bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4995: Impact of radiotherapy on extracellular vesicle mediated anti-tumor immunity in oligometastatic prostate cancer
Authors: Uzendu Chisom J. , Kim Yohan , Lavoie Roxane R. , Dong Haidong , Park Sean , Lucien-Matteoni Fabrice 
Published: March 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 5004: Oncolytic Jurona-driven systemic and intratumoral immunotherapy combined with immune checkpoint blockade boost immune response and survival in hepatocellular carcinoma models
Authors: Tesfay Mulu Z. , Ferdous Khandoker U. , Cios Aleksandra , Shelton Randal S. , Simoes Camila C. , Post Steven R. , Kelly Thomas J. , Cannon Martin J. , Basnakian Alexei , Nagalo Bolni M. 
Published: March 2024

Abstract
The members of the vesiculovirus genus have recently become attractive immunotherapeutic agents due to their natural selectivity for tumors and lack of toxicity in humans. Here, the research shows Intratumoral (IT) or Intraperitoneal (IP) injection of JURV was found to induce dynamic tumor regression in human hepatocellular carcinoma (HCC) xenografts and syngeneic models. Furthermore, IT injections of JURV were also shown to recruit and activate cytotoxic T lymphocytes and decrease tumor-associated macrophage infiltration, resulting in the delay of tumor growth in both local and distant murine HCC tumors established in a syngeneic model. Additionally, the concurrent use of JURV and anti-PD-1 antibodies was found to synergistically modulate the tumor microenvironment (TME) via increased tumor-infiltrating CD4+ T cells and depleted CD8+ PD-1+ and NK cells. Furthermore, using RIL-175, an aggressive metastatic HCC tumor mouse model, we show that intraperitoneal (IP) (systemic) administration of JURV and anti-PD1 significantly improved long-term survival (90%) compared to the (20%) JURV or anti-PD1 alone. Through proteogenomic analysis, the activation of different effectors of the immune system was observed to cooperate to alter the TME to a favorable anti-tumor immune state. These findings further support the development of JURV as an immunovirotherapy platform for HCC, with the potential to induce abscopal effects via the activation of several tumor suppressor genes and the mechanism regulating the T helper cell responses.
Citation Format: Mulu Z. Tesfay, Khandoker U. Ferdous, Aleksandra Cios, Randal S. Shelton, Camila C. Simoes, Steven R. Post, Thomas J. Kelly, Martin J. Cannon, Alexei Basnakian, Bolni M. Nagalo. Oncolytic Jurona-driven systemic and intratumoral immunotherapy combined with immune checkpoint blockade boost immune response and survival in hepatocellular carcinoma models [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 5004.
Abstract 5075: Transcriptomic landscape of tumor microenvironment in gastric cancer in treatment with different types of cancer drugs
Authors: Yamashita Hiroki , Zhang Jason Guoqiang , Mashima Chiaki , Kamata Ryo , Yamamori Tomoko , Nakayama Izuma , Kawazoe Akihito , Shitara Kohei , Yano Tomonori , Xu Qunli , Ohashi Akihiro , Saito Takeshi 
Published: March 2024

Abstract
Gastric cancer (GC) in the fifth-leading types of cancer and the third-leading cause of death from cancer. Characterization of tumor microenvironment (TME) in GC is important not only to comprehensively understand tumor biology in GC but also to develop a novel cancer therapeutics targeting TME. In this study, we conducted multi-omics analyses of single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and whole exome sequencing (WES) using biopsied tumor samples through endoscopy from 23 GC patients: 3 treatment-naïve patients, 7 patients in treatment with chemotherapy (Chemo), 5 patients in combination treatment with chemotherapy and immune checkpoint blockade (Chemo+CPI), 3 patients in combination treatment with chemotherapy and Her2-antibody targeted therapy (Chemo+Her2i), and 5 patients in third-line or later treatment. We initially classified the GC samples into 4 molecular subtypes (CIN, GS, MSI, and EBV) using datasets of WES, bulk RNA-seq and scRNA-seq, showing that our samples were mainly composed of CIN (n=7) and GS (n=16) types. In scRNA-seq, we revealed that drug treatments profoundly modulated not only proportions of TME components but also their molecular characteristics. For instance, Chemo+CPI treated patients showed higher proportion of CD8+ cytotoxic T cells with activation and/or exhaustion markers. Combination treatments with Chemo+Her2i, in addition, resulted in higher Trail and Estrogen signaling pathways in epithelial cells of TME components. These findings suggest that interventions with certain cancer therapeutic drugs could substantially convert transcriptome landscape and reconstitute GC TME components. High-resolution of GC TME analyses should provide a clue for developing a next generation of cancer therapeutic drugs.
Citation Format: Hiroki Yamashita, Jason Guoqiang Zhang, Chiaki Mashima, Ryo Kamata, Tomoko Yamamori, Izuma Nakayama, Akihito Kawazoe, Kohei Shitara, Tomonori Yano, Qunli Xu, Akihiro Ohashi, Takeshi Saito. Transcriptomic landscape of tumor microenvironment in gastric cancer in treatment with different types of cancer drugs [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 5075.
Abstract 5115: Designing targeted approaches for recurrent medulloblastoma
Authors: Blanco Jezabel Rodriguez 
Published: March 2024

Abstract
Designing targeted therapies for recurrent medulloblastomaPediatric brain tumors are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common type. Despite significant progress in the field, approximately 30% of children with MB will relapse. Recurrent MB is commonly metastatic and virtually none of these patients will live beyond the one-year hallmark. These sobering statistics highlight the significant unmet need for effective therapies for recurrent MB. The likely underlying cause of the constant failure of our current clinical approaches, which are based on data obtained from disease models recapitulating primary tumors, is the disparity in genomic and transcriptomic data between primary and relapsed disease. Because of these disparities, we hypothesize that by conducting mechanistic studies and drug screens in relapse disease models, we can improve the outcomes for children with recurrent MB. Our data, obtained through a bioinformatics mining approach to predict tumor response, enabled us to identify a clinically relevant candidate drug for the treatment of recurrent MB: Minnelide. This compound acted on MYC to reduce tumor growth and the metastatic dissemination of tumors with the genetic background often found in relapsed MB patients. Additionally, to further support the translational relevance of our data, Minnelide increased the efficacy of adjuvant therapeutics used in the clinical management of MB. Our findings not only highlight the potential for repurposing Minnelide to treat children with recurrent MB, but also the potential of our research approaches aimed at identifying novel therapeutics for relapsed cancers.
Citation Format: Jezabel Rodriguez Blanco. Designing targeted approaches for recurrent medulloblastoma [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 5115.
Abstract 5117: CK2 inhibiton exhibits synergistic effect in acute lymphoblastic leukemia
Authors: Bogush Daniel Gary , Schramm Joseph , Dovat Katarina , Ding Yali , Singh Chingakham , Dovat Sinisa 
Published: March 2024

Abstract
Survival for pre-B cell Acute lymphoblastic leukemia (B ALL) has improved greatly, however. High risk (HR) subgroups continue to result in significant mortality and morbidity of pediatric oncology patients. Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a lethal disease, often associated with high-risk clinical features. T-ALL therapy has made less improvement than B ALL and continues to represent a significant number of high-risk outcomes. Novel treatment strategies are required to overcome chemotherapy resistance and improve morbidity for HR B ALL. The development of treatments that can overcome chemotherapy resistance is essential for improving survival in T-ALL. Deletions of IKZF1, resulting in decreased IKAROS function, are present in High-risk ALL patients. Casein kinase 2 (CK2), a protein kinase upregulated in ALL, phosphorylates IKAROS preventing DNA binding reducing transcriptional regulation in ALL patients. Past studies have shown that pharmacologic inhibition of CK2 with CX-4945 rescues IKAROS function as a transcriptional regulator. Receptor tyrosine kinase c-KIT is transcriptionally regulated by IKAROS and is often upregulated in cancer. The purpose of this study was to determine whether restoration of IKAROS via CX-4945 would act in a synergistic manner with c-KIT inhibitor imatinib in ALL.Methods/results B-ALL Nalm6 cells were treated with imatinib over 72-hours to establish the half-maximal inhibitory concentration (IC50). The IC50 was used to determine the concentration range of imatinib to be used in combination with CX-4945 in a 72-hour synergy analysis of cytotoxicity.. Cell viability was measured using WST-1 cell proliferation assay. The data were analyzed using Calcusyn and synergy was defined as a combination index below 0.85. The study was repeated to determine a more precise range of synergy. The cytotoxicity of single drug c-KIT inhibitor, Imatinib, in Nalm6 B-ALL yielded an IC50 of 25uM while CK2 inhibitor CX-4945 resulted in 4uM. When a combination was administered with a constant dose of CX-4945 at 4uM and varying concentrations of imatinib, synergy was observed at multiple dose combinations. Conclusion: The data shows that CK2 inhibitor, CX-4945, and c-KIT inhibitor, imatinib, exhibit a synergistic therapeutic effect. Imatinib is indicated for use in Philadelphia positive (Ph+) acute lymphoblastic leukemia so future studies will include testing CX-4945/imatinib synergy in Ph+ BALL where we expect to see more potent synergistic effect.
Citation Format: Daniel Gary Bogush, Joseph Schramm, Katarina Dovat, Yali Ding, Chingakham Singh, Sinisa Dovat. CK2 inhibiton exhibits synergistic effect in acute lymphoblastic leukemia [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 5117.
Abstract 5133: Gastric cancer carrying FAT4 mutations associated with favorable prognosis in comparison to wild-type: Results from Real-World Cohorts
Authors: Wang Shu , Wang Haoyuan , Ma Yuxuan , Wang Yuhao , Zhao Yan , Peng Chaosheng , Duan Weiming , Zhao Feilong , Yang Jianjun 
Published: March 2024

Abstract
Introduction: Gastric cancer (GC) is a complex and heterogeneous disease with variable clinical outcomes. Identifying prognostic factors that can reliably predict patient outcomes is crucial for personalized treatment strategies. In this study, we aimed to investigate the impact of mutations in the FAT4 gene as potential prognostic factors in gastric cancer.
Methods: We conducted a comprehensive analysis of genomic data from a cohort of 236 gastric cancer patients to identify mutations in the FAT4 gene and validated it using the TCGA cohort. The mutational landscape of FAT4 was analyzed using next-generation sequencing (NGS) techniques. Clinical data, including patient demographics, tumor characteristics, and survival outcomes, were collected and correlated with the presence of FAT4 cadherin mutations.
Results: In the real-world cohort, the occurrence of mutations of FAT4 was 19.1% (45/236), while in the TCGA cohort, it was 21.0% (89/423). Specifically, the mutation rates in the single cadherin functional domain of FAT4 were 10.2% (24/236) in the real-world cohort and 8.0% (34/423) in the TCGA cohort. The mutation rates for multiple cadherin sites were 2.5% (6/236) and 2.1% (9/423) in the real-world and TCGA cohorts, respectively. Survival analysis revealed that patients with FAT4 mutations had a significantly better prognosis compared to those with wild-type FAT4 (p=0.0357). Patients with multiple cadherin mutations had a better prognosis compared to those with single cadherin mutations in real-world cohorts (p=0.0651). No significant difference was observed in the TCGA cohort between single and multiple cadherin mutations (p = 0.2003), although FAT4 mutations exhibited a significant improvement in prognosis compared to wild-type patients in the TCGA cohort (p = 0.0226).
Conclusion: Our findings indicate that FAT4 mutations confer a favorable prognosis in gastric cancer patients. The presence of FAT4 mutations was associated with improved survival compared to patients with wild-type FAT4. These findings underscore the potential value of FAT4 mutation status as a prognostic factor, guiding personalized treatment approaches for individuals with gastric cancer.
Citation Format: Shu Wang, Haoyuan Wang, Yuxuan Ma, Yuhao Wang, Yan Zhao, Chaosheng Peng, Weiming Duan, Feilong Zhao, Jianjun Yang. Gastric cancer carrying FAT4 mutations associated with favorable prognosis in comparison to wild-type: Results from Real-World Cohorts [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 5133.
Abstract 519: Targeting MYC as a novel therapeutic strategy for an epigenetic-driven cancer: NUT Carcinoma
Authors: Escudero-Iriarte Carmen , Castro Joel , Beniavides-Puy Iker , Tissera Natalia S. , Querol-Paños Jessica , Agustí Irene , Whitfield Jonathan R. , Vieito Maria , Nonell Lara , Macarulla Teresa , Braña Irene , Soucek Laura , Tian Tian V. 
Published: March 2024

Abstract
Epigenetic dysregulation is widespread in cancer, playing a pivotal role in shaping cell function and contributing to the process of oncogenic transformation. NUT Carcinoma (NC) is an exceptionally rare and aggressive cancer lacking effective treatment, with a dismal prognosis - NC patients typically survive less than seven months after the initial diagnosis. NC is characterized by the presence of chromosomal rearrangements involving the gene encoding for the testis-specific NUT protein and a ubiquitous gene encoding an epigenetic regulator, BRD4 in most cases. Previous studies have demonstrated the role of the BRD4-NUT fusion protein in generating clusters of acetylated histones, namely “megadomains,” throughout NC cell chromatin. These NUT-containing fusion proteins are involved in NC oncogenesis by altering the epigenetic and transcriptional landscapes, promoting cell proliferation while impeding cell differentiation. Indeed, several downstream targets, including P63, SOX2, and MYC, have been identified to be modulated by NUT fusion proteins, independently of the fusion partners. This study focuses on a novel therapeutic approach targeting MYC for NC treatment. We conducted a comprehensive preclinical study of OMO-103, a MYC inhibitor currently undergoing clinical evaluation, using various NC patient-derived cell lines. Through cell viability assays, cell cytometry, western blotting, RNA-seq data analysis in vitro, as well as in vivo drug efficacy evaluation in NC xenografts, we delved into the effects of OMO-103 on NC cells. Our findings reveal that OMO-103 effectively inhibits NC cell growth both in vitro and in vivo. It induces cell apoptosis, differentiation, and cell cycle arrest in vitro, and when tested in xenografts in vivo, OMO-103 reduces tumor growth and enhances mouse survival, particularly when combined with a chemotherapy regimen. This study presents a promising therapeutic strategy for an incurable and aggressive cancer type.
Citation Format: Carmen Escudero-Iriarte, Joel Castro, Iker Beniavides-Puy, Natalia S. Tissera, Jessica Querol-Paños, Irene Agustí, Jonathan R. Whitfield, Maria Vieito, Lara Nonell, Teresa Macarulla, Irene Braña, Laura Soucek, Tian V. Tian. Targeting MYC as a novel therapeutic strategy for an epigenetic-driven cancer: NUT Carcinoma [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 519.
Abstract 5333: NeoMab: A novel platform for fully human therapeutic antibody development
Authors: Zhang Mingkun , Ju Cunxiang , Li Song , Peng Junchao , Zhao Jing , Gao Xiang 
Published: March 2024

Abstract
Antibodies and antibody containing therapeutics, such as multivalent antibodies, chimeric antigen receptors (CARs), and antibody directed conjugates (ADCs), have been proven to be highly prominent in cancer treatment. However, challenges such as immunogenicity stemming from non-human or unnatural sequences and limitations in preclinical animal study systems still impede the rapid development of antibody drugs.
To overcome these hurdles, GemPharmatech has created a novel antibody gene humanized model, the NeoMab mouse, to develop fully human antibodies. The NeoMab model was established via large genomic fragment knock-in technology, retaining native mouse constant region encoding genes and regulatory elements, while incorporating human variable gene repertoires into the endogenous loci. Developed in the BALB/c background, the NeoMab mouse carries fully functional MHC molecules, potentially enhancing antigen presentation. These mice sustain a competent immune system with a B cell development and maturation pattern, immune cell profile, and serum immunoglobulin levels comparable to those of BALB/c mice.
NeoMab mice exhibit a robust humoral immune response, with a rapid increase in antigen-specific serum titers upon immunization using different antigens, such as recombined protein, plasmids, and overexpressing cell lines. Utilizing human V(D)J genes to encode immunoglobulins at a human-like frequency and diversity, antibodies derived from NeoMab mice demonstrate affinity and functional activity comparable to, or even surpassing, FDA-approved drugs.
In conclusion, the NeoMab mouse model in the BALB/c background has been rigorously validated to elicit a robust response to specific antigen immunization, producing antibodies with high affinity, diversity, and functional activity. GemPharmatech's extensive drug-target gene humanized mouse library (comprising over 800 targets) and diverse disease models in oncology and other fields facilitate a seamless connection between in vitro antibody screening and in vivo animal studies. The integration of NeoMab, target humanization animals, and disease models enables GemPharmatech to provide an integrated solution, reducing time and costs while elevating the quality of antibody discovery in the field.
Citation Format: Mingkun Zhang, Cunxiang Ju, Song Li, Junchao Peng, Jing Zhao, Xiang Gao. NeoMab: A novel platform for fully human therapeutic antibody development [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 5333.
Abstract 5351: Tumor PKC-Delta induces immune exclusion in non-small cell lung cancer
Authors: Fan Xing Xing 
Published: March 2024

Abstract
The recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR-mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. To orchestrate host immunity against lung tumors, we proposed that PKCδ, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo models. These findings revealed that PKCδ is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors.
This work was funded by the FDCT project grant to Dr. Xing-Xing Fan (Grant no. 0058/2020/A2).
Citation Format: Xing Xing Fan. Tumor PKC-Delta induces immune exclusion in non-small cell lung 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 5351.