bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1020: Tissue-informed ctDNA MRD assay detects post-surgery minimal residual disease in HCC patients
Authors: Hu Jie , Tang Haoran , Xie Feng , Zhang Yue , Jia Shidong , Zhou Jian 
Published: April 2023

Abstract
Introduction: Residual disease detection is a significant clinical need in post-surgery treatment of resectable hepatocellular carcinoma (HCC) patients. Previous NGS-based studies targeting fixed genomic regions had reported that circulating tumor DNA (ctDNA) could provide evidence for prognosis prediction during HCC treatment. However, the sensitivity of methods was limited and could not reach the threshold of minimal residual disease (MRD) test. Here we reported a baseline tissue -informed ctDNA NGS assay, detecting MRD in HCC patients who received hepatectomy and predicted prognosis in MRD positive patients.
Methods: The study retrospectively enrolled 200 early-stage HCC patients who received surgical resections. Tumor and normal tissue samples were collected respectively through surgery. Plasma samples were collected 7 days or more post-surgery. In the completed pilot study, samples from 17 patients were tested by a baseline tissue-informed MRD assay (PredicineBEACON). Tumor-specific mutations were identified by whole exon sequencing on baseline tumor and normal tissue samples. For each patient, up to 50 mutations were selected through bioinformatics pipelines for personalized MRD panel design, in combination with a fixed panel of 500 tumor actionable hotspots. The post-surgery plasma samples were then tested for MRD with the panel through ultra-deep sequencing(100,000X). Afterward, genomic tumor fraction proportions were calculated.
Results: In the completed pilot study, 12 of 17 patients (70.6%) were called MRD positive based on tests of post-surgery plasma. Among MRD positive patients, 3 were identified as MRD risk high (proportion of tumor fraction≥0.1%) and MRD risk of others were moderate (proportion of tumor fraction&lt;0.1%). The tumor fraction proportion of MRD positive patients varied from 0.013% to 17.84% (median 0.042%). The recurrence free survival (RFS) and overall survival (OS) probabilities were significantly correlated with MRD risk: the median RFS of two groups(risk-high vs. risk-moderate) was 10.1 months vs. 57.4 months (p-value&lt;0.001), while the median OS of two groups (risk-high vs. risk-moderate) was 31.2 months vs. 57.4 months(p-value=0.028).
Conclusions: Baseline-informed ctDNA NGS assay showed ultra-sensitive capability of MRD detection on early-stage HCC patients, with outstanding positive rate through plasma samples collected 7 days post-surgery. The MRD risk provided significant prognostic evidence for patient survival and disease relapse.
Citation Format: Jie Hu, Haoran Tang, Feng Xie, Yue Zhang, Shidong Jia, Jian Zhou. Tissue-informed ctDNA MRD assay detects post-surgery minimal residual disease in HCC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1020.
Abstract 103: Dissecting cell state diversity during melanoma growth and metastasis
Authors: Karras Panagiotis , Bordeu Ignacio , Pozniak Joanna , Nowosad Ada , Pazzi Cecilia , Van Raemdonck Nina , Khoo Jia Hui , Pedri Dennis , Rustgi Anil , Bechter Oliver , Blanpain Cedric , Simons Benjamin , Rambow Florian , Marine Jean Christophe 
Published: April 2023

Abstract
Cellular plasticity endows cancer cells with capacity towards a phenotypic state. Except from the genetic origin of cellular plasticity, cancer cells can transit to reversible phenotypic states as a result of microenvironmental cues and are often driven by stochastic epigenetic and/or transcriptional fluctuations. Melanoma is a prime example of heterogeneous and plastic tumors where the origin and magnitude of cell state diversity remains poorly understood. Combining lineage tracing, 3D imaging and quantitative mathematical modelling in a clinically-relevant mouse model of melanoma, we demonstrated that tumors follow a hierarchical model of growth supported by a population of Melanoma Stem-like Cells (MSCs) that exhibit a transcriptomic signature of pre-migratory neural crest cells established transiently during embryonic development. ScRNA seq in mouse and drug naïve human biopsies revealed that MSCs are evolutionarily conserved and independent of the “genetic makeup” of the tumors. By deploying spatial transcriptomic approaches and multiplex imaging, we developed a spatially and temporally resolved map of the diversity of melanoma showing a non-random tumor organization. Multimodal analysis unraveled unique cell type and state interactions and importantly demonstrated that MSCs reside in perivascular niches favoring tumor growth. Endothelial Cells were found to have a key role in the acquisition of stemness properties. Co-culture assays led to melanoma dedifferentiation and proliferation advantage. Of note, supplementing melanoma cells with ECs accelerated the growth of tumors in vivo, where MSCs pool was increased. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells harboring a mesenchymal-like state revealed that these cells do not contribute to primary tumor growth but, instead, constitutes a pool of metastatic-initiating cells that switch cell identity while disseminating to secondary organs. Taken together, these results will pave the way for the development of strategies that exploit the “chameleonic” nature of cancer cells and, ultimately, target MSC niche-dependent specification mechanisms.
Citation Format: Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Van Raemdonck, Jia Hui Khoo, Dennis Pedri, Anil Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin Simons, Florian Rambow, Jean Christophe Marine. Dissecting cell state diversity during melanoma growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 103.
Abstract 1070: The anti-tumor efficacy of combining oral ATR kinase inhibitor ceralasertib with TIC10/ONC201, an oral Akt/ERK inhibitor, TRAIL pathway and integrated stress response inducer, in prostate cancer treatment
Authors: Xia Yutong , Schwermann Maximilian P. , George Andrew , Ochsner Anna , Carneiro Benedito A. , El-Deiry Wafik S. 
Published: April 2023

Abstract
Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. There are 268,490 estimated new cases and 34,500 estimated deaths in 2022 according to the NIH. Patients with metastatic castration resistant prostate cancer (mCRPC) have a poor prognosis and the current treatment options show limited efficacy. From the TRAP trial, 20% of mCRPC patients are reported to bear DNA repair defects. Ceralasertib, formerly known as AZD6738, is a potent and selective orally bioavailable inhibitor of the ataxia tenlangiectasia and Rad3-related (ATR) kinase, which is involved in DNA repair in response to DNA damage and replication stress. Ceralasertib’s antitumor activity as a monotherapy in treating prostate cancer is moderate. Thus, we investigated a combination therapy of ceralasertib with ONC201, a potent and cytotoxic orally bioavailable inhibitor of the serine/threonine protein kinase Akt and extracellular signal-regulated kinase (ERK). Upon administration, ONC201 can induce tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and activate integrated stress response (IRS). Preliminary results demonstrate synergistic activity with the combination therapy in vitro using CellTiterGLO viability assay 72 hours in a 96 well plate post treatment. Ongoing studies using western blotting and cytokine profiling are intended to illustrate the mechanism behind the proven synergy. Our results aim to solve the overarching need in developing novel therapeutic strategies to overcome resistance in current prostate cancer treatments.
Citation Format: Yutong Xia, Maximilian P. Schwermann, Andrew George, Anna Ochsner, Benedito A. Carneiro, Wafik S. El-Deiry. The anti-tumor efficacy of combining oral ATR kinase inhibitor ceralasertib with TIC10/ONC201, an oral Akt/ERK inhibitor, TRAIL pathway and integrated stress response inducer, in prostate cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1070.
Abstract 1099: Combined treatment with direct hydrogen peroxide administration and irradiation promotes an abscopal effect in mouse models
Authors: Kemmotsu Naoya , zhu Li , Ueda Youki , Dansako Hiromichi , Toyooka Shinichi , Nagasaki Joji , Togashi Yosuke 
Published: April 2023

Abstract
Background: Hydrogen peroxide (H2O2) causes oxidative stress and cytotoxicity and may be used in cancer therapy in combination with radiotherapy (RT). Indeed, H2O2 has been clinically developed as a radiosensitizer (development code: KRC-01). However, effects of H2O2 on antitumor immunity remain unclear. In this study, we investigated the effects, especially an abscopal effect, using mouse models.
Material and Method: We used MC-38 (mouse colon cancer) and B16F10 (mouse melanoma) cell lines. Tumor cells were implanted simultaneously in two locations; hind legs and back of mice. A self-made radiation shielding device was used to prevent irradiation of the tumors on the back. Only the hind legs were directly injected with a mixture of H2O2 and hyaluronic acid (KRC-01), and then irradiated. Immune cells in tumors or tumor draining lymph nodes were analyzed with flow cytometry.
Result: We compared tumor growth among four groups: control, irradiation alone, H2O2 alone, and combination groups. Compared to the other groups, the combination significantly reduced non-irradiated tumor growth (abscopal effect). In immunodeficient SCID mice, this effect was not observed. Flow cytometric analyses of tumor draining lymph nodes showed that dendritic cells were maturated in the combination groups compared to the others. In addition, CD8+ T cells were activated in the non-irradiated tumors from the combination group compared to the others.
Conclusion: Intratumoral H2O2 administration enhanced the abscopal effect through activating antitumor immunity by RT.
Citation Format: Naoya Kemmotsu, Li zhu, Youki Ueda, Hiromichi Dansako, Shinichi Toyooka, Joji Nagasaki, Yosuke Togashi. Combined treatment with direct hydrogen peroxide administration and irradiation promotes an abscopal effect in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1099.
Abstract 112: Multi-omics analysis of molecular landscape and heterogeneity in fetal adenocarcinoma of the lung
Authors: Guo Wei , Sun Li , Chen Xiaoxi , Zhou Haitao , Yan Shi , Zhao Gang , Tang Haimeng , Bao Hua , Wu Xue , Shao Yang , Lin Lin 
Published: April 2023

Abstract
Background: Fetal adenocarcinoma of the lung (FLAC) is a rare form of lung adenocarcinoma and was divided into high-grade (H-FLAC) and low-grade (L-FLAC) subtypes. Until now, much of the knowledge regarding FLAC is from case reports or small case series and there was no comprehensive multi-omics study of FLAC.
Methods: A total of 20 FLAC patients who underwent tumor resection were retrospectively recruited in this study. Three regions from each of the 20 tumor specimens and matched normal tissue specimens were collected. Whole-exome sequencing, targeted bisulfite sequencing and whole transcriptome sequencing were performed on multi-regional tumor samples and normal tissue samples.
Results: We compared our FLAC cohort with a conventional East Asian-ancestry lung adenocarcinoma (LUAD) and revealed lower frequencies of altered driver genes on both somatic mutations and CNV levels, including EGFR, KRAS and ERRB2, in FLAC. Mutational signature analysis showed an enrichment of age-related mutational signatures in FLAC and tobacco-associated and defective DNA mismatch repair-related signatures were more enriched in H-FLAC and in L-FLAC, respectively. Significant differences between H-FLAC and L-FLAC were observed in the genomic and epigenomic landscape. In contrast, the transcriptomic landscape of H-FLAC closely dissembled L-FLAC by pathway enrichment analysis of differentially expressed genes. Furthermore, although genetic and epigenetic changes showed congruent evolutionary trajectories, the relationships between multi-level intratumor heterogeneity (ITH) were distinct in H-FLAC and L-FLAC. The genetic and transcriptional ITH showed a significant negative correlation in H-FLAC but a significant positive correlation in L-FLAC. Moreover, the lower genetic ITH was significantly related to a worse recurrence-free survival and overall survival in FLAC patients whereas lower methylation ITH H-FLAC patients tended to have better survival.
Conclusions: In this study, we first depicted the multi-omics landscapes of this rare lung cancer type and compared the two subtypes in a multi-omics and heterogeneity aspect. Different levels of ITH showed different relationships with survival, and non-genetic ITH, instead of genetic ITH, may contribute to the prognosis in FLAC patients.
Citation Format: Wei Guo, Li Sun, Xiaoxi Chen, Haitao Zhou, Shi Yan, Gang Zhao, Haimeng Tang, Hua Bao, Xue Wu, Yang Shao, Lin Lin. Multi-omics analysis of molecular landscape and heterogeneity in fetal adenocarcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 112.
Abstract 1138: Novel SMARCA2 degrading bifunctional molecules as therapeutics in SMARCA4 mutant lung cancer
Authors: Kotagiri Sasi , Blazanin Nicholas , Xi Yuanxin , Wang Jing , Lissanu Yonathan 
Published: April 2023

Abstract
Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports, and our own data, have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Using global proteomic analysis and quantification of more than 8000 proteins, we showed that our SMARCA2 PROTAC is highly selective for SMARCA2. Importantly, we showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells in vitro. Mechanistically, we demonstrated that YD23 reduces chromatin accessibility only in SMARCA4 deficient cells. In particular, YD23 profoundly decreased chromatin accessibility at enhancers of a number of genes including cell cycle and cell growth regulatory genes. Gene expression profiling and pathway analysis indicated that various cell cycle genes were downregulated by YD23 consistent with the reduced chromatin accessibility at their regulatory regions. In conclusion, our study provides a potent chemical probe for studying the synthetic lethal interaction between SMARCA2 and SMARCA4, dissect the chromatin and epigenetic landscape alterations and lay the foundation for future preclinical and clinical development of SMARCA2 degraders as therapeutics.
Citation Format: Sasi Kotagiri, Nicholas Blazanin, Yuanxin Xi, Jing Wang, Yonathan Lissanu. Novel SMARCA2 degrading bifunctional molecules as therapeutics in SMARCA4 mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1138.
Abstract 1160: A machine learning based method for in-vivo metabolic flux analysis of patient tumors
Authors: Mittal Anjali , Scott Andrew , Achreja Abhinav , Tarnal Vijay , Al-Holou Wajd , Lyssiotis Costas , Wahl Daniel , Nagrath Deepak 
Published: April 2023

Abstract
Metabolic fluxes likely control cancer phenotypes and treatment responses but cannot be measured in cancers in human patients. Machine learning has become a popular tool to study cancer biology and can identify complex patterns in the data which may not be decipherable by traditional analyses. We propose an approach to combine 13C-tracer analysis with machine learning to quantify the metabolism of purines in glioblastoma patients. In recent years, multiple studies have been conducted on isotope tracing in cancer patients. While the data for the enrichment of metabolites in human tumors has improved our understanding of cancer metabolism, we lack methods to estimate metabolic fluxes from these enrichment values. A significant challenge in estimating the fluxes in human subjects is that we are limited to enrichment data from a single in-vivo measurement at isotopic non-steady state. We overcome this challenge by combining INST-MFA (Isotopic Non-Stationary-Metabolic Flux Analysis) with machine learning methods. We use the enrichment of circulating metabolites as an input and simulate the time-dependent metabolite enrichment profiles for randomized flux vectors. We use this data to train a convolutional neural network (CNN) model to predict the flux ratios. Apart from being able to predict the fluxes from a single time-point, a machine learning model drastically reduces the time required to fit a traditional INST-MFA model. We demonstrate the real-world validity of the model by predicting flux ratios in mice models and comparing them to results from traditional INST-MFA models. We apply the model to decipher the heterogeneity of the purine pathway in eight patients with brain tumors.
Citation Format: Anjali Mittal, Andrew Scott, Abhinav Achreja, Vijay Tarnal, Wajd Al-Holou, Costas Lyssiotis, Daniel Wahl, Deepak Nagrath. A machine learning based method for in-vivo metabolic flux analysis of patient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1160.
Abstract 125: Archival single cell sequencing reveals persistent subclones over years to decades of DCIS progression
Authors: Wang Kaile , Kumar Tapsi , wang Junke , Minussi Darlan , Sei Emi , li Jianzhuo , Tran Tuan , Thennavan Aatish , Hu Min , Casasent Anna , Xiao Zhenna , Bai Shanshan , Zhao Yuehui , Zurita Amado , Aparicio Ana , Chapin Brian , ye Jie , Zhang Jianjun , Gibbons Don , Futreal Andrew , King Lorraine , Marks Jeffrey , Hwang E. Shelley , Shah Vandna , Sawyer Ellinor , Kristel Petra , Wesseling Jelle , Lips Esther H. , Navin Nicholas 
Published: April 2023

Abstract
Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer (IBC), yet the genomic progression to recurrent disease remains poorly understood. A main contributor to this gap in knowledge arises from technical challenges with genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. To address this challenge, we developed Arc-well, the first high-throughput method that can perform single cell DNA sequencing of thousands of cells from FFPE materials and frozen tissues. Using Arc-well, we profiled genomic copy number in 27,851 single cells from 26 archival FFPE tissues that were stored for 3-31 years. Analysis of genomic evolution in 10 patients with matched DCIS and recurrent cancers (DCIS or IBC) separated by 2-16 years showed that many primary DCIS lesions had already undergone whole-genome-doubling and had extensive clonal diversity, similar to the paired recurrence. The data from most patients (8/10) suggest an evolutionary bottleneck model of progression, in which a single subclone persisted during the progression to the recurrent disease, revealing copy number aberrations associated with invasion and recurrence.
Citation Format: Kaile Wang, Tapsi Kumar, Junke wang, Darlan Minussi, Emi Sei, Jianzhuo li, Tuan Tran, Aatish Thennavan, Min Hu, Anna Casasent, Zhenna Xiao, Shanshan Bai, Yuehui Zhao, Amado Zurita, Ana Aparicio, Brian Chapin, Jie ye, Jianjun Zhang, Don Gibbons, Andrew Futreal, Lorraine King, Jeffrey Marks, E. Shelley Hwang, Vandna Shah, Ellinor Sawyer, Petra Kristel, Jelle Wesseling, Esther H. Lips, Nicholas Navin. Archival single cell sequencing reveals persistent subclones over years to decades of DCIS progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 125.
Abstract 1253: Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy
Authors: Bender Mackenzie , McPherson Alex , Phelps Catherine , Davar Diwakar , Vignali Dario A. , Zarour Hassane , Meisel Marlies 
Published: April 2023

Abstract
The use of probiotics by cancer patients is increasing, including amongst those undergoing immune checkpoint inhibitor (ICI) therapy. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances spontaneous antitumor immunity and facilitates ICI therapy in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (L.reuteri) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby facilitating ICI therapy efficacy. Moreover, L.reuteri secreted I3A was both necessary and sufficient for antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated L.reuteri’s ability to restrain melanoma growth. Further, a tryptophan-enriched diet potentiated both L.reuteri- and ICI-induced antitumor immunity. Finally, we provide evidence for a potential role of I3A in promoting ICI therapy efficacy and survival in advanced melanoma patients.
Citation Format: Mackenzie Bender, Alex McPherson, Catherine Phelps, Diwakar Davar, Dario A. Vignali, Hassane Zarour, Marlies Meisel. Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1253.