bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA21: Preventing KRAS processing
Authors: Maciag Anna , Yang Yue , Turner David , Dyba Marcin , Kumari Vandana , Smith Brian , Fan Lixin , Gysin Stephan , Wolfe Andrew , Abdelkarim Hazem , Gaponenko Vadim , Lightstone Felice , Nissley Dwight , McCormick Frank 
Published: June 2021

Abstract
Tipifarnib, a drug that targets HRAS through inhibiting farnesyl transferase, is in phase II clinical trials and appears to show activity in tumors harboring oncogenic HRAS mutations (https://kuraoncology.com/pipeline/#tipifarnib). Unfortunately, these drugs are not expected to be effective on KRAS cancers because KRAS, unlike HRAS, can be prenylated by geranylgeranyl transferase following farnesyl transferase inhibition. To address this, we have developed compounds that prevent farnesylation of KRAS 4B by covalent reaction with C185, the site of prenylation. These compounds bind to a pocket in the G-domain that is formed by interaction with the hypervariable region, an interaction that does not seem to occur in other RAS proteins. This existence of this pocket has been demonstrated through biochemical and biophysical analysis, including NMR and small-angle X-ray scattering. The compounds we have developed are active in cells: they prevent proliferation of MEFs driven by oncogenic KRAS proteins but do not affect MEFs supported by myristoylated KRAS G12D C185S at equivalent concentrations. We are currently optimizing these compounds for further preclinical development.
Citation Format: Anna Maciag, Yue Yang, David Turner, Marcin Dyba, Vandana Kumari, Brian Smith, Lixin Fan, Stephan Gysin, Andrew Wolfe, Hazem Abdelkarim, Vadim Gaponenko, Felice Lightstone, Dwight Nissley, Frank McCormick. Preventing KRAS processing [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 IA21.
Abstract IA28: Systematic interrogation of KRAS in cancer
Authors: Hahn William C. 
Published: June 2021

Abstract
To complement ongoing large-scale characterization of cancer genomes, we have developed genome-scale tools to systematically annotate the function of genes involved in cancer initiation and progression. In particular, we have dissected the signaling pathways related to one of the most frequently mutated oncogenes KRAS. Using both gain-of-function (ORFs) and loss-of-function (RNAi and CRISPR-Cas9) approaches, we have identified new components of KRAS effector pathways that are essential for the survival of KRAS driven cancers. We have also performed comprehensive genetic screens to identify genes that modulate the response of KRAS-driven cancer cell lines to clinical-grade MEK inhibitors. Together these ongoing approaches provide new insights into KRAS signaling and identify potential targets for KRAS-driven cancers.
Citation Format: William C. Hahn. Systematic interrogation of KRAS in 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 IA28.
Abstract IA29: Global proteomics reveals the context-dependence of K-Ras signaling
Authors: Haigis Kevin 
Published: June 2021

Abstract
KRAS is the most frequently mutated oncogene in cancer. In the absence of direct inhibitors for most K-Ras mutants, therapeutic strategies focus on targeting downstream pathways that mediate its oncogenic properties. This approach is limited, however, by an incomplete understanding of the contextual cues that modulate the signaling output of activated K-Ras. To determine how tissue context, genetic background, and KRAS allele modulate oncogenic signaling on a global level, we performed multiplexed mass spectrometry on mouse tissues expressing wild-type or mutant K-Ras. Different mutant forms of K-Ras dramatically altered the proteomes and phosphoproteomes of colons, pancreases, and spleens, even when a given mutant allele did not alter tissue homeostasis. The vast majority of changes were context specific (i.e., not conserved between tissues or KRAS alleles), leading to several unique K-Ras-regulated network architectures. We developed an approach to integrate proteomic data from mouse models with proteomic and mutational data from human cancers, identifying key nodes in the K-Ras network that are conserved between primary tumors and a model organism. Comparison of the integrated K-Ras signaling networks to genetic screening data identified several genes that are synthetic lethal with mutant K-Ras. Altogether, these studies demonstrate the extreme context-dependent plasticity of K-Ras signaling and identify noncanonical mediators of K-Ras oncogenicity that lie within the K-Ras-regulated signaling network.
Citation Format: Kevin Haigis. Global proteomics reveals the context-dependence of K-Ras signaling [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 IA29.
Abstract PR03: Modeling the genetic heterogeneity of KRAS mutant lung adenocarcinomas for therapeutic discovery
Authors: Best Sarah A. , Ding Sheryl , Reljic Boris , Song Ji-Ying , Sutherland Kate D. 
Published: June 2021

Abstract
Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer. Oncogenic driver mutations in KRAS are found in 36% of lung ADC cases and with a lack of specific KRAS inhibitors, this subset presents a significant clinical challenge. There is therefore an urgency to identify actionable co-occurring mutations as an alternative therapeutic approach. One of the most critical stress-response pathways in mammals is mediated by the transcription factor Nuclear Factor Erythroid-2-Related Factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-Associated Protein 1 (KEAP1). Loss-of-function mutations in KEAP1 have been identified in 19% of ADC, and often co-occur with KRAS mutations, but appear to be largely mutually exclusive with TP53 mutations. To best model these genetic subgroups of KRAS mutant lung ADC, we generated genetically engineered mouse models (GEMMs) whereby oncogenic KrasG12D was expressed either in combination with loss of p53 (KP mice) or Keap1 (KK mice). Critically, loss of Keap1 promoted KrasG12D-induced malignant transformation, which was associated with a unique metabolic program that could be exploited using pharmacologic inhibitors. Furthermore, bronchiolar epithelial cells appeared to be more sensitive than alveolar epithelial cells to transformation following Keap1 loss. Interestingly, this cell-type bias appeared to directly modulate the immune phenotype of lung tumors. Taken together, we have generated powerful in vivo models that enable us to address the relationship between tumor cells and resident immune cells to evaluate novel treatment strategies aimed at improving the long-term outcomes for patients carrying KRAS alterations.
This abstract is also being presented as Poster B10.
Citation Format: Sarah A. Best, Sheryl Ding, Boris Reljic, Ji-Ying Song, Kate D. Sutherland. Modeling the genetic heterogeneity of KRAS mutant lung adenocarcinomas for therapeutic discovery [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 PR03.
Abstract PR04: Anti peptide-HLA (TCR-like) antibodies specific for the KRAS G12V neoantigen
Authors: Maserati Avisa , Makris Dahna , Kiefel Ben , Beasley Matt , McColl Brad , Clifton Ben 
Published: June 2021

Abstract
The remarkably high prevalence of Ras driver mutations in tumors of diverse origins and stages indicates that Ras neoantigens are poor substrates for HLA-mediated detection by the native immune system. Nevertheless, immunotherapies based upon tumor-infiltrating lymphocytes targeting Ras neoantigens have been reported, indicating that such mutations are subject to HLA display and immune surveillance. Antibodies capable of recognizing specific peptide-HLA complexes at the cell surface have the potential to target intracellular tumor neoantigens for therapeutic intervention. However, such reagents have proved to be challenging to develop. Using a novel antibody discovery platform in combination with a proprietary human germline scFv library, we have developed a rapid method for the isolation of antibodies against peptide-HLA complexes. Applying this technology to KRAS G12V, we have isolated two scFvs that recognize the peptide VVVGAVGVGK in complex with HLA-A*11:01. This peptide-HLA combination forms functional complexes both in vitro and at the cell surface and has been reported to elicit CTL responses in vivo. In contrast, the native peptide is a poor substrate for binding to HLA-A*11:01. Binding affinities of the two scFv binders for the target HLA complex are in the sub-100nM range. Both show highly specific, peptide-dependent recognition of the KRAS-HLA-A*11:01 complex, as demonstrated by the failure to bind complexes containing wild-type KRAS peptides or other control peptides. Alanine scanning mutagenesis reveals multiple residues within the neoepitope peptide that are critical for antibody binding, including the mutated valine residue. The extended binding footprint encompassing the neoepitope and the poor presentation of the unmutated peptide are likely to contribute to the on-target specificity of these antibodies. Incorporation of the scFvs into a bispecific T-cell engager (BiTE) format has demonstrated the simultaneous engagement of both the KRAS HLA-A*11:01 complex and the CD3 surface marker of T cells. Ongoing work is aimed to demonstrate BiTE-dependent CTL-mediated lysis of target cells displaying the KRAS HLA-A*11:01 complex. We are currently developing CAR-T cells carrying peptide-HLA specific scFvs and are screening further mutant Ras peptides in the context of other HLA-A subtypes.
This abstract is also being presented as Poster B48.
Citation Format: Avisa Maserati, Dahna Makris, Ben Kiefel, Matt Beasley, Brad McColl, Ben Clifton. Anti peptide-HLA (TCR-like) antibodies specific for the KRAS G12V neoantigen [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 PR04.
Abstract AP05: OVARIAN CANCER-ASSOCIATED RAD51D MUTATIONS WHICH IMPAIR ITS INTERACTION WITH XRCC2 RESULT IN DNA REPAIR DEFICIENCY
Authors: Baldock Robert A. , Pressimone Catherine A. , Baird Jared M. , Khodakov Anton Y. , Karpenshif Yoav , Garcin Edwige B. , Gon Stéphanie , Modesti Mauro , Bernstein Kara A. 
Published: June 2021

Abstract
The proficiency of ovarian cancer cells to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) is a key determinant in predicting response to targeted therapies such as PARP inhibitors (PARPi). The RAD51 paralogs act downstream of BRCA1/2 to facilitate HR. Numerous epidemiological studies have linked mutations in the RAD51 paralogs with hereditary ovarian cancer predisposition. Despite their substantial links to cancer predisposition and development, RAD51 paralog function during HR has remained elusive, in part due to limitations in studying recombination events downstream of RAD51 filament formation. Here we investigate the impact of cancer-associated mutations in the RAD51 paralog, RAD51D, using yeast 2/3-hybrid assays to screen for altered protein-protein interactions. Following the identification of mutations that disrupt the interaction between RAD51D and XRCC2 in yeast, we validated the interaction by co-immunoprecipitation in human cells. Importantly, we determined the impact of these mutations on HR-proficiency using a direct-repeat recombination assay. By characterizing the impact of cancer-associated mutations in the RAD51 paralogs on HR-proficiency, we aim to develop more effective predictive models for therapeutic sensitivity and resistance in patients who harbor similar mutations in these essential genes.
Citation Format: Robert A. Baldock, Catherine A. Pressimone, Jared M. Baird, Anton Y. Khodakov, Yoav Karpenshif, Edwige B. Garcin, Stéphanie Gon, Mauro Modesti, Kara A. Bernstein. OVARIAN CANCER-ASSOCIATED RAD51D MUTATIONS WHICH IMPAIR ITS INTERACTION WITH XRCC2 RESULT IN DNA REPAIR DEFICIENCY [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 AP05.
Abstract AP18: PRO-INVASIVE TUMOUR-STROMA INTERACTIONS: ROLE OF THE SECRETED OXIDOREDUCTASE CLIC3
Authors: Hernandez-Fernaud Juan R , Ruengeler Elena , Neilson Lisa J , Ismail Shehab , McNeish Iain , Atkinson Samuel , Lilla Sergio , Santi Alice , Valenzuela Stella M , Blyth Karen , Yin Huabing , Mazzone Massimiliano , Norman Jim C , Zanivan Sara 
Published: June 2021

Abstract
Cancer cells are embedded within a microenvironment populated with cancer associated fibroblasts (CAFs) with whom they establish two-way communications through paracrine factors and physical interactions. Through these interactions, CAFs play pivotal roles in cancer and have emerged as promising therapeutic target.
To unravel key contributors of CAF-tumour/stroma cell interactions, we have developed mass spectrometry (MS)-based approaches to map proteins secreted in condition medium and extracellular matrix (ECM). Through an extensive MS-proteomic comparative analysis of CAFs with their normal fibroblasts (NFs) counterpart, we have identified the chloride intracellular channel protein 3 (CLIC3), a protein previously considered an intracellular chloride channel (regulator), as one of the most upregulated proteins in CAFs and deposited in the ECM.
Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive blood vessels growth and increases invasiveness of cancer cells, both in vivo and in 3D cell culture models, via activation of the tissue transglutaminase-2 (TGM2). We found that CLIC3 is a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels in primary tumours and omental metastases correlate with poor clinical outcome.
Our work has unraveled an unprecedented mechanism of cell invasion to be explored for targeting in ovarian cancer.
Citation Format: Juan R Hernandez-Fernaud, Elena Ruengeler, Lisa J Neilson, Shehab Ismail, Iain McNeish, Samuel Atkinson, Sergio Lilla, Alice Santi, Stella M Valenzuela, Karen Blyth, Huabing Yin, Massimiliano Mazzone, Jim C Norman and Sara Zanivan. PRO-INVASIVE TUMOUR-STROMA INTERACTIONS: ROLE OF THE SECRETED OXIDOREDUCTASE CLIC3 [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 AP18.
Abstract GMM-032: UNRAVELLING THE STEROID METABOLOME IN EPITHELIAL OVARIAN CANCER
Authors: Jeevan David N. , Arlt Wiebke , Foster Paul A. , Sundar Sudha 
Published: June 2021

Abstract
INTRODUCTION: Ovarian tissue possesses the capacity for steroidogenesis from as early as seven weeks gestation. Perturbations in the steroidogenic pathways have been implicated in the development and progression of epithelial ovarian carcinoma in adulthood but the evidence has been limited. Analysis of RNA-seq data from ovarian tissue now allows the genes involved in these pathways to be studied comprehensively helping direct future investigations and highlighting possible mechanisms of the disease.
METHODS: RNA-seq data from 293 serous epithelial ovarian carcinomas from The Cancer Genome Atlas were extracted and the genes involved in steroidogenesis were systematically interrogated for high and low expression. Pathway analysis was employed to confirm significant findings. Comparison was made with novel RNA-seq data from first trimester fetal ovary and healthy adult ovary.
RESULTS: Genes involved in the synthesis of androgens (HSD17B1, SRD5A1, AKR1C3, AR and STS) were all significantly upregulated in the high grade serous ovarian carcinoma group when compared to normal healthy ovary (p&lt;0.05).
Expression of several steroidogenic genes in malignancy appeared to mimic increased fetal expression with relative quiescence noted in the healthy ovary group.
CONCLUSIONS: Transcriptome analysis shows upregulated gene expression of the androgen synthesis pathway is associated with epithelial ovarian cancer. This is supported by immunohistochemistry findings in recent studies. Investigation of the androgen pathway does remain a valid opportunity for mechanistic insight into this disease and potentially diagnostic and therapeutic exploitation.
Ovarian steroidogenic gene expression in the first trimester appears to correlate with neoplastic growth in serous ovarian cancer but the significance of this is uncertain.
Citation Format: David N. Jeevan, Wiebke Arlt, Paul A. Foster and Sudha Sundar. UNRAVELLING THE STEROID METABOLOME IN EPITHELIAL 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 GMM-032.
Abstract GMM-039: BUILDING AN ORGANOID-BASED MODEL FOR OVARIAN CANCER
Authors: Lõhmussaar Kadi , Kopper Oded , Clevers Hans C. 
Published: June 2021

Abstract
Over the last few years several studies led to a significant change in the field of ovarian cancer and it is currently believed that the fallopian tube and not the ovary surface epithelium (OSE) is the main origin of high-grade serous ovarian cancer (HG-SOC). Nevertheless, due to the lack of unique markers and adequate model systems the relative contribution of each tissue is not yet clear and the notion that OSE has a role in HG-SOC development was not cast aside altogether. In this work we have established novel organoid systems derived from both mouse OSE and oviduct (Ovi, the equivalent of human fallopian tube). These systems recapitulate their tissue of origin and demonstrate differences in medium requirements as well as gene expression. To establish comparable tumor progression models for both OSE and Ovi we used CRISPR-Cas9 technique and targeted commonly mutated genes in ovarian cancer (Trp53, Brca1, Nf1 and Pten). Thus, we were able to establish clones with different combinations of mutations. Histological, metaphase spread and gene expression analysis of the mutated organoid clones from both OSE and Ovi demonstrated different degrees of deviation from their wild type counterpart. This deviation became more evident as the amount of introduced mutations increased. Preliminary transplantation experiments showed that only triple mutants gave rise to tumors (Trp53, Brca1 and Pten or Trp53, Brca1 and Nf1). Moreover, Ovi mutant clones were more prone to grow into tumors in comparison to OSE as no tumors have been detected in mice transplanted with the OSE equivalent clones so far. Taken together, in this study we present the first comparable Ovi/OSE research platform that enables addressing questions related to origin and early stages of HG-SOC development.
Citation Format: Kadi Lõhmussaar, Oded Kopper, Hans C. Clevers. BUILDING AN ORGANOID-BASED MODEL FOR 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 GMM-039.
Abstract GMM-050: IDENTIFICATION OF NOVEL CHROMOSOMAL REARRANGEMENTS IN HIGH-GRADE SEROUS OVARIAN CANCER
Authors: Sarvilinna Nanna , Pradhan Barun , Faisal Imrul , Tumiati Manuela , Alkodsi Amjad , Kauppi Liisa 
Published: June 2021

Abstract
High-grade serous ovarian cancer (HGS-OVCA) is the most common type of ovarian cancer. HGS-OVCA genomes are usually very complex and unstable. Many studies have addressed cytogenetic changes, and with the advent of high-throughput sequencing, complex chromosomal rearrangements. However, little is known about how gene fusions, potentially causing aberrant transcripts and protein products drive tumorigenesis, cell growth and/or metastasis in HGS-OVCA. Patients with the same histological or morphological phenotype of cancer have tumors with diverse genetic backgrounds or molecular phenotypes. There is thus an urgent need to better stratify patients and their tumors and to understand the chemotherapy and other treatment responses at the molecular level.
The purpose of this study is to find and charaterize novel recurrent chromosomal rearrangements from HGS-OVCA patient samples. We aim to identify rearrangement hotspots from genomic data. However, not only do we need to identify, characterize and stratify the genomic alterations, but also to find those changes with potentially tumorigenic functions at the RNA and protein levels.
We utilise datasets of The Cancer Genome Atlas (https://cancergenome.nih.gov/) and HERCULES Project (http://www.project-hercules.eu/) to identify rearrangement-prone chromosomal regions (putative “breakpoint hotspots”) and complex structural aberrations and variations. We concentrate on exonic aberrations seen in both datasets in at least 2 patients. The findings will be validated using two HGS-OVCA fresh-frozen tumor sample collections from Helsinki and Turku University Hospitals. Clinical data and homologous recombination (HR) score of the tumor samples (HR proficient or HR deficient; Tumiati et al. 2018) will also be analyzed.
Preliminary results of this work will be presented. We believe that combining sequencing and clinical data with state-of-the-art molecular level analyses and functional tests will deepen our understanding of HGS-OVCA biology and help to develop new anti-cancer treatment options for this “silent killer”.
Citation Format: Nanna Sarvilinna, Barun Pradhan, Imrul Faisal, Manuela Tumiati, Amjad Alkodsi, Liisa Kauppi. IDENTIFICATION OF NOVEL CHROMOSOMAL REARRANGEMENTS IN 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 GMM-050.