bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1949: Circulating tumor cells presence shorten the cancer specific survival in colorectal cancer: 10 years follow-up study
Authors: Srovnal Josef , Skalicky Pavel , Rehulkova Alona , Vyslouzil Kamil , Vidlarova Monika , Vrbkova Jana , Hajduch Marian 
Published: June 2022

Abstract
Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide and metastases-related death is the main cause of its high mortality. Circulating/disseminated tumor cells (CTCs/DTCc) are considered as precursors of distant metastatic spread and can act as an independent prognostic biomarker. The impact of CTCs/DTCs presence in perioperative period on long-term cancer specific survival (CSS) was assessed.
Patients and methods: The presence of CTCs/DTCs in peripheral blood, tumor-draining blood, and bone marrow of 188 colorectal cancer patients was analyzed before, immediately after, and one month after surgery using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) to detect the carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) mRNA-positive CTCs. The trial was registered at ClinicalTrials.gov (NCT 03337347), patients were followed-up and the cause of death was determined.
Results: Over a median follow-up period of 116.5 months, 81 of 148 (54.7%) stage I-III CRC patients died. In total, 40.7% of them (33/81) died of cancer. The presence of CTCs/DTCs did not correlate with any conventional clinical or pathological features (tumor node metastasis (TNM) stage, grade, KRAS mutations or microsatellite instability). Patients with CTCs/DTCs in the peripheral blood and bone marrow one month after surgery had significantly shorter CSS (p=0.013, HR=2.6; resp. p=0.019, HR=2.3) than those without CTCs/DTCs. Shorter overall survival was also observed in patients with tumor-draining blood CEA mRNA-positive CTCs before surgery (p=0.014).
Conclusion: The presence of CK20 mRNA-positive CTCs/DTCs in blood and bone marrow after surgery was confirmed as an independent negative prognostic factor for the long-term cancer-specific survival in stage I-III colorectal cancer patients.The study was supported by Ministry of Health of the Czech Republic (NV18-03-00470), Ministry of Education, Youth and Sport of the Czech Republic (LM2018132; LM2018133), Palacky University Olomouc (LF 2021_019) and European Regional Development Fund (ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868, ACGT CZ.02.1.01/0.0/0.0/16_026/0008448).
Citation Format: Josef Srovnal, Pavel Skalicky, Alona Rehulkova, Kamil Vyslouzil, Monika Vidlarova, Jana Vrbkova, Marian Hajduch. Circulating tumor cells presence shorten the cancer specific survival in colorectal cancer: 10 years follow-up study [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 1949.
Abstract 2052: LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses, tumor inhibition, and provides rationale for first-in-human trial
Authors: Rosean Claire Buchta , Karkada Mohan , Koelle David M. , Nghiem Paul , Heiland Teri 
Published: June 2022

Abstract
The majority of Merkel cell carcinomas (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of a truncated form of the viral large T antigen (LT) in infected cells and thus making LT an attractive target for therapeutic cancer vaccines. We designed a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPγV-LT. To activate antigen-specific CD4+ T cells in vivo, we utilized our nucleic acid platform, UNITE࣪ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and a balanced T cell response. LTS220A, encoding a mutated form of MCPγV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE࣪ platform. In pre-clinical studies, vaccination with LTS220A-UNITE࣪ (ITI-3000) induced antigen-specific CD4+ T cells that were sufficient to delay tumor growth, and this effect was dependent on their ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including significantly enhanced numbers of CD4+ and CD8+ T cells as well as NK and NKT cells. These findings strongly suggest that in pre-clinical studies, DNA vaccination using the UNITE࣪ platform enhances CD4+ T cell responses to MCPγV-LT that result in significant anti-tumor immune responses. We are planning a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC. Patients will receive up to four intramuscular vaccinations of 4mg of ITI-3000 using the PharmaJet Stratis® needle-free injection system. The primary objectives will be safety and tolerability, observing dose-limiting toxicities, serious adverse events, standard clinical assessments, and safety laboratory parameters. Immunogenicity of the vaccine will be measured by peripheral blood assessments of T cell activation using ELISpot and flow cytometry assays.
Citation Format: Claire Buchta Rosean, Mohan Karkada, David M. Koelle, Paul Nghiem, Teri Heiland. LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses, tumor inhibition, and provides rationale for first-in-human trial [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 2052.
Abstract 2089: Evaluating in vivo efficacy of anti-TSLP antibodies in humanized B-hTSLP/hTSLPR mice
Authors: Zhang Shujin , Nie Yanhui , Chang Jiahui , Chromikova Veronika , Yu Luke (Zhaoxue) , Kuraguchi Mari 
Published: June 2022

Abstract
Expression of the epithelial cytokine, thymic stromal lymphopoietin (TSLP), has been observed across several barrier surfaces and plays a critical role in both physiological and pathological processes. Via T helper (Th) 2 cytokine production, TSLP has been implicated in asthma, atopic dermatitis, inflammatory bowel disease, multiple sclerosis, and chronic obstructive pulmonary disease. This range in which TSLP exerts its effects on inflammatory diseases makes the TSLP/TSLPR axis an attractive therapeutic target. At Biocytogen, we generated a novel TSLP/TSLPR double humanized mouse model that enables in vivo assessment of human anti-TSLP and anti-TSLPR antibodies. In our B-hTSLP/hTSLPR mice, the murine Tslp and Tslpr genes are replaced with the human TSLP and TSLPR genes by homologous recombination. ELISA analysis showed that human TSLP (after induction with calcipotriol) was exclusively detectable in homozygous B-hTSLP/hTSLPR mice compared to wild type mice. Similarly, flow cytometry analysis indicated TSLPR expression was detectable in monocytes, neutrophils, macrophages, total DCs, cDC1, cDC2, Mo-DC and Pre-DC. Percentages of T cells, B cells, NK cells, DCs, granulocytes, monocytes, macrophages, CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hTSLP/hTSLPR mice were comparable to those in the wild type mice, demonstrating that introduction of human TSLP and TSLPR in place of their mouse counterparts did not impair the overall development, differentiation, or distribution of these cell types. Furthermore, using an asthma mouse model via induction with ovalbumin (OVA), we showed that an anti-TSLP antibody (Tezepelumab, synthesized in house) was efficacious in controlling asthma progression in B-hTSLP/hTSLPR mice. Altogether, B-hTSLP/hTSLPR mice are a promising model for preclinical in vivo pharmacodynamic assessment of TSLP antibodies.
Citation Format: Shujin Zhang, Yanhui Nie, Jiahui Chang, Veronika Chromikova, Luke (Zhaoxue) Yu, Mari Kuraguchi. Evaluating in vivo efficacy of anti-TSLP antibodies in humanized B-hTSLP/hTSLPR mice [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 2089.
Abstract 2093: PEGylated IL-2 with enhanced anti-tumor efficacy and safety profile
Authors: Song Yuntao , Li Hui , Zhang Wei , Fu Dayan , Xu Meng 
Published: June 2022

Abstract
Introduction: Interleukin-2 (IL-2) can activate and expand tumor killing lymphocytes. High doses of IL-2 are needed to activate CD8+ T cells. Severe toxic side effects associated with high doses, as well as the poor PK profile of IL-2, have limited its clinical usage. Various strategies have been employed to prolong half-lives of IL-2 and enable selectivity or bias towards receptor binding to reduce toxicity and maintain good efficacy. Among these, certain PEGylation strategies have generated promising clinical results, but also showed some major limitations. We report a unique PEGylation strategy to produce PEGylated IL-2 with a therapeutic window more than two times larger than the reference PEGylated IL-2.
Methods: CT26 murine syngeneic model was used for evaluation of in vivo efficacy and safety. Each 6-8 weeks old female BALB/c mouse was inoculated subcutaneously in the right front flank region with CT26 tumor cells (5 x 105). Tumors were allowed to grow to mean size ~110 mm3 before randomization and treatment. Body weights and tumor volumes were measured three times per week. The tumor-free mice at the end of the study were re-challenged with CT26 colon tumor cells on the left side.
Results: Utilizing our proprietary PEGylation technology, rhIL-2 was covalently connected with multiple PEG polymers through releasable linkers (RL). The releasable linkers are designed to modulate the release rate of the active IL-2 species. In CT26 syngeneic mouse model, CS-PEG-IL-2 showed significantly enhanced efficacy and safety over IL-2 and reference PEGylated IL-2. rhIL-2 (2 mg/kg, bid x 5, two cycles, i.p.) resulted in complete response (CR) in one out of eight (1/8) mice, while 3 mg/kg dose resulted in death in 8/8 mice. With the reference PEGylated IL-2, 3/8 CR were obtained at 3 mg/kg dose (q1w x 4, i.v.), and 6 mg/kg dose resulted in death in 8/8 mice. Whereas, with three CS PEGylated IL-2 analogs, 5/8 and 6/8 CR were achieved at 3 mg/kg and 6 mg/kg dose respectively, and no obvious toxicity was observed even at the highest dose. After re-challenged with another inoculation of CT26 cancer cells, the CR mice remained tumor-free until the end of the study at day 158.
Conclusions: CS unique PEGylation strategy generated PEG-IL-2 with superior anti-tumor efficacy and safety profiles. Preclinical results support clinical evaluation of this novel class of PEGylated IL-2 analogs.
Citation Format: Yuntao Song, Hui Li, Wei Zhang, Dayan Fu, Meng Xu. PEGylated IL-2 with enhanced anti-tumor efficacy and safety profile [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 2093.
Abstract 2151: Identification and proteogenomic characterization of novel lung adenocarcinoma subtypes with therapeutic relevance
Authors: Roh Whijae , Geffen Yifat , Miller Mendy , Anand Shankara , Kim Jaegil , Heiman David , Meyerson Matthew , Laird Peter , Cherniack Andrew ,   NCI CCG Tumor Molecular Pathology (TMP) Analysis Working Group, Getz Gad 
Published: June 2022

Abstract
Lung adenocarcinoma (LUAD) is one of the most common cancer types with various available treatment modalities. However, better biomarkers of response are still needed for further improving precision medicine. Therefore, a robust LUAD subtyping can substantially aid in determining the most effective therapies that target subtype-specific vulnerabilities. In this study, we integrated multiple datasets: (i) the full 509 LUAD patient cohort from The Cancer Genome Atlas (TCGA) project, (ii) cancer vulnerability data in LUAD cell lines from the Broad Institute’s DependencyMap, and (iii) proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) LUAD patients. Using these datasets, we identified 5 expression subtypes (S1-S5) with unique proteogenomic and dependency profiles that increased the resolution of previously defined subtypes (Proximal Inflammatory [PI]; Proximal Proliferative [PP]; and Terminal Respiratory Unit [TRU]). S4-associated cell lines exhibited specific vulnerability to CDK6 and CDK6-cyclin D3 complex gene, CCND3. S3 was characterized by dependency on CDK4, immune-related expression patterns, and altered MET signaling. Experimental validation showed that S3-associated cell lines responded to MET inhibitors, which also led to increased PD-L1 expression. Finally, we identified a small set of biomarkers for S3 and S4 that could be used in the clinic to classify patients into our therapeutically relevant subtypes. Overall, our lung adenocarcinoma expression subtypes, especially S3 that represents 20% of LUAD patients and S4 that represents 25% of LUAD patients, and their biomarkers could help identify patients likely to respond to CDK4/6, MET, or PD-L1 inhibitors, potentially improving patient outcome.
Citation Format: Whijae Roh, Yifat Geffen, Mendy Miller, Shankara Anand, Jaegil Kim, David Heiman, Matthew Meyerson, Peter Laird, Andrew Cherniack, NCI CCG Tumor Molecular Pathology (TMP) Analysis Working Group, Gad Getz. Identification and proteogenomic characterization of novel lung adenocarcinoma subtypes with therapeutic relevance [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 2151.
Abstract 2159: PRMT5 inhibitor PRT543 displays potent antitumor activity in U2AF1S34F and RBM10LOF spliceosome-mutant non-small cell lung cancer in vitro and in vivo
Authors: Carter Jack , Ito Koichi , Thodima Venkat , Sivakumar Monisha , Hulse Michael , Rager Joseph , Vykuntam Komali , Bhagwat Neha , Vaddi Kris , Ruggeri Bruce , Scherle Peggy 
Published: June 2022

Abstract
PRMT5 (protein arginine methyltransferase 5) is a major Type II PRMT, which catalyzes the symmetric dimethylation of protein arginine residues (sDMA). As an epigenetic regulator, PRMT5 plays essential roles in promoting cancer growth and survival, including through mechanisms that control alternative splicing and RNA processing, and the expression of DNA damage repair genes. Spliceosome mutations have been suggested to represent a potential biomarker for PRMT5 inhibitors, and our previous work highlighted this sensitivity in SF3B1R625C/G expressing uveal melanoma cells. Here, we highlight in vitro and in vivo activity of PRT543, a potent, selective, and orally available PRMT5 inhibitor, in cancer cells harboring mutations in other spliceosome factors such as U2 small nuclear RNA auxiliary factor 1 (U2AF1) and RNA binding motif protein 10 (RBM10). Mutations in U2AF1 (including S34F hotspot mutations) and RBM10 (primarily loss of function (LOF) mutations) occur in 5-10% of all non-small cell lung cancers (NSCLC). Cell proliferation (10-day assay) was assessed in a panel of NSCLC cell lines treated with PRT543, either wild-type or harboring U2AF1S34F or RBM10LOF mutations. Strikingly, both U2AF1S34F and RBM10LOF cell lines were significantly more sensitive to PRT543 compared to wild-type cell lines. Furthermore, PRT543 induced significant dose-related tumor growth inhibition at well-tolerated doses in cell-line derived xenograft (CDX) models harboring the U2AF1S34F or RBM10LOF mutation. Consistent with our previous findings in other tumor types, PRT543 decreased expression of DNA damage repair-associated genes (e.g. BRCA1, RAD51AP1, FANCA, and FANCL) in U2AF1S34F or RBM10LOF mutant NSCLC cells. Combination with PRT543 increased the effectiveness of specific chemotherapeutic agents in both in vitro and in vivo (CDX) models of U2AF1S34F and RBM10LOF NSCLC. Efficacy studies in patient-derived xenograft (PDX) models, as well as genomic profiling of spliceosome-mutant cellular models in response to PRT543 are ongoing. PRT543 is currently under evaluation in a Phase I clinical trial in patients with advanced solid tumors and hematological malignancies (NCT03886831).
Citation Format: Jack Carter, Koichi Ito, Venkat Thodima, Monisha Sivakumar, Michael Hulse, Joseph Rager, Komali Vykuntam, Neha Bhagwat, Kris Vaddi, Bruce Ruggeri, Peggy Scherle. PRMT5 inhibitor PRT543 displays potent antitumor activity in U2AF1S34F and RBM10LOF spliceosome-mutant non-small cell lung cancer in vitro and in vivo [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 2159.
Abstract 2177: Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells
Authors: Apiz-Saab Juan , Muir Alex 
Published: June 2022

Abstract
Arginine is an amino acid critical for various cellular processes, not only protein synthesis but also metabolism of other essential metabolites, like polyamines, as well as a signaling factor for pathways such as the growth regulator mTOR. Previously, our group measured arginine levels in the interstitial fluid of tumors (TIF) of pancreatic ductal adenocarcinoma (PDAC) murine models and found extremely low arginine levels (2-5 uM) in the tumor microenvironment (TME). Despite near complete absence of this critical nutrient in the TME, pancreatic tumors exhibit aggressive growth. We have sought to understand both how the PDAC TME becomes arginine limited and how PDAC cells adapt to proliferate in the absence of arginine. Using genetically engineered mice, we find that arginase activity in the myeloid compartment of PDAC tumors is responsible for arginine depletion in the TME. Staining of Arg1+ myeloid populations in human PDAC samples suggest a similar mechanism reduces arginine availability in human PDAC tumors as well. We then leveraged our newfound knowledge of PDAC TIF composition to develop a novel ex vivo cell culture media formulation with physiologically relevant nutrient levels and monitored arginine acquisition pathways using isotope tracing and metabolomics assays to determine how PDAC cells cope with arginine deprivation. Under TME nutrient conditions, PDAC cells consume available citrulline and use it to produce arginine by de novo synthesis. Starving cells of citrulline or genetically perturbing arginosuccinate synthase (ASS1), key enzyme in arginine biosynthesis, significantly reduces PDAC cellular arginine and proliferative capacity. Immunohistochemical analysis of both human and mouse PDAC tumors indicates that the de novo arginine synthesis pathway is highly expressed in PDAC but not in untransformed pancreas, suggesting a key role for this pathway in PDAC progression. Altogether, we find that myeloid-derived arginase challenges PDAC cells by limiting arginine availability and suggest that de novo arginine synthesis may be a critical metabolic pathway that enables PDAC tumors to cope with this metabolic challenge.
Citation Format: Juan Apiz-Saab, Alex Muir. Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells [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 2177.
Abstract 2178: Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity
Authors: Lilly Anna C. , Surumbayeva Aizhan , Nguyen Theodore , Astsaturov Igor , Golemis Erica A. 
Published: June 2022

Abstract
High levels of dietary fats are associated with pancreatitis, diabetes, and pancreatic cancer. Sterol regulatory element binding protein Cleavage-Activating Protein (SCAP) is an essential intermediate in lipid-regulated activation of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, which induce expression of genes regulating lipid homeostasis. We previously demonstrated that the elevated SREBP1 arising from inhibition of the cholesterol biosynthetic pathway in mice genetically predisposed to pancreatic cancer additionally transcribed genes that induced epithelial-mesenchymal transition, promoting basal rather than glandular cancer. To further evaluate SCAP and SREBP function in the pancreas, we developed a new mouse model with selective pancreatic knockout of the Scapf/f gene under the control of the Pdx1-Cre promoter (ScapΔpanc mice).
Although size of the pancreas in ScapΔpanc neonates was unaffected, and number of islets was normal, there was a reduced number of acinar cells, and some evidence of disorganized tissue structure. Preliminary histopatholgical assessment of pancreatic tissue of ScapΔpanc neonates indicated no acinar cell apoptosis, and unimpaired acinar proliferation, suggesting loss of Scap may cause a differentiation defect. Further supporting this idea, siRNA depletion of Scap in the rat AR42J acinar cell line resulted in loss of markers of mature acinar cell identity. ScapΔpanc pancreata underwent progressive and selective loss of acinar cells as mice aged, with three-month old mice having large areas of acinar cell loss, and mislocalization of ductal cells. Coupled with this loss was a large increase in pancreatic adipocytes and mesenchymal cells, resulting in a highly disorganized tissue morphology accompanied by signs of inflammation. These phenotypes were exacerbated in mice maintained on high fat or high carbohydrate diet. Together, these results imply that SCAP and SREBP signaling in the pancreas plays an important role in mediating dietary modulation of pancreatic development, acinar cell homeostasis, and restraint of pancreatic adiposity. Intrapancreatic fat, associated with obesity and chronic pancreatitis, is a known risk factor for pancreatic cancer, and SCAP polymorphisms have been to interact with diet in regulating obesity and blood pressure in humans; we propose SCAP-SREBP signaling in the pancreas may mediate dietary promotion of pancreatic cancer risk.
Citation Format: Anna C. Lilly, Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, Erica A. Golemis. Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity [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 2178.