bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5991: Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers
Authors: O'Brien Neil A. , McDermott Martina S. , O'Boyle Brendan M. , Hilf Justin A. , Loson Oliver , Chau Kevin , Jia Weiping , Kamranpour Naeimeh , Luo Tong , Ayala Raul , Issakhanian Shawnt , Glaspy John A. , Stoltz Brian M. , Slamon Dennis J. 
Published: April 2023

Abstract
CDK4/6 inhibitors give clinical benefit in the treatment of metastatic ER+/HER2- breast cancer (mBC) in combination with endocrine therapy. Although this class of inhibitor has been extensively studied in several other cancer types, CDK4/6 inhibitors have not been approved as a treatment for outside of ER+/HER2- cancer. We evaluated the clinically approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib—in a 500+ cell line screening platform and identified several cancers outside of breast that may have subpopulations that are sensitive to CDK4/6 inhibitors. Kinome and KiNativ analyses helped identify differences in sensitivity/selectivity that we observed between each CDK4/6 inhibitor. Comprehensive molecular profiling of the cell lines at baseline allowed us to screen for potential associations with sensitivity to these compounds. These analyses identified potential biomarkers of sensitivity in non-small cell lung carcinoma (NSCLC) and colorectal cancer (CRC) that will later be evaluated in human clinical studies. Having thoroughly studied the CDK4/6 class and discovered new opportunities for clinical development, we set out to develop a CDK4/6 inhibitor that would have the best properties of the two distinguished class members. Using our proprietary chemistry, we developed UCT-03-008, a potent CDK4/6 small molecular inhibitor with a pharmacology known to enhance therapeutic benefit in mBC. Pharmacokinetic properties of UCT-03-008 are improved over those of other CDK4/6 inhibitors. UCT-03-008 has activity in preclinical models as a monotherapy and yields in vivo efficacy in multiple cancer models outside of ER+/HER2- breast cancer, including CRC and NSCLC. In summary, UCT-03-008 is a CDK4/6 inhibitor with optimized pharmacological properties. Clinical development of this compound will be guided by the biomarker hypotheses developed here. We are currently enrolling patients for treatment with UCT-03-008 in a Phase 1 clinical trial of advanced solid tumors (NCT05103046).
Citation Format: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Justin A. Hilf, Oliver Loson, Kevin Chau, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Shawnt Issakhanian, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon. Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers [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 5991.
Abstract 6004: DNA methylation diagnostics for upper urinary tract urothelial carcinoma using newly developed high-performance liquid chromatography
Authors: Fujimoto Mao , Arai Eri , Kikushima Takuya , Nishiyama Naotaka , Nakamura Tomofumi , Yamada Yuriko , Taira Hiroaki , Yotani Takuya , Kitamura Hiroshi , Kanai Yae 
Published: April 2023

Abstract
Backgrounds: For diagnosis of upper urinary tract urothelial carcinoma (UTUC), conventional ureteroscopic examinations are invasive, and selective urine cytology has insufficient sensitivity. We have developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions. This method is expected to be very suitable for quantification of DNA methylation levels of cancer cells in urine samples with contamination of various cell lineages.
Purpose: The aim of this study was to establish a less invasive and more accurate method for UTUC diagnosis based on DNA methylation quantification by our newly developed HPLC.
Methods: Urine samples were collected by urinary catheterization during surgery for 218 urological cancer patients. Our previous studies have identified 4 CpG sites showing differences in DNA methylation levels between non-cancerous urothelium and UTUC based on genome-wide DNA methylation analysis using tissue specimens. In the present study, DNA methylation levels of these marker CpG sites were quantified by HPLC using the urine samples.
Results: The thresholds have been set for the retention time by HPLC and the area under the chromatogram. Diagnostic criteria have been established to distinguish cases with current UTUC from non-urothelial cancer cases, bladder cancer cases and post-urothelial cancer treatment cases by combining marker CpG sites. The sensitivity and specificity were 90.9% and 87.0% respectively.
Conclusions: Since HPLC-based DNA methylation diagnostic system was able to discriminate UTUC cells from blood cells and other contaminating cells in urine samples, application of our criteria will ultimately allow non-invasive diagnosis of UTUC in the clinical setting. It may be possible to at least partially replace highly invasive procedures such as ureteroscopy and to enable early initiation of treatment for UTUC resulting in improved prognosis.
Citation Format: Mao Fujimoto, Eri Arai, Takuya Kikushima, Naotaka Nishiyama, Tomofumi Nakamura, Yuriko Yamada, Hiroaki Taira, Takuya Yotani, Hiroshi Kitamura, Yae Kanai. DNA methylation diagnostics for upper urinary tract urothelial carcinoma using newly developed high-performance liquid chromatography [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 6004.
Abstract 6009: An end-to-end workflow for improved methylation detection
Authors: Bonar Lydia , Butcher Kristin , Bocek Michael , Corbitt Holly , Hoglund Bryan , Nassif Cibelle , Cherry Patrick , Murphy Derek , Challacombe Jean , Toro Esteban 
Published: April 2023

Abstract
Introduction: DNA methylation at CpG nucleotide sites in eukaryotes is a key epigenetic mark that can help regulate gene expression. Specific changes in CpG methylation occur in many human cancers, making them a promising biomarker for early cancer detection. However, existing assays can be costly, lack specificity to regions of interest and often provide only semi-quantitative estimates of the methylation fraction. Here, we present a targeted methylome panel to decrease costs associated with next generation sequencing (NGS), methylation controls to calibrate quantitative assays and UMIs for accurate deduplication in low-diversity samples.
Experimental Procedures: Genomic DNA (gDNA) was prepared for sequencing using the Twist Methylation Detection System consisting of enzymatic methylation conversion and hybrid capture using the Twist Human Methylome Panel. Twist’s synthetic CpG methylation level controls were spiked-in to gDNA and taken through the Twist Methylation Detection System to demonstrate their utility in calibrating methylation assays. Additionally, libraries were generated using cell free DNA (cfDNA) and either conventional or UMI-containing adapters to investigate the impact on quantitative detection and total unique coverage.
Results: Using the Twist Human Methylome Panel at 150x raw coverage achieves uniform coverage with low off-bait Picard metrics. 6.59 million CpG sites were detected using a minimum depth of 10X. Target capture with the Human Methylome Panel allows for informative CpG calling of up to 82 samples on a single Illumina Novaseq S4 flowcell, compared to 3 samples per flowcell with a tradition whole-genome bisulfite sequencing (WGBS) assay. The Twist CpG methylation specific controls are constructed of 48 unique contrived sequences that contain a total of 8 different levels of methylation, ranging from 100% to 0%. Including these controls allows for quantitation of methylation levels in the experimental samples and qualification of the enzymatic conversion process.
Conclusions: Our study leverages the Twist methylation detection portfolio to interrogate genome-wide methylation patterns for various applications. In combination, these tools can be used to design cost effective end-to-end assays.
*For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Lydia Bonar, Kristin Butcher, Michael Bocek, Holly Corbitt, Bryan Hoglund, Cibelle Nassif, Patrick Cherry, Derek Murphy, Jean Challacombe, Esteban Toro. An end-to-end workflow for improved methylation detection. [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 6009.
Abstract 6014: Cancer risk diagnosis by epimutation burden: a multicenter prospective study
Authors: Yamada Harumi , Maeda Masahiro , Abe Seiichiro , Shimazu Taichi , Ando Takayuki , Murakami Kazunari , Tanaka Shinji , Maekita Takao , Inatomi Osamu , Sugimoto Ken , Kawagoe Tetsuro , Yamamichi Nobutake , Ushijima Toshikazu 
Published: April 2023

Abstract
Aberrant DNA methylation, induced by aging and accelerated by chronic inflammation, accumulates in normal tissue. Accumulation of DNA methylation in multiple genes, namely epimutation burden, is closely associated with cancer risk. Indeed, we demonstrated that the measurement of the methylation level of a marker gene in normal tissue is useful for cancer risk prediction of metachronous cancers, by a multicenter prospective study with gastric cancer patients (Asada, Gut, 64:388, 2015: Maeda, Gut, 66:1721, 2017). In this study, we attempted to predict the risk of primary gastric cancer by performing a new multicenter prospective study. We recruited 1,880 healthy people, after Helicobacter pylori eradication, with a clinically high risk of gastric cancer. Biopsy specimens were obtained from the antrum and body, and the methylation level of RIMS1, which is a preselected epigenomic risk marker for this study, was measured in 1,757 participants. The participants are annually being followed-up to detect primary gastric cancer, for 5-8 years. Currently, the median follow-up is 4.05 years, and 27 people have developed primary gastric cancers (as of September 2022). The results of statistical analysis are being determined. This study will establish the clinical utility of a cancer risk diagnosis by epimutation burden in normal tissue, and is promising for application in various inflammation-associated cancers.
Citation Format: Harumi Yamada, Masahiro Maeda, Seiichiro Abe, Taichi Shimazu, Takayuki Ando, Kazunari Murakami, Shinji Tanaka, Takao Maekita, Osamu Inatomi, Ken Sugimoto, Tetsuro Kawagoe, Nobutake Yamamichi, Toshikazu Ushijima. Cancer risk diagnosis by epimutation burden: a multicenter prospective study. [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 6014.
Abstract 6073: Distinct subtype of multiple myeloma revealed by whole genome and transcriptome sequencing
Authors: Kim Sheehyun , Yoon Hyundong , Koh Youngil , Yoon Sung-Soo 
Published: April 2023

Abstract
Background: Advanced sequencing technologies have contributed to identifying genomic and transcriptomic features of various types of tumors. Despite several sequencing data from multiple myeloma (MM) being generated, understanding various properties of MM remained insufficient.
Methods: The patients confirmed with MM by bone marrow examination were analyzed in the study. Myeloma cells were enriched from the bone marrow aspirates of the patients using CD138. Whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) were performed for isolated myeloma cells. Mutational signatures were analyzed using somatic mutations detected by WGS.
Results: A total of 37 MM patients (median age 67) were enrolled in this study. WGS revealed somatic mutations of an average of 8872 single nucleotide variants (SNVs) and 934 insertions and deletions (Indels) from the patients, respectively. By the analysis of structural variants, 7 chromothripsis and 4 chromoplexy patients were identified. Mutational signature analysis showed that single base substitution (SBS) 9 signature largely varied between patients. SBS9 signature high patients were mostly diagnosed with non-IgG/non-IgA heavy chain and lambda light chain type myeloma. Notably, IgD myeloma patients were solely detected in the SBS9 signature high group compared to the low group (p = 0.001). Gene expression patterns obtained from WTS were well-divided into SBS9 signature high and low groups, and analysis of differentially expressed genes (DEG) between SBS9 signature high and low groups implied IgD myeloma features including high expression of IGHD. As a validation test, we tried mutational signature analysis on whole exome sequencing (WES) data of 784 MM patients from the MMRF database. Of the 38 patients with more than 500 exonic mutations, only the SBS9 signature high group had IgD myeloma candidates, whereas the SBS9 signature low group had no IgD myeloma candidate (p = 0.014).
Conclusions: DNA and RNA sequencing of myeloma patients could classify specific subtypes of disease categories. Further study for SBS 9 signature high and IgD myeloma is needed to discover the underlying mechanism of distinct features and to find out their clinical implication.
Citation Format: Sheehyun Kim, Hyundong Yoon, Youngil Koh, Sung-Soo Yoon. Distinct subtype of multiple myeloma revealed by whole genome and transcriptome sequencing. [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 6073.
Abstract 6097: Determination of BRCA2 deletion status by copy number estimation using next generation sequencing to predict prognosis of clinically localized prostate cancer
Authors: Sumitomo Makoto , Nukaya Takuhisa , Sugihara Eiji , Takeda Mayu , Nohara Sachio , Tanishima Shigeki , Takenaka Masashi , Zennami Kenji , Takahara Kiyoshi , Shiroki Ryoichi , Saya Hideyuki 
Published: April 2023

Abstract
The significance of BRCA alterations has been implicated in the development of metastatic castration-resistant prostate cancer (PC). On the other hand, the details of the frequency and significance of BRCA alterations in localized PC remain unknown. In this study, we investigated the frequency and clinical significance of BRCA alterations in localized PCs using an in-house next-generation sequencer (NGS) system. NGS analyses revealed that the BRCA2 CN decreased in 17 patients (13.5%) and the BRCA1 CN in six (4.8%). NGS-based CN values were shown to be highly correlated with droplet digital PCR-based CN values. Tissue-specific BRCA expression investigated using the Human Protein Atlas showed that the decreased CN of BRCA2, but not BRCA1, is responsible for the decreased BRCA activity in PC. Ten of the 22 patients with decreased BRCA2 CN were presumed to have somatic heterozygous deletion. There were no observed associations between the heterozygous deletion of BRCA2 and various clinicopathological parameters. Furthermore, three of 10 patients developed biochemical recurrence within 3 months after surgery. Multivariate analyses revealed that the initial prostate-specific antigen levels and BRCA2 CN were independent factors for biochemical recurrence. Our results suggest that a decrease in BRCA2 CN may be used as a biomarker for predicting recurrence after surgery in localized PC. Early screening for somatic alterations in BRCA2 using NGS may help to broadly predict the risk of PC progression.
Citation Format: Makoto Sumitomo, Takuhisa Nukaya, Eiji Sugihara, Mayu Takeda, Sachio Nohara, Shigeki Tanishima, Masashi Takenaka, Kenji Zennami, Kiyoshi Takahara, Ryoichi Shiroki, Hideyuki Saya. Determination of BRCA2 deletion status by copy number estimation using next generation sequencing to predict prognosis of clinically localized 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 6097.
Abstract 611: Sex disparities in cancer immunoediting
Authors: Hunt Katey , Alspach Elise 
Published: April 2023

Abstract
Cancer immunoediting is the process through which tumor specific T cell populations both prevent cancer development and apply selective pressure for the outgrowth of less immunogenic tumors with reduced neoantigen burden. Male and female immune systems demonstrate distinct differences that drive characterized disparities in response to viral infection and immunization. While several recent publications have shown that anti-tumor immune responses are inhibited by male sex hormone signaling, a critical gap in knowledge exists surrounding sex-based differences in the larger-scale process of immunoediting. Because the residual neoantigen burden expressed after tumor escape from immune surveillance is an important determinant of rejection following immune checkpoint blockade, disparities in immunoediting between males and females could have profound impacts on both cancer incidence and response to therapy. The purpose of our studies is to determine if the enhanced functionality of female T cells results in more effective immunoediting of tumors that evolve in females versus those that evolve in males. We have used the 3-methylcholanthrene carcinogen-induced tumor model and several transplant tumor models to determine if T cell function regulates differential cancer development between the sexes. We have also analyzed predicted neoantigen burden in male and female patients with melanoma and lung cancer to identify sex-based differences in tumor immunogenicity. We have found that female T cell responses are more effective at preventing tumor occurrence and delaying tumor outgrowth compared to male T cell responses in mice, which may help to explain established sex-based disparities in cancer incidence in the human population. In comparison, male patient tumors were more likely to express high neoantigen burden compared to their female counterparts. These results suggest that while stronger anti-tumor T cell responses in females are helpful in driving lower cancer incidence in females compared to males, this disparity may also result the development of tumors that express greater numbers of immunogenic neoantigens in males versus females. A better understanding of how sex impacts the entire process of immunoediting will help to explain cancer disparities between the sexes and identify potential new therapeutic strategies that can benefit all patients.
Citation Format: Katey Hunt, Elise Alspach. Sex disparities in cancer immunoediting [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 611.
Abstract 6151: Loss of GPR54 inhibits tumor growth by suppressing AKT/DDC signaling pathway in KRAS-mutant non-small cell lung cancer
Authors: Lee Seo Yeon , Choi Yu-Jeong , Hwang Hyun-Ha , Kang Sooyeon , Lee Kangwook , Ko Seong-Gyu 
Published: April 2023

Abstract
Therapeutic targeting of KRAS-mutant lung cancers has remained a challenge. There are increasing evidence that KISS1/GPR54 signaling pathway is associated with the development of various cancer. Although KISS1 and GPR54 are expressed in the lung, their biological role in the lung tumorigenesis remains unclear. In this study, using the genetically engineered mouse models, we have identified that loss of Gpr54 inhibited Kras-driven lung tumorigenesis by suppressing pathways in oncogenesis such as the MAPK and AKT pathways and inducing apoptosis. Similarly, genomic inhibition of GPR54 suppressed cell proliferation, decreased ERK and AKT signaling pathway, and increased apoptotic cell death in NSCLC cells. RNA-sequencing analysis revealed that DDC expression and glycolysis gene sets were significantly changed in Gpr54 deficient mice. Interestingly, HIF-1α expression is regulated by GPR54/AKT/DDC signaling pathway in NSCLC cells, leading to glycolytic change. Genomic inhibition of DDC suppressed cell proliferation and enhanced apoptotic cell death in NSCLC cell lines. Also, pharmacological inhibition of GPR54 and DDC lower glucose consumption and lactate production in NSCLC cell lines. Taken together, we demonstrate GPR54, as a potential therapeutic target, suggesting a new strategy to cure for lung cancer patients.
Citation Format: Seo Yeon Lee, Yu-Jeong Choi, Hyun-Ha Hwang, Sooyeon Kang, Kangwook Lee, Seong-Gyu Ko. Loss of GPR54 inhibits tumor growth by suppressing AKT/DDC signaling pathway in KRAS-mutant non-small cell 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 6151.