bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5038: Validation of a comprehensive next-generation sequencing liquid biopsy assay for clinical diagnostics and clinical trial applications
Authors: Tan Xin-Xing , Peters Tricia , Berry Meredith , Barber Kimberly , Jeter Kristyn , Lovell Brigitte , Elizondo Paula , Mou Yanglong , Thomas Brad , Xie Heng , Guo Jiannan 
Published: March 2024

Abstract
Liquid biopsy next generation sequencing (NGS) provides a powerful non-invasive approach to detect solid tumor derived somatic variants in a massively parallel manner. Liquid biopsy NGS has rapidly become an invaluable choice of testing technologies for clinical utility where invasive tissue biopsy is inaccessible and/or inadequate for molecular characterization. We present here a targeted NGS gene panel assay designed and validated specifically for liquid biopsy characterization. The assay was designed to test cell free DNA and cell free RNA from blood plasma for detection of single nucleotide variants (SNV), insertion/deletion (Indel), copy number variants (CNV), and gene fusions present in 52 most commonly mutated genes in cancers. The validation was performed to assess assay accuracy, specificity, sensitivity, repeatability, and reproducibility, with including pre-characterized reference controls, retrospective plasma samples from cancer patients, and prospectively-collected clinic blood specimen. Triplicates were included and testing was performed at different times and by different operators to assess the assay precision. Over 100 clinic blood specimens were collected in Streck cfDNA tubes from multiple trial centers, including treatment naïve phase III-IV patients with solid tumor (lung cancer, breast cancer, brain cancer, prostate cancer, kidney cancer, melanoma, etc) as well as heathy donors, processed within 7 days for plasma separation and total nucleotide acid (TNA) extraction, and assessed by the NGS assay for mutation detection. The identified mutations and wild-types were verified with orthogonal ddPCR. Assay sensitivity as low as 0.1% for SNV and Indel, 1.3 fold change for CNV, and 10 copies for gene fusion were observed, with near-perfect assay specificity (&gt;99.99%) at these sensitivity levels. In conclusion, a targeted NGS liquid biopsy assay was analytically validated under medical oversight, with a demonstrated rigor of the test by its high sensitivity/specificity and robust reproducibility. The validated assay has been utilized for clinical diagnostics and to support research and development efforts in clinical trials.
Citation Format: Xin-Xing Tan, Tricia Peters, Meredith Berry, Kimberly Barber, Kristyn Jeter, Brigitte Lovell, Paula Elizondo, Yanglong Mou, Brad Thomas, Heng Xie, Jiannan Guo. Validation of a comprehensive next-generation sequencing liquid biopsy assay for clinical diagnostics and clinical trial applications [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 5038.
Abstract 5119: Exploring the relationship between metabolism and the epigenome in MYCN-amplified neuroblastoma
Authors: Dalton Krista M. , Lochmann Timothy L. , Coon Colin , Calbert Marissa L. , Dozmorov Mikhail , Shock Lisa , Koblinski Jennifer , Faber Anthony C. 
Published: March 2024

Abstract
Background: Neuroblastoma (NB) is the most common cancer of infancy and is responsible for the most cancer-related deaths in children under the age of five. The transcription factor MYCN is the most studied oncogene in NB and automatically confers high-risk. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. NB has also been demonstrated to be a highly methylated cancer, with DNA methyltransferases (DNMTs) largely responsible for these modifications. Epigenetics and metabolism are closely connected, with oncogene-driven metabolic rewiring modifying the epigenetic landscape through increases of metabolites that are critical for the activities of epigenetic enzymes, and conversely the enhanced epigenetic activity further regulating the activity of metabolic enzymes.
Aims: As metabolism is believed to be a key regulator of the epigenome, the objective of this proposal is to understand the connection between MYCN-DNMT1-driven epigenetic alterations and dysregulated metabolism in MYCN-amplified NB.
Methods: RNA-seq and mass spectrometry analyses were performed to explore the MYCN-driven metabolome in NB and changes that occur with DNMT1 inhibition. The efficacy of DNMT1 inhibition in MYCN-amplified NB was tested in vivo.
Results: Our data demonstrate that sensitivity to DNMT1 inhibition is linked to MYCN status in NB. We found that MYCN indeed dysregulates metabolism in NB, and DNMT1 inhibition led to a global decrease in oxidative phosphorylation and exacerbated mitochondrial dysfunction in MYCN-amplified NB. Expression of MYCN was linked to an increase in methionine and subsequently SAM, the universal methyl donor, further supporting reliance on DNMT1. Most importantly, we have found that treatment with DNMT1 inhibitors in vivo inhibited tumor growth, even after treatment had stopped.
Conclusion: We have found a correlation between MYCN and metabolism that supports DNMT1 activity. This relationship allows for a potential treatment for a high-risk disease in which there is few clinically actionable targets.
Citation Format: Krista M. Dalton, Timothy L. Lochmann, Colin Coon, Marissa L. Calbert, Mikhail Dozmorov, Lisa Shock, Jennifer Koblinski, Anthony C. Faber. Exploring the relationship between metabolism and the epigenome in MYCN-amplified neuroblastoma [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 5119.
Abstract 5147: Identification of pharmacodynamic biomarkers in PBMCs and cancer cells for SIK2 kinase inhibitor therapy
Authors: Yang Hailing , Mao Weiqun , Rask Philip , Peter Markus , Swaminath Gayathri , Morris Stephan W. , Lu Zhen , Bast Robert C. 
Published: March 2024

Abstract
Salt-inducible kinase 2 (SIK2) is an AMPK family kinase involved in multiple signaling pathways including the LBK1-SIK-HDAC, LKB1-SIK-CRTC/CREB, PI3K-PKA-mTOR and Hippo pathways. The expression of SIK2 is significantly upregulated in fraction of ovarian and breast cancers, and associated with poor prognosis. Inhibition of SIK2 kinase activity suppresses growth of ovarian and breast cancers as well as progression of acute myeloid leukemia. SIK2 inhibitors synergistically enhance sensitivity of ovarian and breast cancer cells to paclitaxel, carboplatin and PARP inhibitors. Utilization of SIK2 inhibitors to treat cancers has been investigated in preclinical studies and in a Phase I clinical trial (NCT04711161). To enable pharmacodynamic (PD) analysis in clinical studies, we have developed biomarkers that measure the effect of GRN-300, a SIK2/3 inhibitor, on SIK2 signaling in ovarian cancer cells. Class IIa histone deacetylases (HDAC4/5/7) are SIK2 substrates in cancer cells; and are also expressed in peripheral blood mononuclear cells (PBMCs). We found that GRN-300 decreased phosphorylated HDAC4/5/7 levels in ovarian and breast cancer cells (Lu et al. J Clin Invest, 2022) and now report that this SIK2 inhibitor also decreases pHDAC4/5/7 in PBMCs ex vivo in a dose-dependent manner using Western blot analysis. We also identified three mRNA markers in PBMCs by RNAseq analysis - SEPP1, RNASE1 and MS4A6A - which are up-regulated by GRN-300 in PBMCs isolated from healthy donors. However, these mRNA markers were either expressed at very low levels or not dramatically changed in cancer cells. We identified an additional mRNA marker panel using RNAseq technology by screening seven ovarian and six breast cancer cell lines: A2780, Caov3, IGROV1, OC316, OVCAR3, OVCAR8, SKOv3ip, BT549, Cal51, HCC1937, MDA-MB-231, MDA-MB-436 and MDA-MB-468. mRNA expression of three genes - DDIT4, NUPR1 and IL6 - is upregulated by GRN-300 in more than 9 of 13 cell lines tested. Five genes - ID1, ID2, ID3, ID4 and TGFBI - are down-regulated in response to GRN-300 treatment in more than 10 of 13 cell lines. The decrease in HDAC4/5/7 phosphorylation, and alterations in mRNA markers we discovered could serve as PD biomarkers for clinical trials to evaluate the effects of SIK2 inhibitors and provide insights in the mechanisms of drug action.
Citation Format: Hailing Yang, Weiqun Mao, Philip Rask, Markus Peter, Gayathri Swaminath, Stephan W. Morris, Zhen Lu, Robert C. Bast. Identification of pharmacodynamic biomarkers in PBMCs and cancer cells for SIK2 kinase inhibitor therapy [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 5147.
Abstract 5162: Tumor transcriptional identity as a key predictor of clinical outcome in EGFR-Mutant non-small cell lung cancer
Authors: Heeke Simon , Nilsson Monique , Gibbons Don , Zhang Jianjun , Wistuba Ignatio I. , Park Keunchil , Heymach John V. , Le Xiuning 
Published: March 2024

Abstract
Background: EGFR tyrosine-kinase inhibitors (TKIs) produce significant clinical benefit in patients (pts) harboring EGFR-activating mutations, however, patient outcomes remain heterogeneous, highlighting the need to identify novel biomarkers for treatment response prediction. We aim to investigate the association of tumor transcriptional identity with clinical outcomes in EGFR-mutant NSCLC.
Methods: We used consensus classification to derive unsupervised transcriptionally distinct clusters in EGFR-mutant NSCLC from the TCGA (N= 44). Then, we built a predictive model using extreme-gradient boosting to (1) classify an additional 88 surgically resected tumors from the LCCS study and analyzed for overall survival (OS) prediction; (2) classify metastatic EGFR-mutant NSCLC from the RELAY trial with available RNAseq data (N = 106) and analyzed for progression-free survival (PFS) with erlotinib treatment.
Results: Consensus clustering revealed two distinct clusters, one associated with more lineage-preserving features and one with more lineage-independent features that could transcriptionally distinguish EGFR-mutant lung cancer. No differences in primary EGFR mutations were detected across the two clusters. Ingenuity Pathway Analysis revealed TGFB1 as the most significantly enriched pathway in the lineage-independent cluster which was also significantly more mesenchymal (p = 0.0028). For surgically resectioned EGFR-mutant NSCLC, OS was consistently shorter in the lineage-independent cluster for TCGA (23.6 vs 58.3 mo; p = 0.049; HR = 0.4) and the LCCS cohort (55.7 vs not-reached; p = 0.0073; HR = 0.27). In the metastatic setting with erlotinib treatment, there was a trend for PFS to be shorter in the lineage-independent cluster (15.2 vs 19.4 mo; p = 0.12; HR = 0.61).
Conclusions: Transcriptional identity in EGFR-mutant lung cancer are prognostic of clinical outcome. The lineage-independent tumors have inferior benefit to EGFR TKI as well as inferior OS, indicating that transcriptional biomarkers can be independent of oncogene biomarkers. These transcriptional biomarkers may help identify pts with poor outcome for future intensification of therapies.
Citation Format: Simon Heeke, Monique Nilsson, Don Gibbons, Jianjun Zhang, Ignatio I. Wistuba, Keunchil Park, John V. Heymach, Xiuning Le. Tumor transcriptional identity as a key predictor of clinical outcome in EGFR-Mutant 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 5162.
Abstract 5208: Dynamic changes in circulating tumor DNA and T cell receptor repertoire predict disease progression in patients with unresectable esophageal squamous cell carcinoma
Authors: Zhang Baidong , Zhan Xiang , Li Qiang , Wang Chenxuan , Pang Jiaohui , Zhang Yaru , Wang Song , Ou Qiuxiang , Tang Haimeng , Feng Alei , Yang Zhe 
Published: March 2024

Abstract
Background: Patients with unresectable esophageal squamous cell carcinoma (ESCC) showed variations in their response to treatments and experienced inevitable disease progression. The development of non-invasive and clinically viable biomarkers is urgently needed. Therefore, this study aimed to investigate prognostic value of circulating tumor DNA (ctDNA) and T cell receptor (TCR) repertoire in these patients.
Methods: A total of 21 ESCC patients who underwent definitive chemoradiotherapy, radiotherapy, or immune checkpoint inhibitor (ICI)-combined therapy from October 2020 to March 2022 were retrospectively evaluated. Baseline tumor samples were collected for genomic profiling using targeted NGS. Baseline and post-therapy plasma were collected for genomic and TCR profiling.
Results: We found that ctDNA detection rates were significantly reduced after treatment (P&lt;0.001). Post-treatment ctDNA positivity were associated with worse local recurrence-free survival (P=0.001) and progression-free survival (P=0.001), but not overall survival. Moreover, TCR clonality was significantly increased after treatment, including CDR3 diversity (P=0.003), TCR clonotype (P=0.004), and VJ pairs (P=0.010), indicating an increased T cell expansion and complexity. Specifically, we identified two increased and four reduced VJ rearrangements after treatment, and the four reduced VJ rearrangements (Vβ12-2Jβ2-4, Vβ6-9Jβ1-5, Vβ6-7Jβ1-5, and Vβ6-9Jβ1-1) were significantly associated with worse progression-free survival.
Conclusion: Our findings suggest the prognostic implication of plasma ctDNA and TCR profiles in patients with unresectable ESCC receiving definitive therapy, supporting the future development of non-invasive monitoring of disease progression in these patients.
Citation Format: Baidong Zhang, Xiang Zhan, Qiang Li, Chenxuan Wang, Jiaohui Pang, Yaru Zhang, Song Wang, Qiuxiang Ou, Haimeng Tang, Alei Feng, Zhe Yang. Dynamic changes in circulating tumor DNA and T cell receptor repertoire predict disease progression in patients with unresectable esophageal squamous cell 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 5208.
Abstract 5217: Genome instability in renal tumors
Authors: Cho Hanbyul , Li Ginny X. , Mannan Rahul , Hosseini Noshad , Hsiao Yi , Zhang Yuping , Dagar Aniket , Kumar-Sinha Chandan , Cieslik Marcin P. , Dhanasekaran Saravana M. , Nesvizhskii Alexey I. , Chinnaiyan Arul M. , Consortium Clinical Proteomic Tumor Analysis 
Published: March 2024

Abstract
Genome instability (GI), a recognized cancer hallmark, encompasses CNV burden, tumor mutational burden (TMB), and microsatellite instability and is variably associated with several clinical/prognostic features in solid tumors. GI and intratumor mutational heterogeneity in clear cell renal cell carcinoma (ccRCC) were associated with poor prognosis in a large multi-site sequencing study. As 10-15% of renal tumors exhibit copy number burden associated GI, the development of proteogenomic biomarkers to identify this subset of tumors will be of high clinical value. In our in-depth analysis of CPTAC renal cancer cohorts namely, ccRCC discovery and rare RCC, we first estimated absolute copy number using CNVEX TPO analysis pipeline. Copy number burden-based genome instability was estimated by calculating whole genome instability index (wGII) from DNA sequencing data, in addition to the estimation of genome ploidy and purity of the tumors. Genome instability was associated with survival outcomes in both ccRCC and rare RCC (Ref. 1 and 2). Differential proteogenomic analysis identified IGF2BP3, IGF2BP1, PYCR1 RNA and protein, to be upregulated among high wGII tumors. High wGII tumors showed upregulation of cell proliferation and other cell cycle/proliferation concepts in gene set enrichment analysis. Interestingly, transcriptional module analysis revealed transcription factors and target genes specifically upregulated in GI cases and this pattern showed certain degree of overlap to 9p loss ccRCC tumors (another molecular ccRCC subset that is also associated with poor prognosis). Differential expression analysis also identified, kinases, phosphosites and co-regulated kinase-substrates that are dysregulated in genome instable renal tumors. IGF2BP3 immunohistochemistry staining showed specific overexpression in high wGII tumors and the high positivity was observed exclusivity in the tumor cells. Prognostic biomarkers IGF2BP3, IGF2BP1, PYCR1, and UCHL1 show great promise to be developed as clinical prognostic assays and warrants additional characterization.
Citation Format: Hanbyul Cho, Ginny X. Li, Rahul Mannan, Noshad Hosseini, Yi Hsiao, Yuping Zhang, Aniket Dagar, Chandan Kumar-Sinha, Marcin P. Cieslik, Saravana M. Dhanasekaran, Alexey I. Nesvizhskii, Arul M. Chinnaiyan, Clinical Proteomic Tumor Analysis Consortium. Genome instability in renal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5217.
Abstract 5298: BSI-093, a best-in-class anti-BTN3A monoclonal antibody for cancer immunotherapy by activation of Vg9Vd2 T cells
Authors: Dai Wenwen , Li Jun , Liu Jinyu , Li Hongyan , Liu Xiaodong F. , Xia Shukai , Lyu Qun , Davis Hugh M. , Chen Mingjiu , Peng Zeyu 
Published: March 2024

Abstract
Background: Gamma delta T (γδ T) cells are potent anti-cancer effectors with the potential to target tumors broadly, independent of patient-specific neoantigens or human leukocyte antigen background. Among tumor-infiltrating lymphocytes, the presence of γδ T cells is the most favorable prognostic marker for overall survival of patients with various solid and hematologic tumors. Vγ9Vδ2 T cells are the predominant γδ T cells in peripheral circulation. Butyrophilin 3A (BTN3A) members, widely expressed in tumors, have emerged as novel molecules modulating the function of Vγ9Vδ2 T cells. Targeting BTN3A for activation of Vγ9Vδ2 T cells provides an alternative strategy for cancer immunotherapy.
Experimental procedures: BALB/c mice were immunized with recombinant BTN3A1-ECD-Fc. The Biosion proprietary H3 (High-throughput, High-content and High-efficiency) antibody discovery platform was used to identify an anti-BTN3A monoclonal antibody lead candidate - BSI-093. The target binding specificity, binding activity, and affinity of BSI-093 were evaluated by protein-based ELISA, cell-based FACS and Biacore-based SPR. Ex vivo assays were used to evaluate the cellular bioactivity of BSI-093 on activating Vγ9Vδ2 T cells for killing activity of various tumor cells. B-NDG mice bearing Jurkat-GFP-Luc tumors were used to evaluate the tumor inhibitory activity of the anti-BTN3A antibody.
Summary: BSI-093 is a humanized monoclonal antibody with the following critical properties: (1) binds to all BTN3A members (BTN3A1, BTN3A2 and BTN3A3) with high affinity; (2) has potentially longer half-life and silenced Fc-effector function by Fc-engineering; (3) exhibits cross-reactivity to rhesus BTN3A members; (4) demonstrates strong activity on activating Vγ9Vδ2 T cells to kill a variety of natural cancer cells in ex vivo assays; and (5) shows significant anti-tumor efficacy in a CDX model.
Conclusion: BSI-093 demonstrates potential best-in-class biophysical properties and functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies.
Citation Format: Wenwen Dai, Jun Li, Jinyu Liu, Hongyan Li, Xiaodong F. Liu, Shukai Xia, Qun Lyu, Hugh M. Davis, Mingjiu Chen, Zeyu Peng. BSI-093, a best-in-class anti-BTN3A monoclonal antibody for cancer immunotherapy by activation of Vg9Vd2 T 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 5298.
Abstract 5312: Agonist CD40 engineered smart immunosomes induced anti-tumor immunity, reduced associated toxicities and showed tumor free survival in murine glioblastoma model
Authors: Gaur Vidit , Tyagi Witty , Das Sanjeev , Ganguly Surajit , Bhattacharyya Jayanta 
Published: March 2024

Abstract
CD40 agonist antibodies (αCD40) have proven great potential as an anti-cancer immunotherapeutic by showing promising anti-tumor response in both preclinical and early clinical studies. However, it has been observed that the systemic administration of αCD40, even at low dose, is associated with serious immune- and hepato- toxicities. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed an immunosome where αCD40 is conjugated on the surface and VJ23, a small molecule immune-modulator was encapsulated inside it . Immunosome showed higher tumor accumulation till 96 hr of administration and displayed sustained release of αCD40 in vivo. Immunosome significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma tumor by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+M1 macrophage in TME. In addition, Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the expression of PD-L1 to modulate immunosuppressive TME. Moreover, Immunosomes significantly enhanced the level of pro-inflammatory cytokines (IFN-γ, IL-6, IL-2) and lowered anti-inflammatory cytokines (IL-4 and IL-10) level which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. Our results suggested that this novel formulation can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while reducing the associated toxicities.
Citation Format: Vidit Gaur, Witty Tyagi, Sanjeev Das, Surajit Ganguly, Jayanta Bhattacharyya. Agonist CD40 engineered smart immunosomes induced anti-tumor immunity, reduced associated toxicities and showed tumor free survival in murine glioblastoma model [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 5312.