bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2157: SCR-6277, a potent and high selective arginine methyltransferase 5 (PRMT5) inhibitor with high tumor/plasma distribution ratio demonstrated robust anti-tumor activities and decreased hematological toxicities
Authors: Zhou Feng , Yang Guimei , Tang Feng , Xue Liting , Yang Wenqing , Chen Ping , Tang Renhong 
Published: June 2022

Abstract
Protein arginine methyltransferase 5 (PRMT5) is observed dysregulation in both solid and hematological tumors. Increasing evidences demonstrated that PRMT5 is a potential therapeutic target. Given the essential role in maintenance of adult hematopoietic cells, inhibition of PRMT5 leads to hematological toxicity. Anemia is the most common treatment related adverse event observed by PRMT5 inhibitor, such as GSK3326595, which limited the dose escalation. Therefore, developing a PRMT5 inhibitor with tumor-biased distribution could be an effective approach to avoid these target related toxicities. In this study, a novel and high selective PRMT5 inhibitor, SCR-6277 was identified. SCR-6277 inhibited the PRMT5 enzyme with an IC50 of 1.5 nM, and showed a high selectivity against other five methyltransferase isoforms (selectivity folds &gt;1000). SCR-6277 potently inhibited the PRMT5-mediated SDMA production in Z-138 cells (IC50, 0.6 nM) and the cell proliferation (IC50, 3 nM). SCR-6277 also demonstrated robustly anti-proliferation activities on multiple PRMT5 proficient solid tumor cell lines (IC50 values ranging from 20 - 130 nM) and no inhibitory effects on PRMT5 deficient cell lines. SCR-6277 had good oral bioavailability and favorable pharmacokinetic properties. In Z-138 and 5637 xenograft models, SCR-6277 robustly inhibited tumor growth. In contrast to GSK3326595, SCR-6277 showed tumor biased distribution. Exposure of SCR-6277 in tumors were 50 folds higher than that in plasma. The extremely high T/P ratio made SCR-6277 achieve the better anti-tumor activities at lower blood exposure (Table 1). In conclusion, SCR-6277 is a novel, potent and high selective PRMT5 inhibitor. And higher tumor/plasma distribution ratio predicts SCR-6277 is a more tolerant and effective PRMT5 inhibitor in human.
Table 1. Distribution and anti-tumor activity of SCR-6277 Dose TGI Plasma Conc. (ng/mL) * Tumor Conc. (ng/g) * T/P ratio GSK3326595 50 mpk,BID 87% 45 106 2 SCR-6277 15 mpk,BID 117% 20 668 50
Citation Format: Feng Zhou, Guimei Yang, Feng Tang, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang. SCR-6277, a potent and high selective arginine methyltransferase 5 (PRMT5) inhibitor with high tumor/plasma distribution ratio demonstrated robust anti-tumor activities and decreased hematological toxicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2157.
Abstract 2167: Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features
Authors: Nguyen Luan , Schipper Luuk , Roepman Paul , Monkhorst Kim , van Hoeck Arne , Snaebjornsson Petur , Cuppen Edwin 
Published: June 2022

Abstract
Tumor tissue of origin (TOO) is an important factor for guiding treatment decisions. However, TOO cannot be determined for ~3% of metastatic cancer patients that present in the clinic and are categorized as cancers of unknown primary (CUP). As whole genome sequencing (WGS) of tumors is now transitioning from the research domain to diagnostic practice in order to address the increasing demand for biomarker detection, its use for detection of TOO in routine diagnostics also starts becoming within reach. While proof of concept for the use of genome-wide features has been demonstrated before, more complex WGS mutation features, including structural variant (SV) driver and passenger events, have never been integrated into TOO-classifiers even though they bear highly characteristic links with tumor TOO. Using a uniformly processed dataset containing 6820 whole-genome sequenced primary and metastatic tumors (ICGC/PCAWG and Hartwig cohors), we have developed Cancer of Unknown Primary Location Resolver (CUPLR), a random forest based TOO classifier that employs 502 genome-wide features based on simple and complex somatic driver and passenger mutations. Our model is able to distinguish 33 cancer (sub)types with an overall accuracy of 91% and 89% based on cross-validation (n=6139) and hold out set (n=681) predictions, respectively. We found that SV derived features increase the accuracy and utility of TOO classification for specific cancer types. To ensure that predictions are human-interpretable and suited for use in routine diagnostics, CUPLR reports the top contributing features and their values compared to cohort averages. The comprehensive output of CUPLR is complementary to existing histopathological procedures and may thus improve diagnostics for patients with CUP. CUP is the first reimbursed indication for WGS in The Netherlands. We will report on the prospective use and clinical utility of WGS for CUP patients in routine diagnostics but also highlight the added value of CUPLR for unsolved differential diagnosis cases and incidental cases where the independent WGS analysis was discrepant with the original tumor diagnosis.
Citation Format: Luan Nguyen, Luuk Schipper, Paul Roepman, Kim Monkhorst, Arne van Hoeck, Petur Snaebjornsson, Edwin Cuppen. Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2167.
Abstract 2169: New telomeres and chromosomal arm fusions in cancer genomes revealed by long-read genome sequencing
Authors: Tan Kar-Tong , Slevin Michael K. , Garrity-Janger Max , Li Heng , Meyerson Matthew 
Published: June 2022

Abstract
Chromosomal rearrangements are widespread features of cancer genomes, and often lead to the generation of both larger and smaller chromosomes that are readily observed by cytogenetics analysis. The generation of these chromosomal alterations likely involves alterations in the structure and location of telomeres at chromosome ends, though these events have been difficult to assess due to the long and highly repetitive nature of telomeres. Here, we developed an analytic method (TeloFuse) to identify new telomeres and chromosomal arm fusions which are characterized by telomeric repeats at intra-chromosomal locations. We applied TeloFuse to identify telomere-containing fusions as well as novel sites of telomere addition using short-read genome sequencing data from 326 cancer cell lines followed by long-read genome sequencing and cytogenetic analysis of selected cell lines. We observed new telomeres at sites of terminal deletion in long read data (telomere length = 2-9 kb), and in 76/326 (23%) of cell line genomes with short read data. Telomere sequence-containing fusions at intra-chromosomal sites were detected in 75/326 (23%) of cancer cell lines and confirmed as chromosomal arm fusion events by long-read genome sequencing. Long-read genome sequencing further suggests that new telomeres have similar telomere length as telomeres found on normal chromosomal arms (median = 5kb). Conversely, telomeric repeats at sites of chromosomal arm fusions were found to be critically short (~200-500bp long). Extending our analysis to 97 lung adenocarcinoma patient samples from The Cancer Genome Atlas, we further found new telomeres in 17/97 (18%) and chromosomal arm fusions in 28/97 (29%) patients with short-read data. Notably, new telomeres and chromosomal arm fusion events were also found to disrupt protein-coding genes, suggesting that these events represent a poorly appreciated mode for gene inactivation in cancer. Our results suggest that the formation of new telomeres and chromosomal arm fusions are prevalent events during cancer genome evolution and are likely critical for the stabilization of new chromosomes in human cancers. More broadly, our findings also highlight the utility of long-read genome sequencing in delineating chromosomal-scale alterations that have been widely observed by cytogenetics analysis.
Citation Format: Kar-Tong Tan, Michael K. Slevin, Max Garrity-Janger, Heng Li, Matthew Meyerson. New telomeres and chromosomal arm fusions in cancer genomes revealed by long-read genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2169.
Abstract 217: A novel class of dimeric quinacrine compounds induce DNA damage and increase the anticancer activity of radiation
Authors: Karagounis Ilias V. , Karar Jayashree , Thomas Christoforos , Koumenis Constantinos , Winkler Jeffrey , Amaravadi Ravi , Maity Amit 
Published: June 2022

Abstract
Radiation therapy is commonly used to treat cancers in the definitive setting, but the local control often remains suboptimal, thereby motivating us to search for novel radiosensitizers. Recently a series of novel quinacrines based upon a previously reported dimeric chloroquine has been synthesized. We studied one of these agents, DQ660. By itself, the drug upregulates both p53 protein and p53 transcriptional targets and also increases apoptosis in p53-wildtype H460 lung cancer cells. Furthermore, we found that DQ660 is a potent radiosensitizer in vitro. This radiosensitization is not contingent upon wildtype p53 as it occurs in cells null for p53 and containing mutant p53. The combination of radiation and DQ660 proded significant growth retardation of human xenografts grown in vivo compared to radiation or DQ660 alone. We saw higher levels of γ-H2AX foci with combined treatment compared to either alone, suggesting that the drug increases DNA damage induction. Using agarose gel electrophoresis and kinetoplast DNA (kDNA) as a substrate, we found that DQ660 can inhibit topoisomerase II activity. DQ660 did not potentiate the phosphorylation of ATM at S1981 seen after radiation. However, the drug did lead to an increase in Ser428 phosphorylation of ATR. This phosphorylation was not seen in response to radiation alone, suggesting that DQ660 and radiation activate different signaling pathways in response to DNA damage. We saw similar results with another dimeric quinacrine, DQ550, suggesting that this class of agents may be radiosensitizers. Our findings have uncovered a novel class of radiosensitizers that work at nanomolar concentrations and will spur investigations for its use in combination therapy for tumors treated with radiation
Citation Format: Ilias V. Karagounis, Jayashree Karar, Christoforos Thomas, Constantinos Koumenis, Jeffrey Winkler, Ravi Amaravadi, Amit Maity. A novel class of dimeric quinacrine compounds induce DNA damage and increase the anticancer activity of radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 217.
Abstract 2220: Immunohistochemical detection of prostate cancer heterogeneity by using ETS and PTEN monoclonal antibodies
Authors: Schafer Cara , Young Denise , Song Yingjie , Jiang Jiji , Dobi Albert , Petrovics Gyorgy , Drake Bettina F. , Chesnut Gregory T. , Sesterhenn Isabell A. , Tan Shyh-Han 
Published: June 2022

Abstract
The multifocality and highly variable molecular pathology of prostate cancer are underlying features of this clinically heterogeneous disease. Most patients harbor multiple molecularly distinct cancer foci at diagnosis that likely arose as independent clones. There is a critical need for molecular biomarkers that can distinguish the multifocality and inter-focal heterogeneity of tumors and help stratify patients for treatment. PTEN loss and ETS gene rearrangements are among the most prevalent genomic alterations in prostate carcinogenesis. The detection of both ERG overexpression and PTEN protein loss by immunohistochemistry (IHC) have proven to be reliable substitutes for detecting genomic alterations by fluorescence in situ hybridization (FISH) assay. We developed monoclonal antibodies against ETV1 and ETV4 and evaluated their performance in prostate cancer specimens. The expression of ETV1, ETV4, were examined in relation to ERG and loss of PTEN expression in TMAs constructed from primary prostate cancer specimens of two independent patient cohorts. The first TMA was constructed from multiple 1 mm cores representing distinct tumor focus from multifocal tumors from 50 African American (AA) and 50 Caucasian American (CA) men. The second was constructed from a single 2 mm core of individual tumors from an independent cohort of 152 AA and 304 CA men. We present results on the expression of each protein biomarker in the context of patient race and their association with clinico-pathologic features, together with concurrence or mutual exclusiveness for each event. These results support the application of ETS monoclonal antibodies in IHC assays to detect prostate cancer tumor heterogeneity and to identify subsets of prostate cancer.
Citation Format: Cara Schafer, Denise Young, Yingjie Song, Jiji Jiang, Albert Dobi, Gyorgy Petrovics, Bettina F. Drake, Gregory T. Chesnut, Isabell A. Sesterhenn, Shyh-Han Tan. Immunohistochemical detection of prostate cancer heterogeneity by using ETS and PTEN monoclonal antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2220.
Abstract 2249: A metabolomic analysis of adiposity measures and pre- and postmenopausal breast cancer risk in the Nurses’ Health Studies
Authors: Brantley Kristen D. , Zeleznik Oana A. , Dickerman Barbra A. , Balasubramanian Raji , Clish Clary B. , Avila-Pacheco Julian , Rosner Bernard , Tamimi Rulla M. , Eliassen A. Heather 
Published: June 2022

Abstract
Adiposity is consistently positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk. In this nested case-control study of 1651 breast cancer cases and 1651 matched controls from the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII), we selected lipids and polar metabolites correlated with BMI, waist circumference, weight change since age 18, or derived fat mass, developed a metabolomic score for each measure using LASSO regression, and used logistic regression to investigate the association between this score and breast cancer risk adjusted for risk factors. Analyses were stratified by menopausal status at blood draw and diagnosis. We further explored risk of ER+ and ER- breast cancer.Metabolite correlations were similar across adiposity measures. Metabolite scores developed among only premenopausal or postmenopausal women were highly correlated with scores developed in all women (r=0.94-0.96). Higher metabolomic adiposity scores were generally inversely related to breast cancer risk among premenopausal women. Among postmenopausal women, significant positive trends with risk were observed for higher metabolomic adiposity scores (e.g., metabolomic waist circumference score OR Q4 v. Q1=1.55, 95% CI=1.08-2.22, p-trend=0.01). Metabolites associated with adiposity and breast cancer risk, glycerophosphocholines and branched-chain amino acids, are also associated with metabolic dysregulation. The same metabolites represented adiposity in pre- and postmenopausal women, though breast cancer risk associations still differed by menopausal status. Thus, metabolic dysregulation may have a differential association with pre- vs. postmenopausal breast cancer. Investigation of these metabolites and their role in adiposity-related breast cancer risk should be further explored.
Citation Format: Kristen D. Brantley, Oana A. Zeleznik, Barbra A. Dickerman, Raji Balasubramanian, Clary B. Clish, Julian Avila-Pacheco, Bernard Rosner, Rulla M. Tamimi, A. Heather Eliassen. A metabolomic analysis of adiposity measures and pre- and postmenopausal breast cancer risk in the Nurses’ Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2249.
Abstract 2255: Alu retroelement copy number alterations and non-Hodgkin lymphoma
Authors: Hu Wei 
Published: June 2022

Abstract
Background: Alu retrotransposons are repetitive DNA elements that make up nearly 10% of the human genome and reflect genomic instability. Genomic instability plays an important role in the pathogenesis of non-Hodgkin lymphoma (NHL). However, the relationship between Alu retrotransposons and future risk of NHL is unclear.
Methods: We conducted a nested case-control study of NHL risk and Alu retroelement copy number within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, a prospective cohort with prediagnostic blood samples from 29,133 male Finnish smokers. We measured Alu copy number in 107 incident NHL cases and 1:1 matched controls (± 5 years age). DNA samples extracted from blood were assayed in triplicate using a monochrome multiplex quantitative polymerase chain reaction. We used the albumin gene for the single copy gene to control for genome content in samples. The odds ratios (OR) and 95% confidence intervals (CI) for all NHL were estimated using conditional logistic regression models, adjusting for age at randomization, number of cigarettes smoked per day and smoking duration. Polytomous logistic regression models were fit to compute ORs with Alu copy number for NHL subtypes. To determine if the association might be driven in part by elevated Alu copy number among undiagnosed cases at the time of blood sample collection, we excluded cases diagnosed within the first two years of follow-up.
Results: Higher Alu copy number (using the median as the cut-point) was associated with an increased risk of NHL, both overall [OR, 95% CI=3.80 (1.76-8.17)] as well as for the diffuse large B-cell lymphoma [OR, 95% CI=4.83 (1.50-15.55)] and chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL) [OR, 95% CI=2.66 (1.10-6.40)] subtypes. These associations were similar after excluding individuals diagnosed with NHL within two years after blood draw.
Conclusions: These findings, which require replication, suggest that higher Alu copy number in prediagnostic leukocytes may play a role in the pathogenesis of NHL.
Citation Format: Wei Hu. Alu retroelement copy number alterations and non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2255.
Abstract 226: Recurrent trisomies, variable selection and precancerous evolution in the normal gastric epithelium
Authors: Coorens Tim H. , Collord Grace , Jung Hyungchul , Wang Yichen , Zumalave Sonia , Leongamornlert Daniel , Moore Luiza , Mahbubani Krishnaa , Saeb-Parsy Kourosh , Leung Suet Yi , Stratton Michael R. 
Published: June 2022

Abstract
Gastric cancer is the third leading cause of cancer-related mortality globally and is often associated with infectious agents such as the bacterium Helicobacter pylori. However, the background mutational landscape in normal gastric epithelium and the first genomic steps towards the formation of gastric cancer remain poorly understood. Here, we use whole-genome sequencing of microdissected gastric glands (n=271) from 30 patients, 18 of whom had gastric cancer. We show that gastric glands are clonal structures and accrue approximately 27 single base substitutions per year. While the mutational signatures in most normal glands reflect age-related mutagenesis, gastric glands sampled close to a tumor showed exposure to a mutagenic process enriched in tumors (COSMIC reference mutational signature SBS17). Phylogenetic analysis shows that acquisition of SBS17 substitutions is closely linked to overt malignant transformation. We also observe widespread trisomies of specific chromosomes, which are recurrently and independently acquired in many gastric glands of the same patient. Mutations in genes encoding epigenetic modifiers and chromatin remodelers showed evidence of positive selection and were highly enriched in some patients. This was confirmed by targeted sequencing of cancer genes in a further 1008 gastric glands. Strikingly, glands that exhibit driver mutations, a recurrent trisomy or elevated mutation loads only overlap minimally, suggesting a highly variable and patient-specific mutation and selection landscape in the normal gastric epithelium. Taken together, these results give novel insights into the preclinical evolution of gastric malignancies.
Citation Format: Tim H. Coorens, Grace Collord, Hyungchul Jung, Yichen Wang, Sonia Zumalave, Daniel Leongamornlert, Luiza Moore, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Suet Yi Leung, Michael R. Stratton. Recurrent trisomies, variable selection and precancerous evolution in the normal gastric epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 226.