bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3070: Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate cancer
Authors: Park Bobae , Knapczyk-Stwora Katarzyna , Liu Yaguang , Song Chung S. , Chatterjee Bandana 
Published: April 2023

Abstract
Advanced prostate cancer is a heterogeneous disease driven by diverse genetic alterations, with metastasis and lethal progression as the inevitable outcome. We observed that a subset of clinical primary prostate cancer is markedly reduced for SULT2B1b (SULT2B) sulfotransferase, which is an oxysterol-sulfating enzyme. Metastasized castration-resistant prostate cancer (CRPC) uniformly lacks SULT2B. Oxysterols are oxidized cholesterol metabolites and in agonist function, they activate liver X receptors (LXRα/β), which are members of the nuclear receptor family and regulators of lipogenesis, cholesterol homeostasis and immune functions. LXR signaling is enzymatically inhibited by SULT2B activity since sulfated oxysterols are LXR-inert. We previously reported that genetic silencing of SULT2B led to escalated CRPC proliferation; enhanced xenograft tumor growth; increased cell migration, invasion; reduced stiffness, adhesiveness; and EMT activation. SULT2B-depleted CRPC cells showed robust upregulation of AKR1C3 aldo-keto reductase and AKR1C3-dependent activation of the ERK1/2 survival signal. AKR1C3 regulates intratumoral androgen biosynthesis, and it is known to be elevated in advanced prostate cancer. In the current study, we validate our previous result by showing that ectopic expression of SULT2B caused AKR1C3 reduction in CRPC cells. Mechanistically, we observed that enhanced AKR1C3 expression in SULT2B-depleted cells was prevented upon genetic or pharmacologic inactivation of LXR. In addition, ERRα, another non-steroid nuclear receptor, was reduced in LXR-inactivated cells and notably, AKR1C3 was reduced in CRPC cells upon ERRα degradation by an ERRα-selective PROTAC. The LXR dependence of ERRα and AKR1C3 expression was observed in both androgen receptor expressing and non-expressing CRPC cells.
Conclusion & Translational Significance: Above results reveal a novel LXR-ERRα-AKR1C3-ERK axis which is activated in SULT2B-deficient CRPC cells irrespective of the androgen receptor status of these cells. Notably, elevated ERRα portends poor prognosis for prostate cancer and cholesterol is an ERRα agonist. Considering that statin can diminish ERRα activity (PMID 26777690) and AKR1C3 inhibitors are in clinical trials, this novel axis revealed from our study may be actionable for the clinical interception of the progression in SULT2B-low advanced prostate cancer.
Citation Format: Bobae Park, Katarzyna Knapczyk-Stwora, Yaguang Liu, Chung S. Song, Bandana Chatterjee. Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate 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 3070.
Abstract 3099: Hnd-01: a potent inhibitor of wild type mutant BTK
Authors: Zhang Jing , Samatar Ahmed A. , Tan Yue , Pi Shiqing , Zhou Zhigang , Xu Yan , Yang Daihong 
Published: April 2023

Abstract
Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Based on the in vitro and in vivo characterization studies of dasatanib, several metabolites were identified. Dasatinib and its metabolite 20 were the major circulating species identified which represented 25.5% and 12.5% of total radioactivity in human plasma respectively. Here, we report the identification of HND-01, a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) which was achieved by modifying metabolite 20 of dasatinib. Bruton’s tyrosine kinase (BTK) is a non-receptor kinase and a key regulator of the B-cell receptor (BCR) signaling pathway. BCR is critical for proliferation and survival of leukemic cells in many B cell malignancies, including chronic lymphocytic leukemia (CLL). BTK is a key target for the development of small molecule inhibitors in B cell malignancies. There are several covalent BTK inhibitors including ibrutinib that have been approved. These covalent inhibitors bind with high affinity to Cys-481 in the active site of BTK. However, some patients develop acquired resistance to ibrutinib due to Cys-481 mutation in the BTK binding site. The acquired resistance to covalent inhibitors can be overcome with the design of new reversible BTK inhibitors. The reversible BTK inhibitors will bind to different sites other than the cysteine residue of BTK and inactivate BTK. These drugs would potentially be active in the presence or absence of the cysteine-to-serine mutation. HND-01, a novel and potent reversible BTK inhibitor inhibits wild type & C481S mutant BTK with IC50 values of 0.157 nM for WTBTK and 0.032 nM for C481SBTK. HND-01 inhibits K562 cell proliferation (IC50 0.183 nM) and it is more stable than dasatinib in human liver microsomes (in vitro clearance; 142 mL/min/kg for HND-01 vs 211 mL/min/kg for dasatinib). In an established human lymphoma efficacy model (TMD-8 model), HND-01 showed stronger tumor inhibition (80.6%) than Ibrutinib (58%). These data demonstrates that HND-01 is a BTK inhibitor that is more potent with potential desirable ADME properties than ibrutinib. HND-01 was filled for international patents, China patent application # 202080030953.6, US patent application #17/636,476, EU application # EP 20853834.8, and Canada application # CA 3148436.
Citation Format: Jing Zhang, Ahmed A. Samatar, Yue Tan, Shiqing Pi, Zhigang Zhou, Yan Xu, Daihong Yang. Hnd-01: a potent inhibitor of wild type mutant BTK [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 3099.
Abstract 3106: Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma
Authors: Cheng Jeffrey , Xing Enming , Mohammed Shabber , Montgomery Emma , Granchie Lauren , Coss Christopher , Li Pui-Kai 
Published: April 2023

Abstract
Hepatocellular Carcinoma (HCC) is the leading form of liver cancer, the 6th most common type, and the 4th leading cause of cancer death worldwide. Interestingly, HCC occurs two to four times more in males than females. A possible explanation for this sexual dimorphism is the implication of androgen and the Androgen Receptor (AR). However, previous clinical trials among HCC patients have shown no significant survival benefit after the administration of antiandrogen drugs (e.g. Enzalutamide) that block the Ligand-Binding Domain (LBD) of the Full-length Androgen Receptor (AR-FL). Instead, our lab has developed a novel approach using small molecular analogs of the previously FDA-approved drug, Niclosamide, to degrade full-length AR and its spliced variants within HCC cell lines. The primary goal of this project was to evaluate the minimal necessary pharmacophores for the biological activity of the Niclosamide scaffold. To do so, 23 analogs were synthesized and tested on three different HCC cell lines (SNU 475, 423, and LM3) using a CCK8 cell viability assay. Preliminary results have shown that only Niclosamide analogs with i.) electron-withdrawing groups on the aniline ring; ii) a conserved hydroxy group on the salicylic ring, and iii) a free amide group in the middle have cytotoxic activity. Further work will be completed using western blot to determine if there’s any correlation between androgen receptor degradation and in vitro potency. In conclusion, Niclosamide analogs have indicated promising potential to inhibit HCC cell lines by targeting the Androgen Receptor.
Citation Format: Jeffrey Cheng, Enming Xing, Shabber Mohammed, Emma Montgomery, Lauren Granchie, Christopher Coss, Pui-Kai Li. Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma [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 3106.
Abstract 3120: Sex differences in pediatric cancer genomics
Authors: Oh Jieun , Zhu Chenghao , Zeltser Nicole , Li Constance H. , Tsai Brandon L. , Boutros Paul C. 
Published: April 2023

Abstract
Sex differences have been observed in the incidence, prognosis and mortality of many different adult cancer types, linked to differences in tumor genomics. By contrast, sex differences in pediatric cancers have been understudied, with almost no genomic studies. To fill this gap, we have performed analyses on the genome, epigenome and transcriptome in eight different pediatric cancer types in nearly 3,000 tumors. Pediatric cancers had distinctive somatic mutational patterns when it came to sex differences, with acute lymphoblastic leukemia exhibiting sex-biases in its transcriptome and other cancer types showing stronger biases in their methylomes. However, no sex differences in somatic mutational profiles were identified. This stands in stark contrast to adult tumors, where we further previous genomic and transcriptomic studies by identifying sex differences in the proteomes, in drug sensitivity profiles and in functional genomics. In summary, our study reveals that sex differences in pediatric cancers are more modest than those in adult tumors and this may shed light into potential mechanisms by which sex influences the cancer genome.
Citation Format: Jieun Oh, Chenghao Zhu, Nicole Zeltser, Constance H. Li, Brandon L. Tsai, Paul C. Boutros. Sex differences in pediatric cancer genomics [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 3120.
Abstract 3137: Somatic structure variants as a biomarker to predict immune checkpoint inhibitor response by generating anti-tumour antigen
Authors: Cha Hongui , Simpson Benjamin , Swanton Charles , Litchfield Kevin , Consortium Genomics England Research 
Published: April 2023

Abstract
The introduction of checkpoint inhibitors (CPI) has revolutionised the treatment of advanced cancers, which act to ameliorate the anti-tumour response through blocking inhibitive immune checkpoint receptors. Whole-exome sequencing (WES) based estimates of tumour mutational burden (TMB) has been robustly associated with response to CPI therapy across multiple tumour types and a threshold of ≥10 mutations per megabase (Mb) is now an FDA-approved biomarker for treatment with pembrolizumab. However, studies to date have been limited to whole exome sequencing (WES), with no data yet reported on the utility of whole genome sequencing (WGS) as a biomarker to predict CPI response. WGS data can identify non-coding alterations which impact the expression of immune regulatory genes, variants likely to form non-coding epitopes, including novel open reading frame mutations especially structure variants (SV). Here, we have identified a pan-cancer cohort of n=364 patients treated with CPI from Genomics England 100,000 Genomes Project (GEL). We find that SV burden is highly associated with worse CPI response (HR =1.3 (1.0-1.8) , p-value = 0.037) and high SV burden group have low tumour-infiltrating lymphocyte (TIL) score (P-value &lt; 0.0001). However, we found that patients who have high proportion of SV derived neoantigen group improved overall survival (HR = 0.44 (0.27-0.73) , p-value = 0.002). In addition, enhancer region alteration of antigen present gene was observed in 43 patients (12%) and was associated with worse CPI response. (HR = 1.5 (1.0-2.2), P-value = 0.034). We further explored the SV derived neoantigen generate neoantigen-specific T cell response.
Summary of Cox Model from structure variant Variables No. patients HR (95% CI) P Sex Female 164 Male 200 1.15 ( 0.87-1.52) 0.3285 Cancer Type Others 59 Lung 88 1.39 (0.91-2.14) 0.1255 Melanoma 155 0.84 (0.56-1.28) 0.4267 Renal 62 0.84 (0.52-1.38) 0.495 TMB estimated WGS 364 0.98 (0.97-0.99) 0.0036 SV burden Low 182 High 182 1.36 (1.02-1.81) 0.0358 Proportion of anti-tumour antigen from SV Low 49 High 47 0.48 (0.29-0.8) 0.0045 antigen non-generate 268 0.49 (0.35-0.7) &lt; 0.0001
Citation Format: Hongui Cha, Benjamin Simpson, Charles Swanton, Kevin Litchfield, Genomics England Research Consortium. Somatic structure variants as a biomarker to predict immune checkpoint inhibitor response by generating anti-tumour antigen [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 3137.
Abstract 3138: Topological analysis of spatial transcriptomics reveals different spatial interaction patterns in tumor microenvironment of lung cancer
Authors: Bae Sungwoo , Lee Hyekyoung , Na Kwon Joong , Lee Dong Soo , Choi Hongyoon , Kim Young Tae 
Published: April 2023

Abstract
Background: As the tumor microenvironment (TME) consists of various cell types with complex spatial interaction, its spatial organization patterns affect response to immune-oncology treatment. Therefore, describing the spatial composition and interaction of cells in the tumor microenvironment (TME) is necessary. Here, we developed a tool, STopover, which adopts topological analysis in spatial transcriptomics to reveal cell-cell colocalization patterns in TME and capture the key components and niche of intercellular communication, and applied it to human lung cancer data.
Methods: The spatial colocalization pattern of pairs of features was defined using topological data analysis with Morse filtration. The spatial network of spatial gene expression data was generated for each sample and then the patterns were summarized as connected components (CCs) based on the spatial distance between unit tissue regions and the persistence of each CC. The global and local extent of spatial overlap of a feature pair was calculated as Jaccard indices between extracted CC pairs. We applied STopover to 11 barcode-based spatial transcriptomic data of human lung adenocarcinoma with different PD-L1 expressions. Spatial mapping of cell types in TME was performed by CellDART. In addition, image-based spatial transcriptomic data of lung cancer were also used to find key spatial molecular interactions in TME using STopover.
Results: First, STopover disclosed the distinct immune and stromal infiltration patterns in lung cancer tissues. Spatial colocalization of cancer cells and T-cells was heterogeneous and correlated with the immune-related markers such as MHC class I signature. The cancer types were clustered according to spatial colocalization patterns of various immune cells with cancer cells, which showed different infiltration patterns of immune cells. Moreover, STopover could estimate the top cell-cell interaction and emphasize the key locations based on the literature-supported ligand-receptor database.
Conclusion: STopover is expected to account for significant spatial cell interactions in tumor-immune and tumor-stromal components and could be utilized as a platform to decipher the mechanisms underlying immune-oncology treatment response.
Citation Format: Sungwoo Bae, Hyekyoung Lee, Kwon Joong Na, Dong Soo Lee, Hongyoon Choi, Young Tae Kim. Topological analysis of spatial transcriptomics reveals different spatial interaction patterns in tumor microenvironment of 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 3138.
Abstract 3174: Integrative analysis of genome-wide DNA replication origins in human cells
Authors: Tian Mengxue , Wang Zhenjia , Zang Chongzhi , Su Zhangli , Shibata Etsuko , Shibata Yoshiyuki , Dutta Anindya 
Published: April 2023

Abstract
Dysregulated DNA replication is associated with cancer development. DNA replication initiates from ~50,000 sites in each cell cycle. Genome-wide profiles of replication origins can be generated using various sequencing-based methods following different molecular capture strategies. No previous study has integrated the results from these different experiments to characterize the most reproducible origins or their association with the replication initiation factor, Origin Recognition Complex (ORC), known to be important for origin-specification. We conducted an integrative analysis of 98 human origin profiling datasets from four different techniques including NS-seq, Repli-seq, Rerep-seq and Bubble-seq, and identified a total of 1,460,610 origins in the human genome. Of these, only 0.12% (1,746) were high-confidence “shared origins” that were detected by all four techniques. Compared with all origins, the shared origins have higher GC content and overlap more with gene promoters, CTCF binding sites, transcription factor (TF) binding hotspots, G-quadruplex sites and activating histone marks. Only ~20% of the shared origins (343) overlap with known ORC binding sites. Despite the low overlap between shared origins and ORC binding sites, permutation tests suggest that the overlap between shared origins, ORC binding sites, R-loops and promoters are all significantly higher than random expectation. The variability in origin identification by different techniques and by same techniques in different groups suggests that replication origins are specified by highly variable stochastic events influenced by epigenetic variability.
Citation Format: Mengxue Tian, Zhenjia Wang, Chongzhi Zang, Zhangli Su, Etsuko Shibata, Yoshiyuki Shibata, Anindya Dutta. Integrative analysis of genome-wide DNA replication origins in human cells [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 3174.
Abstract 3219: Development of a quality-of-life assessment module in patients with radiation dermatitis
Authors: Allen Olivia S. , Moadel-Robblee Alyson B. , Fox Jana , Yap Johnny , McLellan Beth N. 
Published: April 2023

Abstract
Introduction: Radiation dermatitis (RD) is one of the most common side effects of radiation therapy (RT), experienced by up to 95% of oncology patients. RD can be progressive, painful, and difficult to manage, thereby profoundly affecting patients’ quality of life (QOL). Current QOL assessments address dermatologic or oncologic concerns, with no existing tool integrating both areas to enable assessment of RD-specific QOL. Furthermore, RD grade does not consistently correlate with QOL scores in these assessments. The aims of this study are to identify unexplored QOL concerns in patients with RD and to create a new, RD-specific, validated assessment module to evaluate QOL in this patient population.
Methods: We conducted open-ended interviews with 20 patients with breast cancer with current or former RD during a radiation oncology clinic visit to determine RD-specific QOL concerns. We analyzed the most high-yield concerns to determine areas that are not addressed by current QOL assessments. With a workgroup of radiation oncologists, dermatologists, a psycho-oncologist, and patients, we evaluated our findings and used common themes to generate a new QOL survey.
Results: Among our patient cohort, 3 (15%) were undergoing current RT, 7 (35%) were at their first post-RT visit, 9 (45%) were at a follow-up visit within 12 months of completing RT, and 1 (5%) was at a follow-up visit over 12 months after completing RT. We uncovered four key areas affecting patients that are not incorporated into current QOL assessments: changes in clothing in 18 (90%) patients (e.g. wearing looser clothing, changing to a different bra, using a layer of bandages), changes in skin color in 17 (85%) patients (hyper- or hypopigmentation), changes in sleep due to skin changes in 13 (65%) patients (e.g. difficulty finding a comfortable position), and changes in ability to use the affected side in 9 (45%) patients (e.g. carrying items, avoiding contact with irritating material). We incorporated these four areas of concern into a six-question, RD-specific QOL assessment module to the Skindex-16, a validated and widely used QOL assessment in dermatology.
Conclusions: This pilot study enabled us to discover previously unexplored QOL concerns in patients with RD that are not addressed in current dermatology and oncology focused assessments. Future work includes validation of this module in patients with acute RD with the goal of identifying opportunities to optimize treatment and enhance patient-centered care for this population.
Citation Format: Olivia S. Allen, Alyson B. Moadel-Robblee, Jana Fox, Johnny Yap, Beth N. McLellan. Development of a quality-of-life assessment module in patients with radiation dermatitis [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 3219.
Abstract 3224: TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report
Authors: Ding Yuxuan , Wang Qiang , Wang Feijiang , Wu Nan , Li Jianrui , He Xia , Pan Hao , Wang Lijun 
Published: April 2023

Abstract
Epithelioid glioblastoma (EGBM, classified as glioblastoma, wild type, grade IV according to 2021 WHO CNS5 classification of neurological malignancies) is a highly aggressive malignancy, the median progression-free survival (mPFS) of which is about 4.0 months. Although, the introduction of tumor treating fields (TTFields, possessing anti-cancer capability via anti-mitotic effects) in the maintenance of TMZ chemotherapy was demonstrated beneficial for prolonging the mPFS of GBM patients to 6.9 months in the EF-14 clinical trial, studies centering on the significance of TTFields in EGBM treating are very limited due to the rarity of EGBM. Therefore, a 28-year-old patient (male, recurrent left-sided limb twitching for 1 month and dizziness for 1 week) was chosen as a clinical trial participant. A right frontal lobe occupancy was detected based on magnetic resonance imaging (MRI), and total tumor resection was performed on the patient. Meanwhile, postoperative histopathology test, including immunohistochemical and molecular characterization, was conducted and the results revealed a BRAF V600E mutation, no codeletion of 1p and 19q, and negative MGMT promoter methylation, which confirmed EGBM. In this context, chemoradiotherapy was conducted on the patient at first, and then concurrent TTFields and TMZ was performed. Notably, a long-term PFS of 33 months and KPS score of 90 were achieved over the patient upon TTFields combined TMZ, whose average daily usage of TTFields was higher than 90%. This clinical case corroborated the importance of TTFields in EGBM treating, and the higher compliance of TTFields is more beneficial for EGBM patient without additional side effect. YD, QW contributed equally to this work.
Citation Format: Yuxuan Ding, Qiang Wang, Feijiang Wang, Nan Wu, Jianrui Li, Xia He, Hao Pan, Lijun Wang. TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report [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 3224.