bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA10: Multiscale simulations of k-Ras on lipid bilayers
Authors: Streitz Frederick H. 
Published: June 2021

Abstract
Simulating proteins on lipid membranes could provide unprecedented insights into cancer biology and a host of other phenomena. However, such simulations face conflicting computational constraints: reaching biologically relevant time and length scales (milliseconds and microns) requires continuum-level models but understanding the processes of interest requires molecular level detail. I will present a new type of massively parallel, multiscale simulation framework that brings together these two modeling paradigms. Using a machine learning algorithm, we couple a novel continuum model to an ensemble of molecular dynamics simulations. The result is a simulation at macro length- and time-scales that incorporates microscale precision. We demonstrate this capability with a large-scale simulation of several hundred k-Ras proteins on a realistic lipid bilayer spanning 1 μm2.
Citation Format: Frederick H. Streitz. Multiscale simulations of k-Ras on lipid bilayers [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA10.
Abstract IA11: Tissue- and cell-specific functions of Hras, Kras4A, and Kras4B in skin and lung cancer
Authors: Balmain Allan 
Published: June 2021

Abstract
Mouse models of cancer have been instrumental in the development of our understanding of the processes that drive multistage carcinogenesis from the initiation stage to metastasis. Tumors induced in mice by exposure to carcinogenic chemicals replicate many of the biologic and genetic features of multistage cancer in human populations. Skin and lung tumors initiated by chemical mutagens generally have carcinogen-specific mutations in Hras or Kras, respectively, but the reasons for this selectivity are unknown. We have used mouse models of skin and lung cancer to address some of the unanswered questions in cancer biology related to the specific functions of Hras, Kras4A, and Kras4B in cancer development in vivo. The KRAS gene, encoding two splice isoforms (KRAS4A and KRAS4B), is mutated in many lethal human tumors and has become a major target for cancer drug discovery. We show that germline deletion of either the major Kras4B or the minor Kras4A isoform in mice confers complete resistance to development of Kras mutant lung cancers. Double heterozygotes that are able to express both isoforms, but in which splicing has been uncoupled, are also tumor resistant, suggesting that coordinated expression of both splice variants is necessary for cancer initiation in vivo. KRAS4A is enriched in human tumor cells with stem cell properties, and the two splice variants show different responses to inducers of hypoxia or ER stress. Our data help to rationalize previous conflicting information on metabolic changes in KRAS mutant tumors and suggest that KRAS4A and 4B may require separate targeting in cancer stem and progenitor cells.
Citation Format: Allan Balmain. Tissue- and cell-specific functions of Hras, Kras4A, and Kras4B in skin and lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA11.
Abstract IA27: Context-dependent role of KRAS in GI malignancies
Authors: Liao Wen-Ting , Overman Michael J. , Boutin Adam , Dey Prasenjit , Zhao Di , Wang Guocan , Li Jiexi , Lan Zhengdao , Li Jun , Shang Xiaoying , Tang Ming , Jiang Shan , Ma Xingdi , Chen Peiwen , Katkhuda Riham , Korphaisarn Krittiya , Chakravarti Deepavali , Chang Qing , Zhang Jianhua , Maru Dipen M. , Maeda Dean Y. , Zebala John A. , Kopetz Scott , Wang Y. Alan , DePinho Ronald A. 
Published: June 2021

Abstract
Oncogenic Kras (Kras*) plays a key role in tumor maintenance and therapeutic resistance in several cancer types, although the precise biologic functions and mechanisms are not completely understood. We had previously shown in pancreatic ductal adenocarcinoma that some tumors underwent spontaneous relapse and were devoid of Kras* expression and downstream canonical MAPK signaling, instead acquiring amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras*-independent tumor maintenance. In a second previous study, we developed a faithful colorectal cancer (CRC) mouse model and showed that Kras* drove invasion and maintenance in CRC. Here, utilizing this CRC mouse model, we demonstrate that KRAS* promotes a pronounced immune-suppressive profile distinguished by a predominance of myeloid-derived suppressor cells (MDSCs). We performed integrated transcriptomic and genomic analyses that identified IRF2 (Interferon Regulatory Factor 2) as a key KRAS* effector mediating immune suppression. IRF2 suppresses MDSC migration and infiltration in KRAS*-expressing CRC tumors by targeting the CXCL3/CXCR2 axis. We also observed that de novo resistance of KRAS*-expressing tumors to anti-PD1 therapy could be overcome by enforced IRF2 expression or by treatment with SX-682, a small-molecule CXCR2 antagonist. In addition, CRC patient tumors with higher IRF2 expression showed increased response to anti-PD1 therapy. This KRAS*-mediated immune-suppressive mechanism provides a framework for CRC patient selection and combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in advanced disease.
Citation Format: Wen-Ting Liao, Michael J. Overman, Adam Boutin, Prasenjit Dey, Di Zhao, Guocan Wang, Jiexi Li, Zhengdao Lan, Jun Li, Xiaoying Shang, Ming Tang, Shan Jiang, Xingdi Ma, Peiwen Chen, Riham Katkhuda, Krittiya Korphaisarn, Deepavali Chakravarti, Qing Chang, Jianhua Zhang, Dipen M. Maru, Dean Y. Maeda, John A. Zebala, Scott Kopetz, Y. Alan Wang, Ronald A. DePinho. Context-dependent role of KRAS in GI malignancies [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA27.
Abstract PR08: Biochemical and structural analysis of the neurofibromin (NF1) protein and a potential role for protein destabilization in Rasopathy diseases
Authors: Sherekar Mukul , Han Sae-Won , Messing Simon , Drew Matthew , Ye Xiaoying , Gillette William , Juneja Puneet , O’Neill Hugh , Stanley Christopher , Ramanathan Arvind , de Val Natalia , Lorenzo Claire , McCormick Frank , Esposito Dominic 
Published: June 2021

Abstract
Neurofibromin is the 320-kilodalton protein product of the NF1 gene that is mutated in the Rasopathy disease neurofibromatosis type I. Defects in NF1 lead to abrogation of the GTPase-activating activity of the protein, leading to aberrant signaling through the RAS-MAPK pathway. Very little is known about the function of the majority of the NF1 protein—to date, only the GAP domain and a region containing a Sec-PH motif have detailed structural information. To better understand the role of this large protein, we have carried out a series of biochemical and biophysical studies that clearly show that full-length NF1 protein exists primarily as a dimer. Data from in vivo experiments confirmed that this dimerization also occurs in cells, and presumably has biologic implications. A model was generated from negative-stain EM data that suggests that NF1 monomers form both intermolecular contacts to form dimers and intramolecular contacts that stabilize the individual monomers. Deletion analysis permitted us to map these two interacting domains to different parts of the NF1 protein, and crosslinking studies coupled with mass spectrometry helped to identify regions of possible interaction. In addition, introduction of point mutations observed in patients with NF diseases caused a dramatic decrease in the stability of proteins both in vitro and in vivo, potentially arguing for a rationale for loss of NF1 activity by these single mutations.
This abstract is also being presented as Poster A03.
Citation Format: Mukul Sherekar, Sae-Won Han, Simon Messing, Matthew Drew, Xiaoying Ye, William Gillette, Puneet Juneja, Hugh O’Neill, Christopher Stanley, Arvind Ramanathan, Natalia de Val, Claire Lorenzo, Frank McCormick, Dominic Esposito. Biochemical and structural analysis of the neurofibromin (NF1) protein and a potential role for protein destabilization in Rasopathy diseases [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr PR08.
Abstract AP03: DISTINCT CELL/TISSUE SOURCES OF HIGH-GRADE SEROUS OVARIAN CANCER
Authors: Zhang Shuang , Neel Benjamin G. 
Published: June 2021

Abstract
The cell-of-origin of high grade serous ovarian carcinoma (HGSC) has been a focus of debate. Here, by using genetic mouse models as well as cognate organoid systems, we assessed the tumor forming capacity and properties of the fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) bearing the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ fallopian tube secretory cells causes transformation and characteristics of Serous Tubal Intraepithelial Carcinoma (STIC). This genetically engineered mouse HGSC model is faithfully recapitulated in fallopian organoids, from which serous ovarian cancer with broad abdominal metastasis is generated upon orthotropic injection. The same genetic events in Lgr5+ OSE cells organdies derived from these cells also result in an apparent neoplastic process, expressing markers of early serous carcinoma (but not Pax8), which subsequently develop into serous-like tumors. Hence, both Pax8+ fallopian tube epithelial cells and Lgr5+ ovarian surface epithelial cells can undergo similar neoplastic transformation, suggesting that HGSC might derive from distinct cell and tissue sources. Similar organoid systems can be used to rapidly model other gene combinations associated with HGSC.
Citation Format: Shuang Zhang, Benjamin G. Neel. DISTINCT CELL/TISSUE SOURCES OF HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP03.
Abstract AP08: DEVELOPMENT OF A MULTI-PROTEIN CLASSIFIER FOR OVARIAN CANCER DETECTION BY SIMULTANEOUS MEASUREMENT OF 92 SERUM PROTEINS ON PROSEEK MULTIPLEX ONCOLOGY II PLATES
Authors: Skubitz Amy P.N. , Boylan Kristin L.M. , Geschwind Kate , Cao Qing , Starr Timothy K. , Geller Melissa A. , Celestino Joseph , Bast Robert C. , Lu Karen H. , Koopmeiners Joseph S. 
Published: June 2021

Abstract
There are no FDA approved screening tools for detecting ovarian cancer in the general population. The two best known ovarian cancer biomarkers, CA125 and HE4, are neither adequately sensitive nor specific when used alone to screen the general population for early stage disease. By using a combination of protein biomarkers for screening, it may be possible to increase the sensitivity and specificity over CA125 alone. In this study, we used Proseek Multiplex Oncology II plates to simultaneously measure the expression of 92 cancer-related proteins in serum using proximity extension assays. This technology combines the sensitivity of the polymerase chain reaction with the specificity of antibody-based detection methods, allowing multiplex biomarker detection and high throughput quantification. We analyzed one microliter of serum from 61 women with advanced stage high grade serous ovarian cancer and compared the values obtained to 88 age-matched healthy women. Principle component analysis and unsupervised hierarchical clustering separated the ovarian cancer patients from the healthy, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with previously measured clinical values for CA125 (correlation coefficient of 0.91). CA125 and HE4 were detected at low levels in samples from healthy women, while higher levels were observed in the ovarian cancer cases. We identified 52 proteins that differed significantly (p &lt; 0.006) between ovarian cancer and healthy samples; several of which are novel serum biomarkers for ovarian cancer. In total, 40 proteins had an estimated area under the ROC curve of 0.70 or greater. CA125 alone achieved a sensitivity of 93.4% at a specificity of 98%. However, by adding five proteins to CA125, we increased the assay sensitivity to 98.4%, while holding the specificity fixed at 98%. Our data demonstrate that the Proseek technology can replicate the results established by conventional clinical assays for known biomarkers, identify new candidate biomarkers, and improve the sensitivity and specificity of CA125 alone.
Citation Format: Amy P.N. Skubitz, Kristin L.M. Boylan, Kate Geschwind, Qing Cao, Timothy K. Starr, Melissa A. Geller, Joseph Celestino, Robert C. Bast Jr., Karen H. Lu, and Joseph S. Koopmeiners. DEVELOPMENT OF A MULTI-PROTEIN CLASSIFIER FOR OVARIAN CANCER DETECTION BY SIMULTANEOUS MEASUREMENT OF 92 SERUM PROTEINS ON PROSEEK MULTIPLEX ONCOLOGY II PLATES [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP08.
Abstract GMM-033: CONDITIONAL BRCA2 SWITCH IN HUMAN CELLS TO STUDY TUMOR PROGRESSION
Authors: Jimenez-Sainz J. , Jensen R.B. 
Published: June 2021

Abstract
The BRCA2 (Breast Cancer Susceptibility 2) gene is a caretaker of genome integrity. Germline mutations in BRCA2 predispose individuals to a high risk for ovarian and breast cancer. The BRCA2 protein plays an important role in repair of DNA double-strand breaks (DSBs) by homologous recombination. The hallmarks found in BRCA2 mutant tumors involve: genome instability including chromosome aberrations, sensitivity to cross-linking agents, presence of micronuclei, an abnormal number of centrosomes, and severe defects in homologous recombination. However, the initial steps of tumor progression in BRCA2 carriers remain elusive as the majority of cellular models are derived from tumor cell lines that have undergone prior selection in an environment of genomic instability. Here, we present the generation of isogenic, inducible BRCA2 human fallopian tube cell lines providing a model to study the acute loss of BRCA2 protein in the setting of initiation and progression towards tumorigenesis. In these otherwise normal human somatic cells, we have found that acute loss of BRCA2 impinges upon viability as well as other cellular abnormalities that may drive the accumulation and tolerance for further somatic mutations. We have discovered copy number variations modulated by crosslinking compounds in our inducible BRCA2 human fallopian tube cells. We are analyzing both the genetic and biochemical functions of BRCA2 in these processes. Our long-term goal is to elucidate the underlying molecular mechanisms that drive and sustain tumor initiation in the absence of normal BRCA2 function.
Citation Format: Jimenez-Sainz J., and Jensen R.B.. CONDITIONAL BRCA2 SWITCH IN HUMAN CELLS TO STUDY TUMOR PROGRESSION [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-033.
Abstract GMM-035: TARGETING SPSB1 SENSITIZES PLATINUM-RESISTANT OVARIAN CANCER CELLS TO CISPLATIN
Authors: Kim Mi-Kyung , Kim Hyun-Jung , Kim Yun Hwan , Kim Seung Cheo , Ju Woong 
Published: June 2021

Abstract
OBJECTIVE: Emergence of chemoresistance remains a critical clinical issue responsible for treatment failure in patients with ovarian cancer. The precise mechanisms underlying the development of chemoresistance are not fully understood. In our previous study using methylomic and transcriptomic analyses, SPRY domain-containing SOCS box protein 1 (SPSB1) was found to be differentially expressed between cisplatin-sensitive and –resistant ovarian cancer cells. Here, we investigated the roles of SPSB1 as a new therapeutic target for ovarian cancer cells resistant to cisplatin.
METHODS: Knockdown of SPSB1 gene was performed by transfection of SPSB1 siRNA. Ovarian cancer cell lines were cultured for 5 days and 12 days after transfection for MTT assay and colony forming assay, respectively. Protein level was analyzed by western blot analysis. Cell migration assay was performed using Boyden chamber method.
RESULTS: Knockdown of SPSB1 using RNAi method dramatically inhibited cell viability and migratory capability of ovarian cancer cells. Also, SPSB1 knockdown significantly induced CDK inhibitors, p21 and p27 and inhibited anti-apoptotic Bcl-2, indicating that SPSB1 inhibition induces cell cycle arrest and apoptosis in ovarian cancer cells.
CONCLUSION: Our results suggest that SPSB1 might be a potential therapeutic target for cisplatin-resistant ovarian cancer.
Citation Format: Mi-Kyung Kim, Hyun-Jung Kim, Yun Hwan Kim, Seung Cheol Kim, Woong Ju. TARGETING SPSB1 SENSITIZES PLATINUM-RESISTANT OVARIAN CANCER CELLS TO CISPLATIN [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-035.
Abstract GMM-037: CARBONIC ANHYDRASE 9 AND TUMOR HYPOXIA ARE ASSOCIATED WITH RECURRENCE AND RESISTANCE IN BRCA1-EXPRESSING HGSOC
Authors: Krieg Adam J. , Campbell Shawn , Mhawech-Fauceglia Paulette , Lim Jeong Youn , Pejovic Tanja 
Published: June 2021

Abstract
Tumor hypoxia contributes to poor outcome in multiple cancer types, in part by influencing the expression of DNA repair enzymes. The objective of this study was to examine the possible relationship between Carbonic Anhydrase 9 (CA-IX, an indicator of tumor hypoxia), BRCA1 expression (a potential indicator of competent DNA repair), and patient outcome in epithelial ovarian cancer. BRCA1 and CA-IX were evaluated by immunohistochemistry in a tissue microarray of 167 epithelial ovarian cancer (EOC) patient samples, and their respective expression correlated to other biological parameters in all patients. The correlations between BRCA1 and CA-IX expression, and clinical outcome were determined in the High Grade Serous Ovarian Carcinoma (HGSOC) samples (N = 101) on the array using Spearman's correlation and log-rank (Mantel-Cox) tests. Elevated expression of BRCA1 strongly correlated with shorter intervals for disease recurrence and mortality (median time to recurrence = 1.05 yrs vs 1.94 yrs, P &lt;0.001; median time to mortality: 2.01 yrs vs 4.72 yrs, P &lt;0.001). There was a significant positive correlation between CA-IX and BRCA1 expression (Spearman's r = 0.486, P &lt; 0.001). CA-IX expression was significantly associated with recurrence-free survival (restricted to first 1500 days, P &lt;0.01). When patients were stratified by BRCA1 expression, co-expression of CA-IX and BRCA1 correlated with the shortest recurrence-free interval (P &lt;0.05). In complementary in vitro studies, exposure of multiple BRCA1-wild-type cell lines to hypoxia (1% O2, mimicking general tumor hypoxia) had only a minimal effect on BRCA1 expression. Additionally, in MTT viability assays, application of the hypoxia-activated pro-drug TH-302 preferentially killed cells in 1% O2 compared to standard conditions (21% O2). In contrast, the PARP inhibitor olaparib was 2-5 times less effective in hypoxic conditions than in standard growth conditions, suggesting that tumor hypoxia promotes a more resistant phenotype.
CONCLUSION: The co-expression of CA-IX and BRCA1 may be a useful prognostic indicator for rapid recurrence in high grade serous ovarian cancer. Dissecting the mechanisms regulating therapeutic resistance in hypoxic ovarian cancer cells could lead to more effective treatment options for HGSOC patients.
Citation Format: Adam J. Krieg, Shawn Campbell, Paulette Mhawech-Fauceglia, Jeong Youn Lim, Tanja Pejovic. CARBONIC ANHYDRASE 9 AND TUMOR HYPOXIA ARE ASSOCIATED WITH RECURRENCE AND RESISTANCE IN BRCA1-EXPRESSING HGSOC [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-037.
Abstract GMM-057: A FUNCTIONAL HOMOLOGOUS RECOMBINATION ASSAY PREDICTS PRIMARY CHEMOTHERAPY RESPONSE AND LONG-TERM SURVIVAL IN OVARIAN CANCER PATIENTS
Authors: Tumiati Manuela , Hietanen Sakari , Hynninen Johanna , Pietilä Elina , Färkkilä Anniina , Alkodsi Amjad , Li Yilin , Lehtonen Rainer , Erkan Erdogan Pekcan , Tuominen Minna M. , Lehti Kaisa , Hautaniemi Sampsa K. , Vähärautio Anna , Grénman Seija , Carpén Olli , Kauppi Liisa 
Published: June 2021

Abstract
PURPOSE: Homologous recombination deficiency (HRD) correlates with platinum sensitivity in ovarian cancer patients, which clinically is the most useful predictor of sensitivity to PARPi. For this reason, there is clearly a critical need to identify homologous recombination deficiency (HRD) as early as possible. Currently, HRD is mostly diagnosed by genetic testing, which however fails to identify a large proportion of HR-deficient tumors and predict a patient's response to chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments.
METHODS: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n=32). Samples clustered in 3 categories: HR-deficient, HR-low and HR-proficient. We analysed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed whole-genome sequencing and targeted DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening.
RESULTS: Low HR scores predicted primary platinum sensitivity with high statistical significance (p=0.0103), associated with longer PFI (HR-deficient vs HR-proficient: 531 vs 53 days), and significantly correlated with improved OS (HR score &lt;35 vs ≥35, hazard ratio=0.08, p=0.0116). At the genomic level, we identified a few unclear mutations in HR genes and the mutational signature associated with HRD, but, overall, genetic screening failed to predict functional HRD.
CONCLUSIONS: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of ovarian cancer patients.
Citation Format: Manuela Tumiati, Sakari Hietanen, Johanna Hynninen, Elina Pietilä, Anniina Färkkilä, Amjad Alkodsi, Yilin Li, Rainer Lehtonen, Erdogan Pekcan Erkan, Minna M. Tuominen, Kaisa Lehti, Sampsa K. Hautaniemi, Anna Vähärautio, Seija Grénman, Olli Carpén, and Liisa Kauppi. A FUNCTIONAL HOMOLOGOUS RECOMBINATION ASSAY PREDICTS PRIMARY CHEMOTHERAPY RESPONSE AND LONG-TERM SURVIVAL IN OVARIAN CANCER PATIENTS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-057.