bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1047: Plasma KRAS mutations as predictive biomarkers for pancreatic cancer in high-risk group
Authors: Cervena Klara 
Published: April 2023

Abstract
Pancreatic cancer (PANC) has among solid malignancies one of the lowest 5-years survival rates - less than 10%. To improve the prognosis of PANC, it is necessary to develop tools that will enable earlier diagnosis. More than 90% of PANC cases are characterized by the presence of KRAS mutations in tumor tissue that play a critical role in the initiation of PANC. Recently, attention has been focused on liquid biopsy which can better reflect the whole genetic profile of the tumor and may enable early diagnosis.
Our study aims to discover whether KRAS gene mutations can be detected in the plasma isolated from the PANC risk group patients - diabetes mellitus II (DMII) and chronic pancreatitis (CP). The KRAS mutations were analyzed in 34 PANC, 89 DMII, and 31 CP patients by droplet digital PCR. Plasma cell-free DNA was investigated for three mutations hotspots: KRAS p.G12D c.35G&gt;A, p.G12V c.35G&gt;T, p.G12R. Detailed results of the study are currently under evaluation and will be presented during the meeting. We believe that these results discover whether plasma analysis of KRAS mutation can serve as a biomarker for early diagnosis of malignant transformation in risk group patients.
Supported by grant AZV NU-21-07-00247, by Czech science Foundation 22-05942S and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102).
Citation Format: Klara Cervena. Plasma KRAS mutations as predictive biomarkers for pancreatic cancer in high-risk group [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 1047.
Abstract 1048: Enabling higher sensitivity liquid biopsies with multiplex digital PCR NSCLC-relevant drug resistance panels
Authors: Granitsiotis Michael , Gutierrez Kimberly , Wang Youxiang , Li Jialuo , Yang Zhijie 
Published: April 2023

Abstract
Cancers, for example, non-small cell lung cancer (NSCLC) and colorectal cancer, are frequently associated with specific genetic mutations that serving as biomarkers to guide more specific treatments (targeted therapy). The most frequently mutated genes include EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MET, etc. Unfortunately, screening and monitoring the most common cancer related mutations and identifying the breadth of the most common drug-resistant mutations in MRD monitoring has previously required NGS - but cost, and time for execution, limits testing frequency. Furthermore, sensitivity is typically 1-5% VAF, thus limiting early detection. While digital PCR (dPCR) can be run at a fraction of the cost, and with higher sensitivity (VAFs of 0.1 to 0.01%), due to the lack of high level of multiplexing, it was historically impractical for routine screening. Here, we show that the use 6-color naica® system (Stilla Technologies), incorporating a series of high multiplex panels developed by Atila BioSystems, is able to group and efficiently detect the most frequently druggable mutations in a single reaction within three hours. Furthermore, we are demonstrating the coverage, precision, and sensitivity necessary to make high-plex digital PCR a viable option for future liquid biopsy testing.
Citation Format: Michael Granitsiotis, Kimberly Gutierrez, Youxiang Wang, Jialuo Li, Zhijie Yang. Enabling higher sensitivity liquid biopsies with multiplex digital PCR NSCLC-relevant drug resistance panels [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 1048.
Abstract 1075: Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer
Authors: Waters Andrew Michael , Chang Wen-Hsuan , Stalnecker Clint , Edwards Cole , Yang Runying , Goodwin Craig M. , Cox Adrienne D. , Der Channing J. 
Published: April 2023

Abstract
KRAS mutations occur in 95% of pancreatic ductal adenocarcinomas (PDAC) and are a well-validated driver of PDAC growth. Therefore, anti-KRAS therapies are expected to make a significant impact on the treatment of this deadly cancer, where there are currently no effective targeted therapies. Supporting this premise, early clinical trial results with KRASG12C inhibitors have shown promising disease control rates (84-100%) in KRASG12C-mutant PDAC. Despite these observations, two key issues limit the impact of KRASG12C inhibitors in PDAC. First, KRASG12C(OFF) mutations comprise less than 2% of KRAS mutations in PDAC. Second, patients initially responsive to KRASG12C inhibitors invariably relapse due to treatment-induced resistance. To begin qualifying KRAS inhibitors that target KRAS mutations more frequently found in PDAC, we characterized a RAS inhibitor that targets the multiple KRAS mutations as well as wild-type RAS proteins. We evaluated the impact of this inhibitor on RAS signaling and anti-proliferative activity in KRAS-mutant pancreatic cancer human cell lines and in a panel of RASless MEFs (ras-null mouse embryo fibroblasts) stably expressing exogenous RAS mutant proteins that are commonly found in PDAC. To identify genetic mechanisms of resistance to KRAS inhibition in pancreatic cancer, we applied CRISPR-Cas9 loss-of-function screens to KRASG12C-, KRASG12D-, KRASG12R-, and KRASQ61H-mutant PDAC cells treated with KRAS inhibitors to identify genes that modulate KRAS inhibitor anti-proliferative activity. We identified expected and novel mechanisms of resistance, including those that have been observed in patients treated with KRASG12C inhibitors.
Citation Format: Andrew Michael Waters, Wen-Hsuan Chang, Clint Stalnecker, Cole Edwards, Runying Yang, Craig M. Goodwin, Adrienne D. Cox, Channing J. Der. Identification of resistance mechanisms to direct KRAS inhibition in pancreatic 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 1075.
Abstract 1078: Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines
Authors: Hernandez-Pedro Norma Yanet , Barrios-Bernal Pedro , Lucio-Lozada José , Ramos-Ramirez Maritza , Arrieta Oscar 
Published: April 2023

Abstract
KRAS is the most frequently mutated oncogene in lung adenocarcinoma (50%) and it is associated with a poor response to antineoplastic treatments, as well as poorer survival rates. KRAS activates the MAPK pathway, promoting cell survival and increasing protein synthesis. Novel inhibitors of KRAS G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to avoid this inconvenience by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the mTOR pathway in lung cancer cell lines with or without KRAS mutations.
Methods: We performed dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin. Then, these doses were used to treat lung cancer cell lines A549 (KRAS G12S), H522 (without KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by MTT assay, apoptosis induction through flow cytometry with Annexin V and 7AAD, and the activity of P70S6K and AKT proteins by western blot. Main outcomes and measures: cell survival, apoptosis, expression, and phosphorylation of intermediaries belonging to the mTOR pathway.
Results: The combined treatment showed a synergic effect on cytotoxicity, increased apoptosis induction, and notable inhibition of AKT and P70S6K1 proteins, compared to sotorasib alone or to control groups in all the cell lines, but predominantly in KRAS-mutated cells (H23 and A549).
Conclusions: The combination of metformin with sotorasib showed synergic effects on cytotoxicity, increased apoptosis induction, and a remarkable inhibition of downstream proteins involved in the signaling of growth factor receptors in all tested cells. Moreover, these results suggest a sensitizing effect of metformin to sotorasib treatment in cells without KRAS mutations, such as H522.
Citation Format: Norma Yanet Hernandez-Pedro, Pedro Barrios-Bernal, José Lucio-Lozada, Maritza Ramos-Ramirez, Oscar Arrieta. Sotorasib and metformin combination enhances cytotoxicity and apoptosis in KRAS mutant lung cancer cell lines [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 1078.
Abstract 1089: High grade serous ovarian cancer: Detecting stemness and EMT levels in response to chemo and radiation therapy
Authors: Jung Yeonkyu , Keniston Aaron , Antonissen Ashley , Morcos Ann , Bertucci Antonella , Vazquez Marcelo , Unternaehrer Juli 
Published: April 2023

Abstract
High-Grade Serous Ovarian Cancer (HGSOC) is the most fatal of gynecological cancers. The recurrence rate of HGSOC after treatment is more than 80%. The available treatment options for HGSOC are limited; standard of care includes surgery combined with chemotherapy, with radiation therapy in some advanced cases. Both chemotherapy and radiation therapy are known to induce tumor cell aggressiveness. Many cancer studies have demonstrated that cancer stem cells (CSCs) and the epithelial-mesenchymal transition (EMT) promote cancer aggressiveness, invasion, metastasis, and drug resistance. Therefore, to better understand the cause of the poor prognosis in HGSOC, our objective is to scrutinize the role of CSCs and EMT in chemo- and radiation resistance. To lead our inquiry, we utilized the SORE6 reporter to identify Sox2/Oct4 expression, which indicates the stemness, and the Zeb1 3’ UTR reporter to detect EMT. Using flow cytometry, we quantified the reporter activity in 10 ovarian cancer cell types, including chemo-sensitive and chemo-resistant ones, considering both cell lines and patient-derived cells. Chemo-resistant cells are grown under cisplatin treatment. We exposed some of these ovarian cancer cell lines to 0, 1, 2, 4 and 8Gy of 250 MeV proton and 6 MeV photon beams, then analyzed the reporter activity 72 hours post-radiation. Our findings exhibit that chemo-resistant cells express higher stemness and EMT levels than chemo-sensitive cells and have higher resistance to radiation. These reporters can detect radiation-induced stemness and EMT. Furthermore, stemness and EMT levels positively correlate with the radiation dosage increment. We conclude that these reporters are an efficient surrogate for detection of stemness and EMT and can be used to test strategies for prevention of therapy-induced aggressive phenotypes.
Citation Format: Yeonkyu Jung, Aaron Keniston, Ashley Antonissen, Ann Morcos, Antonella Bertucci, Marcelo Vazquez, Juli Unternaehrer. High grade serous ovarian cancer: Detecting stemness and EMT levels in response to chemo and radiation therapy [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 1089.
Abstract 1091: MDM2 inhibition as a novel radio-sensitizing strategy for endometrial cancer
Authors: Petty Aaron , Yard Brian , Durmaz Arda , Scott Jacob , Vargas Roberto 
Published: April 2023

Abstract
Introduction: As opposed to other malignancies, the majority of endometrial cancer (EC) cases are wild-type for TP53. Approximately 15% of TP53-mutated EC have heterozygous mutation, preserving a fraction of wild-type signaling. Given the demonstrated impact of p53 signaling on radiotherapy (RT) response in EC, we explored the role of MDM2 inhibition as a novel radio-sensitizing strategy for EC.
Methods: To assess the impact of MDM2 inhibition on cell viability and radiation response, we employed 3 parental EC cell lines of differing TP53 status (JHUEM2, Hec108, Hec1B), as well as monoclonal isolates of JHUEM2 after TP53 knockout. An intron-targeting approach facilitated TP53 cDNA complementation. Radiation response was determined by assessing cell viability with CellTiter-Glo and calculating area under the curve (AUC) with multiple dose points. Nutlin-3 and AMG-232 were both tested. All experiments were carried out in triplicate. Highest Single Agent (HSA) analysis was used to determine additive versus synergistic effects.
Results: Nutlin-3 and AMG-232 were both observed to have a negative impact on cell viability, dependent on TP53 context. In the wild-type TP53 cell line (JHUEM2), IC50s for Nutlin-3 and AMG-232 were observed to be 1.417 and 0.218 μM, respectively. The heterozygous TP53-mutated cell line, Hec108, had corresponding IC50s of 6.04 and 1.10 μM. The Hec1B cell line did not exhibit a response to either drug. Subsequently, IC50 curves were calculated in the presence of multiple dose points of gamma irradiation administered as one fraction. A synergistic effect was observed with Nutlin-3 and AMG-232 in JHUEM2, while only AMG-232 reached synergy in Hec108.
Conclusions: Overall, these findings nominate MDM2 inhibitors as potential radio-sensitizing strategies that would be applicable to a large proportion of EC. Given the lack of benefit from cisplatin-based radio-sensitization for recurrent EC in a recent clinical trial, this provides a novel biomarker driven strategy.
Citation Format: Aaron Petty, Brian Yard, Arda Durmaz, Jacob Scott, Roberto Vargas. MDM2 inhibition as a novel radio-sensitizing strategy for endometrial 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 1091.
Abstract 1094: 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model
Authors: Roy Sanjit , Dukic Tijana , Bhandary Binny , Molitoris Jason , Ko Young H , Shukla Hem D 
Published: April 2023

Abstract
Pancreatic cancer (PC) is the deadly cancer in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of only 8%. Pancreatic cancer is characterized by dense fibrotic stroma that constitutes up to 90% of the total tumor volume and contains extracellular matrix (ECM), immune cells, vasculature, and cancer-associated fibroblasts which are hallmark of immunosuppressive tumor microenvironment. In present investigation we have tested anti-cancer effect of 3-BromoPyruvate (3-BP), an inhibitor of aerobic glycolysis employing Panc-2 cancer cells, and syngeneic pancreatic cancer mouse model. Panc-2 cancer cells treated with 40 uM of 3-BP showed significant inhibition in cell proliferation and ATP production. Cells treated with 60 uM dose level, showed drastic phenotypic changes (membrane blebbing) within 2 hours of treatment. The qRT PCR data showed 3BP inhibited hexokinase II (HK2) expression at 40uM, suggesting 3-BP regulate HK2 expression at transcriptional level. We also observed that 3-BP in combination with low doses of irradiation was more effective in killing cancer cells than 3-BP alone in both 2D and 3D culture model. Treatment of C57BL/6 subcutaneous pancreatic tumor model with 10 and 20 mg/kg of 3BP also showed significant reduction of tumor growth. The Transmission Electron Microscopy of tumor tissues treated with 3-BP revealed severely damaged mitochondrial structure which might have severely affected ATP generation in cancer cell. Altogether, the results in this study demonstrated that 3-BP could be a promising anti-tumor drug against pancreatic cancer and its efficacy could be improved in combination with radiation therapy.
Citation Format: Sanjit Roy, Tijana Dukic, Binny Bhandary, Jason Molitoris, Young H Ko, Hem D Shukla. 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model [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 1094.
Abstract 1134: Therapeutic potential of an antibody-drug conjugate directed against a tumor-specific epitope on podocalyxin
Authors: Dean Pamela M. Austin , Hernaez Diana Canals , Brassard Julyanne , Hughes Michael R. , Bell Erin M. , McNagny Kelly M. , Roskelley Calvin D. 
Published: April 2023

Abstract
Podocalyxin (Podxl) is a cell surface sialomucin that is frequently upregulated in tumors with high metastatic potential and its expression is associated with poor outcome in several human cancers. As such, Podxl is emerging as an important prognostic and theragnostic marker. While Podxl is expressed on normal vascular endothelia and kidney podocytes, we sought to produce a novel anti-Podxl antibody that selectively recognizes a tumor-restricted glycoepitope on the extracellular mucin domain of Podxl. The antibody we have produced, PODO447, is specific to the tumor glycoform of Podxl, demonstrated by a lack of binding to normal tissues that are known to express Podxl. In contrast, we show binding of the antibody to tumor cell lines, patient-derived cell lines, and primary tumor tissues. We have previously shown that the majority of tumors in an ovarian carcinoma array (219 cases), including 65% of the high-grade serous histotype, are positive for PODO447. Here, we further show the presence of PODO447 in tumors of the breast, urothelium, pancreas, endometrium, colon, prostate, lung (both small cell and non-small cell), and glioblastoma. To assess the therapeutic potential of our antibody as an antibody drug conjugate (ADC), we coupled PODO447 to the microtubule disruptor monomethyl auristatin E (MMAE) with an enzyme cleavable linker carbamoyl p-aminobenzyl carbamate (PABC), resulting in the ADC PODO447-Vedotin. We demonstrate promising in vitro activity of the ADC to various human tumor cell lines as well as in vivo efficacy to xenografted ovarian and pancreatic tumor lines. Our data reveals PODO447-Vedotin as a tumor-specific and highly efficacious therapeutic agent for the targeting of human tumors and as such, PODO447 exhibits potential for further development as a targeted clinical immunotherapy.
Citation Format: Pamela M. Austin Dean, Diana Canals Hernaez, Julyanne Brassard, Michael R. Hughes, Erin M. Bell, Kelly M. McNagny, Calvin D. Roskelley. Therapeutic potential of an antibody-drug conjugate directed against a tumor-specific epitope on podocalyxin [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 1134.
Abstract 1161: Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
Authors: Bennett Neal K. , Nakaoka Hiroki J. , Laurent Danny , Okimoto Ross , Sei Yoshitaka , Horvai Andrew E. , Bivona Trever G. , Batsios Georgios , Viswanath Pavithra , Hoeve Johanna ten , Graeber Thomas G. , Nakamura Ken , Nakamura Jean L. 
Published: April 2023

Abstract
The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells downregulate glycolytic mechanisms. Metabolic shifts associated with silencing mito-respiratory genes can be detected in vivo with metabolic imaging. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors.
Citation Format: Neal K. Bennett, Hiroki J. Nakaoka, Danny Laurent, Ross Okimoto, Yoshitaka Sei, Andrew E. Horvai, Trever G. Bivona, Georgios Batsios, Pavithra Viswanath, Johanna ten Hoeve, Thomas G. Graeber, Ken Nakamura, Jean L. Nakamura. Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function [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 1161.