely inhibited by an IL4R-blocking antibody. In the same context, IL4RPep-1-Abx induced higher levels of cytotoxicity to IL4R-high tumor cells and reprogramming of M2-type macrophages into M1-like phenotype than untargeted Abraxane. In vivo fluorescence imaging showed that IL4RPep-1-Abx homed to tumor, with little accumulation in the liver and lung, more efficiently than untargeted Abraxane. In addition, IL4RPep-1-Abx inhibited tumor growth and metastasis to the lung in 4T1 or LLC tumor-bearing mice and reduced the number of tumor nodules in the lung of K-ras transgenic mice more efficiently than untargeted Abraxane. Liver function was maintained within the normal ranges after treatment with IL4RPep-1-Abx. In 4T1 and LLC tumor tissues, IL4RPep-1-Abx reduced the population of immune-suppressive cells such as M2-type macrophages and increased that of immune-stimulatory cells such as CD8+ T cells compared with untargeted Abraxane. These results suggest that IL4R-targeted Abraxane can enhance the therapeutic efficacy and anti-tumor immunity of Abraxane and is a promising strategy for targeted cancer therapy.
Citation Format: Poongkavithai Vadevoo Sri Murugan, Gunassekaran Gowri Rangaswamy, Byungheon Lee. Interleukin-4 receptor-targeted Abraxane inhibits tumor growth by enhancing drug delivery and reprogramming of M2-type macrophages into M1 phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 245.
Abstract 2501: Identification and characterization of key players in the Ewing Sarcoma metastatic process
Authors: Serra Sara Sanchez , Bosch Mariona Chicon , Velazquez Judith Besalú , Marcos Susana Maqueda , Monaco Paola , Viera Laura Santana , Alemany Roser Lopez , Tirado Oscar M. 
Published: June 2022

Abstract
Metastasis at diagnosis is the most adverse prognostic factor in Ewing Sarcoma (ES), drastically decreasing patients’ overall survival down to &lt;30%1. However, mechanisms leading to metastasis in this disease remain poorly understood. To deepen our knowledge on the main players in ES metastasis, Microarray (Clariom™ D Array, Affymetrix) and phosphoarray (Phospho Explorer Antibody Arrays, Full Moon Biosystems) analyses were performed on primary tumours (n=5) and metastases (n=12) samples from an spontaneous metastatic ES mouse model2. After normalisation and bioinformatics analysis, a list of differentially expressed genes/proteins between the 2 sample groups was obtained. Candidates were validated by qPCR (TaqMan™ probes) and Western Blot, and further characterised in vitro through loss-of-function phenotypic assays (proliferation, clonogenic and migration) using siRNAs and/or inhibitors. Several genes and proteins of interest, including LOXHD1, confirmed to be overexpressed in metastases samples compared to primary tumours as identified by microarray/phosphoarray analyses and qPCR/Western Blot validation. Also, candidates subjected to transient loss-of-function phenotypic assays significantly decreased in all cases tumorigenic and/or metastatic capabilities of ES cells when suppressed. Additionally, LOXHD1 showed upregulation in sphere-growing ES cells, validating its role in ES hypoxia and metastasis as demonstrated previously3. Using stable knock-out models of the genes of interest, the exact mechanism and pathways in which these candidates play a role in ES metastasis will be further studied in vitro and in vivo. Also, their clinical relevance will be explored in several cohorts of patients by immunohistochemistry on Tissue Microarrays. [1] Grünewald, TGP et al. 2018, Nat Rev Dis Prim, 4(1), pp.1-22. [2] Lagares-Tena, L et al. 2016, Oncotarget, 7(35), pp.56889-903. [3] Deng, Q et al. 2021, bioRxiv 2021.02.22.432287.
Citation Format: Sara Sanchez Serra, Mariona Chicon Bosch, Judith Besalú Velazquez, Susana Maqueda Marcos, Paola Monaco, Laura Santana Viera, Roser Lopez Alemany, Oscar M. Tirado. Identification and characterization of key players in the Ewing Sarcoma metastatic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2501.
Abstract 2695: Transcriptomic profiling of human patients with acute myeloid leukemia reveals critical effects of growth hormone responsiveness on patient survival and mechanisms of tumor therapy resistance
Authors: Davis Emily , Basu Reetobrata , Kopchick John J. 
Published: June 2022

Abstract
Growth hormone (GH) has been reported to drive leukemia cell proliferation as early as 1977, while downstream effectors of the GH signaling pathway (i.e., insulin-like growth factor 1; IGF1) have more recently been widely implicated in the aggressive pathology and robust therapy resistance phenotypes of acute myeloid leukemia (AML). It is also known that patients with acromegaly (high levels of circulating GH and IGF1) develop AML at a significantly higher rate than the general population, while individuals with GH resistance remain completely resistant to all types of cancer. Despite all of the aforementioned evidence pointing to a critical role of GH in AML progression and prognosis, a detailed transcriptomic analysis of human patients is lacking. We aim to address this gap by thorough in silico studies aimed at revealing the nature and extent to which the GH axis can be suitable targeted in AML. Here, we present a summary of our analyses of clinical and transcriptomic data from 200 human patients with AML from The Cancer Genome Atlas database, using multiple bioinformatics software programs in the public domain. Our study revealed that GH receptor (GHR) is expressed more highly in AML than in normal myeloid cells, and a robust correlation exists between GH responsiveness and patient survival. A sex-specific profiling of the patient transcriptomic data identified critical pathways related to therapy resistance, extracellular matrix remodeling, metastasis, and immune evasion to be upregulated differentially in male and female AML patients with relatively elevated GHR expression compared to patients with relatively lower GHR expression. Furthermore, we identified microRNAs which are differentially expressed in AML patients with higher than median GHR expression. We validated these miRNAs to be effective indicators of disease progression and prognosis and can be valuable markers in liquid biopsy approaches.
Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Edison Biotechnology Institute.
Citation Format: Emily Davis, Reetobrata Basu, John J. Kopchick. Transcriptomic profiling of human patients with acute myeloid leukemia reveals critical effects of growth hormone responsiveness on patient survival and mechanisms of tumor therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2695.
Abstract 2699: Glucocorticoid receptor biology in lobular breast cancer
Authors: Frerich Candace , Durdana Ishrat , Hanker Ariella , Arteaga Carlos L. , Bennett Lynda , Conzen Suzanne 
Published: June 2022

Abstract
While considered uncommon, there are an estimated 39,000 new invasive lobular carcinoma (ILC) cases in the US yearly, making it the sixth most common among all tumor types. ILC is recognized for unique metastatic organotropism. Its propensity to metastasize to serosal surfaces lining the gut (peritoneum) and lung (pleura) make it particularly challenging to diagnose and consequently is associated with overall unfavorable prognosis. We hypothesize that GR activation will slow cell proliferation and reduce metastatic potential of ILC cells in vitro and in vivo. Using transcriptome data from 142 ILC tumors with long-term follow up clinical data from the METABRIC dataset we found a trend towards improved overall patient survival with increased GR (NR3C1) expression (and presumably activity). Preliminary in vitro data showed slowed cell proliferation in an ILC cell line (MDA-MB-134IV) treated with GR agonist dexamethasone relative to vehicle control. ILC cell lines (MDA-MB-134IV and SUM44PE) have dramatically different adhesion preference for extracellular components and we will study whether GR mediates the metastatic organotrophism of ILC cells. Preliminary transcriptome data lends insight into the proliferative and adhesive gene expression changes elicited by both ER and GR activation. Two GR+ ILC patient derived organoid lines have GR dependent proliferative and adhesive phenotypes. In future studies we will utilize an in vivo mouse model that recapitulates ILC progression from an in situ to invasive breast carcinoma and finally to metastatic colonization of distant organs to determine the role of GR activity in proliferation and metastasis to the serosal surfaces.
Citation Format: Candace Frerich, Ishrat Durdana, Ariella Hanker, Carlos L. Arteaga, Lynda Bennett, Suzanne Conzen. Glucocorticoid receptor biology in lobular breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2699.
Abstract 2784: A robust copy number based clonality classification for multiple pulmonary tumors in routine pathology practice by shallow next generation sequencing of formalin fixed clinical specimens
Authors: Barbosa Bárbara Andrade , Radonic Teodora , Kim Yongsoo , Ylstra Bauke 
Published: June 2022

Abstract
Multiple synchronous or metachronous independent tumors in one patient, particularly those with thoracic involvement, can be as high as 20%. Defining whether a patient has multiple primary cancers (MPC) or metastatic disease is an urgent clinical need due to differences in treatment strategies, with curative intend for MPCs. Discerning the clonal and non-clonal relationship of two lesions for metastases and MPCs, respectively, has been done since the 1970s by analyzing histological characteristics, which nowadays are complemented with genomic features. However, one or few mutation features are insufficient to unequivocally diagnose tumor clonality, due to intratumoral heterogeneity and common mutations. We and others have demonstrated convincing clonality classification by genome-wide copy number aberrations (CNAs) analysis, which is the recommendation from the International Association for the Study of Lung Cancer (IASLC), independent of histological differences or similarities. Notwithstanding, a gold standard clonality assessment is currently lacking such that quality evaluation and calibration of the diagnostic tests are not possible. Gold-standard data: Genetic data from non-clonal cancer samples has become virtually endless by means of Whole Exome and Whole Genome sequencing (WES and WGS) since the mutational discrepancies by WES between two MPCs from a single lung cancer patient is the same as those of two primary cancers from different patients. Therefore, publicly available WES or WGS data from tumors of different lung cancer patients can serve as a gold standard reference for non-clonality. A gold standard reference for clonal samples can be derived from WES data from multiple biopsies of one patient, i.e. from the TRACERx initiative. These datasets now allow for the first time to calibrate CNA clonality testing against a gold standard and calculate the sensitivity and specificity of multiple lung tumors in one patient. Diagnostic test: Shallow Whole Genome Sequencing (sWGS) based genome-wide CNA analysis on Formalin-Fixed Paraffin-Embedded (FFPE) specimens has been used as the diagnostic routine at the Cancer Center Amsterdam (CCA), Amsterdam UMC over the past 5 years. The pipeline was calibrated against gold standard clonal and non-clonal WES data. We present sensitivity and specificity for an adequate, fast, and more economic clonality test based on genome-wide CNAs.
Citation Format: Bárbara Andrade Barbosa, Teodora Radonic, Yongsoo Kim, Bauke Ylstra. A robust copy number based clonality classification for multiple pulmonary tumors in routine pathology practice by shallow next generation sequencing of formalin fixed clinical specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2784.
Abstract 2803: A renewable IHC control tool CytoSections࣪ for defining MAGEA3, MAGEA4, and MAGEA9 antibody specificity
Authors: Zewdu Eden B. , Gonzalez Rachel M. , Ma Yan , Ling Derek , Hu Xiaomin , Ren Qi , Zhang Ranran , Lei Li-Hui , Allampallam Krishnan , Yin Dezhong , Liu Xuan , Fu Wei 
Published: June 2022

Abstract
Melanoma-associated antigen gene A (MAGEA) family proteins are expressed in a variety of tumors with each MAGEA protein having unique roles in cancer pathogenesis. The MAGEA members lack of expression in normal tissue and their role in cancer make them well suited for targeted cancer immunotherapy. Thus, knowing which MAGEA protein expression exists in a tumor is important. However, the MAGEA family shares sequence similarity that makes it difficult to find antibodies that are specific to just one family member. It is also challenging to source tissue generally with HIPAA regulation and even more so to get tissue representation of all 12 MAGEA family members. Here we present CytoSections as an alternative to patient control tissues. CytoSections are formalin fixed, paraffin embedded (FFPE) section of over-expression cell pellets. These cells were transfected with expression plasmids coding for genes of individual MAGES family. In this study, CytoSections are used to screen antibodies to all 12-member MAGEA family of proteins. The MAGEA family members were initially shown positive by targeted protein expression in western and immunohistochemistry using DDK tag antibody. Then multiple MAGEA3, MAGEA4, MAGEA9 antibodies were assessed by IHC to determine their specificity to their intended target. Using MAGEA family as a pilot project, we show that CytoSections is a verified, reproducible, and renewable alternative to human control tissues and serves as an ideal tool for antibody specificity assessment.
Citation Format: Eden B. Zewdu, Rachel M. Gonzalez, Yan Ma, Derek Ling, Xiaomin Hu, Qi Ren, Ranran Zhang, Li-Hui Lei, Krishnan Allampallam, Dezhong Yin, Xuan Liu, Wei Fu. A renewable IHC control tool CytoSections࣪ for defining MAGEA3, MAGEA4, and MAGEA9 antibody specificity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2803.
Abstract 2816: A novel in vivo model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy
Authors: Yang Jiwon , Lee Won , Jiao Jing , Cai Danying , Gustafson Heather , Gardner Rebecca , Cheng Mingshan , Keck James G. 
Published: June 2022

Abstract
Over the past few years, chimeric antigen receptor T (CAR T)-cell therapy has emerged as a novel treatment option for certain hematologic malignancies. Several CAR T-cell therapies produced highly efficacious responses from patients with hematologic malignancies. However, wider adoption of CAR T-cell therapy is challenged due to the potential development of life-threatening toxicities including cytokine release syndrome (CRS). CRS symptoms can range from mild fever to life-threatening events, including death. Preclinical animal models to assess the efficacy and toxicity of CAR T-cell therapies have been lacking. Here, we developed a novel mouse model to assess the efficacy and toxicity of CAR T-cell therapy simultaneously. Two different PBMC humanized NSG™ variants were used. NSG-MHC Class I/II double knock-out strain is known to have a delayed onset of GvHD, and NSG-SGM3xIL15 strain shows a higher engraftment level of human NK and myeloid cells, in addition to human T cells. Mice were humanized using PBMCs and treated with autologous or allogeneic CAR T cells, and efficacy and toxicity were assessed. Compared to the control treatment, CD19 CAR T-cells caused a decrease in the human CD19+ cell population in the blood and spleen, and induced cytokine release. Both T-cell and myeloid cytokine releases, including IFNgamma, IL-10, RANTES, and MIP-1alpha, were induced in our animal models. The in vivo platform can also be used to determine individual PBMC/CAR T donor differences and show the extent of efficacy and toxicity of each PBMC donor treated with autologous and allogeneic CAR T-cell therapy. We further confirmed anticancer efficacy using luciferase-tagged human B-cell lymphoma Raji tumor cells, which express a high level of CD19. In summary, we have developed a novel in vivo model to test the efficacy and toxicity of both autologous and allogeneic CAR T-cell therapy simultaneously.
Citation Format: Jiwon Yang, Won Lee, Jing Jiao, Danying Cai, Heather Gustafson, Rebecca Gardner, Mingshan Cheng, James G. Keck. A novel in vivo model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2816.