bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3293: In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma
Authors: Jing Yuqi , Guerrero F Bustamante , Merchan Jaime 
Published: June 2022

Abstract
Oncolytic vaccinia virus has several advantages over other OV platforms, including an efficient life cycle, multiple mechanisms of viral spread, large genome, allowing acceptance of foreign therapeutic DNA inserts, and proven safety in humans, due to its use as smallpox vaccine. JX-594 (Pexavec, SillaJen) is an attenuated (TKdeactivated ) oncolytic vaccinia VV, engineered to express GM-CSF and to selectively target tumor over non-tumor tissues. It is currently being investigated as a novel therapeutic option in patients with advanced Renal Cell Carcinoma (RCC, NCT03294083). The present study was undertaken to investigate the effects of JX-954 in a panel of clear and non-clear cell RCC cell lines and characterize the potential mechanisms of JX-594 oncolysis in vitro. We evaluated the oncolytic potency of JX-594 in human clear cell RCCs (VHL mutant 786-0, A498, VHL wild type Caki-1), non-clear cell RCC (ACHN, papillary RCC, and UOK-262, an FH deficient papillary RCC cell) and murine renal cancer cells (RENCA). Potent and persistent cytotoxic effects were induced by JX-594 in all human RCC cells, regardless of the histological subtype, and by mJX-594 (a Western Reserve strain of vaccinia virus expressing murine GMCSF) in RENCA cells. Moreover, we observed efficient viral replication in human (786-0, ACHN) and murine (RENCA) cells, confirming RCC permissiveness to viral infection. Functional proteomics analysis of JX-594 treated 786-0 cells was performed by reverse phase protein array (RPPA) to gain knowledge on potential mechanisms of viral oncolysis. JX-594 treatment had significant effects on the expression levels of proteins related to inducing cell cycle, apoptosis, necrosis, Akt signaling, MAPK signaling, autophagy and stress induction. In particular, the proteins related to cell cycle (Wee1, Cdc25c, CHK1/2, and Cyclin B1) and Akt signaling (PI3K, mTOR, Rictor and FOXO), MAPK signaling (JAK2, PAK1, FAK and MEK1) were down regulated, while proteins involved in apoptosis and necrosis were upregulated. In summary, our studies show that human and murine renal cancer cells are permissive to infection and replication by JX-594 and mJX-594, which induce potent oncolytic effects in clear and non-clear cell RCC, effects associated with significant modulation of RCC pathways associated with cell cycle, proliferation, and survival and stress responses.
Citation Format: Yuqi Jing, F Bustamante Guerrero, Jaime Merchan. In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma [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 3293.
Abstract 3299: Development of ONCR-788, a synthetic oncolytic virus based on Seneca Valley virus for the treatment of neuroendocrine tumors
Authors: Kennedy Edward M. , Denslow Agnieszka , Hewett Jacqueline , Kong Lingxin , De Almeida Ana , Bryant Jeffrey , Lee Jennifer S. , Jacques Judy , Feau Sonia , Hayes Hayes , McMichael Elizabeth L. , Wambua Daniel , Adhikari Sanmit , Deterling Jessica , Scott Matthew , Haines Brian H. , Finer Mitchel H. , Ashburn Ted , Quéva Christophe , Lerner Lorena 
Published: June 2022

Abstract
Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration. Still, the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. Systemic administration of ONCR-788, the Synthetic RNA virus drug candidate encoding the vRNA of Seneca Valley virus (SVV), led to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. After a single intravenous administration of ONCR-788, we demonstrated vRNA delivery, viral replication, spread, and lysis of tumor cells. Robust anti-tumor efficacy was observed across diverse neuroendocrine tumor models, including tumor CDX and PDX xenografts, lung orthotopic, and GEMM-derived models. In a syngeneic model, ONCR-788 stimulated both tumor lysis and modulation of the tumor microenvironment. Enhanced T cell recruitment and activation, increased expression of PD-L1 on tumor cells and myeloid cells, and M2 to M1 macrophage conversion were observed. Combination of ONCR-788 with anti-PD-1 resulted in improved anti-tumor activity versus the monotherapy arms. Altogether, ONCR-788 provides an innovative approach that enables repeat intravenous administration of viral immunotherapy.
Citation Format: Edward M. Kennedy, Agnieszka Denslow, Jacqueline Hewett, Lingxin Kong, Ana De Almeida, Jeffrey Bryant, Jennifer S. Lee, Judy Jacques, Sonia Feau, Hayes Hayes, Elizabeth L. McMichael, Daniel Wambua, Sanmit Adhikari, Jessica Deterling, Matthew Scott, Brian H. Haines, Mitchel H. Finer, Ted Ashburn, Christophe Quéva, Lorena Lerner. Development of ONCR-788, a synthetic oncolytic virus based on Seneca Valley virus for the treatment of neuroendocrine tumors [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 3299.
Abstract 3341: Synthetic lethality by targeting ribonucleotide reductase in PP2A deficient uterine serous carcinoma
Authors: O'Connor Caitlin M. , Taylor Sarah E. , Miller Kathryn M. , Hurst Lauren , Haanen Terrance J. , Suhan Tahra K. , Zawacki Kaitlin P. , Noto Fallon K. , Trako Jonida , Mohan Arathi , Sangodkar Jaya , Zamarin Dmitriy , DiFeo Analisa , Narla Goutham 
Published: June 2022

Abstract
Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, encoding the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30-40% of cases, the clinical actionability of these mutations has not been studied. Here, we show that mutation to Aα results in synthetic lethality to treatment with inhibitors of ribonucleotide reductase (RNR), and multiple models of Aα mutant uterine serous tumors were sensitive to Clofarabine, an RNR inhibitor in vivo. Aα mutant cells displayed impaired checkpoint signaling upon RNRi treatment, and subsequently accumulated more DNA damage than wild type cells. This was PP2A dependent as complete inhibition of PP2A activity using LB-100, a catalytic site inhibitor, sensitized wild type USC cells to RNRi. Analysis of TCGA data indicated that inactivation of PP2A, through loss of PP2A subunit expression, was prevalent in USC, with 88% of USC patients harboring loss of at least one PP2A gene. In contrast, loss of PP2A subunit expression was rare in uterine endometrioid carcinomas. While RNR inhibitors are not routinely used for uterine cancers, we identified a cohort of patients with recurrent disease treated with gemcitabine at MSKCC as a second or later line therapy. In a retrospective analysis of this cohort there was a trend for improved outcomes in USC patients treated with RNRi gemcitabine compared to patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC.
Citation Format: Caitlin M. O'Connor, Sarah E. Taylor, Kathryn M. Miller, Lauren Hurst, Terrance J. Haanen, Tahra K. Suhan, Kaitlin P. Zawacki, Fallon K. Noto, Jonida Trako, Arathi Mohan, Jaya Sangodkar, Dmitriy Zamarin, Analisa DiFeo, Goutham Narla. Synthetic lethality by targeting ribonucleotide reductase in PP2A deficient uterine serous carcinoma [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 3341.
Abstract 3345: ERAS-601, a potent inhibitor of SHP2, synergistically enhances the activity of a FLT3 inhibitor, gilteritinib, in FLT3-mutated AML tumor models
Authors: Martin Leenus , Patel Roopal , Zhang Jingchuan , Nevarez Robin , Congdon Taylor , Brail Les , Shoemaker Robert 
Published: June 2022

Abstract
ERAS-601 is a potent, small molecule allosteric inhibitor of wildtype SHP2, a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. ERAS-601 inhibits wildtype SHP2 biochemically with an IC50 of 4.6 nM and demonstrates selectivity across panels of 300 kinases and 12 phosphatases. SHP2 mediates upstream receptor tyrosine kinase (RTK) signaling via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). ERAS-601 inhibits the SHP2 dependent cycling of KRAS from the inactive GDP-bound state to the active GTP-bound state and demonstrates anti-proliferative activity in FLT3-mutated human cancer cells. Gilteritinib is a second-generation FLT3 inhibitor and has demonstrated clinical activity, but emerging resistance limits the benefit of monotherapy. Here, we explored the combination of gilteritinib with ERAS-601 in FLT3 mutated AML nonclinical models. The combination of ERAS-601 with gilteritinib inhibits the oncogenic RAS/MAPK signaling as measured by pERK1/2 and synergistically inhibits the cellular viability of FLT3-mutated AML cells in vitro. The combination of ERAS-601 with gilteritinib achieves a more durable tumor growth inhibition than the respective gilteritinib and ERAS-601 monotherapies in vivo. These preclinical data support the clinical development of ERAS-601 in combination with gilteritinib in FLT3-altered AML.
Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent inhibitor of SHP2, synergistically enhances the activity of a FLT3 inhibitor, gilteritinib, in FLT3-mutated AML tumor models [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 3345.
Abstract 3361: Distinct biological response of uterine corpus serous and endometrioid carcinomas to obesity may contribute to differences in clinical outcomes
Authors: Wichmann Ignacio A. , Gómez Fernán , Salazar Cristián , Suárez Felipe , Kato Sumie , Cuello-Fredes Mauricio A. 
Published: June 2022

Abstract
Despite growing evidence linking obesity to the development and overall survival of cancer patients, the impact of increased body mass index (BMI) on gene expression patterns in gynecologic cancers is unclear. To address this, we herein downloaded RNAseq gene expression data from The Cancer Genome Atlas (TCGA) UCEC (uterine corpus endometrial carcinoma) dataset and matched it with clinical data entries including patient height and weight. We calculated BMI for each patient and used it to stratify patients as normoweight (BMI &lt; 25), overweight (25 ≤ BMI &lt; 30) or obese (BMI ≥ 30). BMI and nutritional status were matched to RNAseq gene expression data. Considering the known differences between endometrioid and serous uterine corpus tumors, analyses were performed separately for endometrioid (n = 356) and serous carcinomas (n = 117). Gene set enrichment analysis (GSEA) was performed between normoweight, overweight and obese patients. GSEA shows that tumors from obese patients display multiple dysregulated Gene Ontology (GO) terms (Biological Process, BP), which also differ between serous and endometrioid tumors. We further explored the impact of obesity on transcriptomic profiles of serous and endometrioid carcinomas by nutritional status independently by differential expression analysis using limma-voom. Significantly up- or downregulated genes were defined as those with logFC ≥ 1.5 at a non-adjusted P-value ≤ 0.01. Despite a clear enrichment or suppression of GO terms as evidenced by GSEA, transcriptomic analyses did not clearly separate patients according to their nutritional status. Therefore, obesity may impact on the dysregulation of biological processes through the cumulative effects of subtle differences in gene expression that, individually, do not seem to play a major role in oncogenesis. These results spotlight the relevance of obesity on the biology of uterine corpus cancers, which impact on the clinical course and treatment response of obese patients is yet to be determined. Funding: This work was supported by CONICYT FONDAP 15130011 (MC, IW), CONICYT-PFCHA/Doctorado Nacional 2019-Folio 21190421 (FG) and FONDECYT 1201083 (MC).
Citation Format: Ignacio A. Wichmann, Fernán Gómez, Cristián Salazar, Felipe Suárez, Sumie Kato, Mauricio A. Cuello-Fredes. Distinct biological response of uterine corpus serous and endometrioid carcinomas to obesity may contribute to differences in clinical outcomes [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 3361.
Abstract 3370: Fatty acid desaturase 1 (FADS1) is associated with cancer survival via altering cell growth and can be a novel drug target for cancer treatment
Authors: Heravi Gioia , Jang Hyejeong , Kim Seongho , Liu Wanqing 
Published: June 2022

Abstract
Polyunsaturated fatty acid (PUFA) plays an important role in cancer biology. Fatty acid desaturase1 (FADS1) is a key rate-limiting enzyme in omega-3 and omega-6 PUFA metabolism. We aim to investigate the association between FADS1 and survival outcomes among cancer patients. Univariable and multivariable Cox regression models were performed for FADS1 mRNA expression levels on disease-free survival (DFS) and overall survival (OS) using The Cancer Genome Atlas (TCGA) public datasets. We also investigated the pathways associated with altered FADS1 expression in the TCGA dataset. A FADS1 inhibitor (D5D-IN-326) was used to study the proliferation in vitro in 6 different cancer cell lines. FADS1-shRNA knockdown system was introduced in the renal cell carcinoma (RCC) 786-O cell line to further study the signaling pathway associated with proliferation. Transcriptomic, metabolomic, and lipidomic profiles of stable cell lines were studied. Our analysis showed that among all cancer patients (N=11,490), those with a higher FADS1 mRNA expression in their tumor have a significantly worse DFS and OS (p.value &lt;0.001 and 0.01, respectively). This association was particularly significant in RCC subtypes. Pathway analysis demonstrated that cell cycle and DNA replication were significantly enriched as the top pathways associated with FADS1 expression. Administration of FADS1 inhibitor compound 326 decreased cell proliferation in cell lines of several major cancers in a dose-dependent manner. The proliferation result was confirmed in RCC FADS1 knockdown model. RNA-seq analysis of FADS1 knockdown stable cells also showed downregulation of DNA biosynthesis, cell division, and cell proliferation. In our metabolomic study, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) was significantly reduced in FADS1 knockdown (KD) cells which may be attributed to altered purine metabolism (p-value &lt; 0.001). As we expected, the total omega-6 and omega-3 fatty acids were lower in KD cells. We further identified lower P38 phosphorylation in KD cells which is consistent with lower cell proliferation. These results suggest that FADS1 overexpression is prognostic to lower survival in cancer patients via changing cancer metabolism, which is potentially mediated via altering cell proliferation through MAPK pathway. This study has a potential to discover a new mechanism of cancer biology and develop a novel precision treatment for cancer patients. The detailed causal relationship is warranted for continued investigation.
Citation Format: Gioia Heravi, Hyejeong Jang, Seongho Kim, Wanqing Liu. Fatty acid desaturase 1 (FADS1) is associated with cancer survival via altering cell growth and can be a novel drug target for cancer treatment [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 3370.
Abstract 3376: Novel reference materials for the analysis of methylation in liquid biopsies
Authors: Ramprakash Jayanthi , Butler Matthew G. , Garlick Russell K. , Konigshofer Yves 
Published: June 2022

Abstract
Here we describe new reference materials (RMs) for liquid biopsies that are designed to mimic the methylation found in circulating cell-free DNA (ccfDNA). Methylation is an important epigenetic modification that influences cellular differentiation and gene expression. Recently, liquid biopsies have started to incorporate analyses of epigenetic modifications for screening purposes to detect cancer-derived DNA in the blood. Additionally, epigenetic modifications are being used to also assign a tissue of origin to the cancer to direct confirmatory diagnostic procedures. Obtaining sufficient amounts of ccfDNA for assay development, validation, and proficiency testing is difficult. Furthermore, methods of analyzing the epigenetic modifications, such as bisulfite conversion, can damage a significant fraction of the input material; but, failing to carry them out to completion can result in an over-estimation of methylation. To address the challenges associated with assessing the methylation of ccfDNA, we created and characterized three types of RMs. The first type of RM is a fragmented genome of the GM24385 reference cell line that is used to create a set of RMs with different degrees of methylation (0%, ~25%, ~50%, ~75% and close to 100%). The exact degree of methylation was assigned by digital PCR using assays for heterozygous SNPs, where one allele is both a site for CpG methylation and a recognition site for a methylation-sensitive restriction enzyme while the other allele is not. The second type of RM is an amplified ccfDNA sample that has been methylated similarly but also reproduces the fragment lengths and genomic representation biases of ccfDNA. The degree of methylation was assigned by digital PCR, but only a subset of assays was useful because not all SNPs were heterozygous. The third type of RM is an amplified ccfDNA sample that has been processed to mimic the methylation found in the original ccfDNA. Analyses of the RMs by whole genome sequencing (WGS) showed that, while bisulfite conversion and/or the amplification of the resulting dU-containing DNA appeared to lead to significant biases in genomic representation, the resulting data was generally in agreement with the amount of methylation assigned by digital PCR. Additionally, it was possible to prepare an RM that generally reproduces the methylation found in ccfDNA; although, this was limited to individual molecules having either no or close to full methylation, which is unlikely to be the case for all molecules of ccfDNA in vivo.
Citation Format: Jayanthi Ramprakash, Matthew G. Butler, Russell K. Garlick, Yves Konigshofer. Novel reference materials for the analysis of methylation in liquid biopsies [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 3376.
Abstract 3398: Exploring the biology of ctDNA release in colon cancer
Authors: Kisistok Judit , Henriksen Tenna Vesterman , Bramsen Jesper Bertram , Reinert Thomas , Mattesen Trine Block , Birkbak Nicolai Juul , Andersen Claus Lindbjerg 
Published: June 2022

Abstract
Background: Colorectal cancer is responsible for 9.4% of cancer-related deaths worldwide. Early detection of the disease has the potential to improve patient outcomes, therefore, developing an efficient and minimally invasive method for carrying out surveillance has been a clinically relevant effort in recent years. Circulating tumour DNA has garnered interest as a marker for early cancer detection, however, deeper understanding of the underlying biology of ctDNA release is needed in order to maximize its utility in clinical practice. In this project, we aimed to investigate whether a phenotype conductive to ctDNA shedding can be defined in a colorectal cancer cohort, including transcriptomic, genomic and clinical data collected from stage I to stage IV colon cancer patients at Aarhus University Hospital.
Methods: Transcriptomic data from 102 patients and whole exome sequencing data from 60 patients were analyzed. Differential gene expression and differential pathway enrichment analyses between ctDNA positive and ctDNA negative patients were conducted by performing Student’s t-test. The resulting p-values were adjusted according to the Benjamini-Hochberg method. The genes in the transcriptomic analyses were assigned to pathways with regard to the MSigDB Hallmark gene sets and pathway enrichment was assessed using Gene Set Variation Analysis (GSVA). Using an extended cohort of 537 patients, we performed Wilcoxon’s signed rank test to investigate the association between tumour size, histological subtypes and ctDNA shedding behavior. Additionally, we modelled the expected ctDNA fraction as a function of birth rate, death rate and tumour mass.
Results: In colon cancer, ctDNA release is primarily associated with tumour size, molecular subtypes and proliferative transcriptomic signatures. A moderate but significant correlation was observed between the tumour’s largest diameter and the detected ctDNA fraction. Furthermore, molecular subtypes associated with less aggressive disease tended to shed lower amounts of ctDNA. Notably, we have found that pathways associated with proliferation are enriched in the ctDNA positive subgroup.
Conclusions: Our results demonstrate that enhanced proliferative capacity in connection with tumour size and molecular subtypes may contribute to a higher ctDNA release rate. We anticipate our study to be a starting point for further investigation of ctDNA shedding dynamics in colorectal cancer.
Citation Format: Judit Kisistok, Tenna Vesterman Henriksen, Jesper Bertram Bramsen, Thomas Reinert, Trine Block Mattesen, Nicolai Juul Birkbak, Claus Lindbjerg Andersen. Exploring the biology of ctDNA release in colon cancer [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 3398.