bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2420: Characterizing the oncogenic activity of ERBB4 mutations and their sensitivity to neratinib
Authors: Suominen Peppi , Chakroborty Deepankar , Kurppa Kari J. , Diala Irmina , Eli Lisa D. , Lalani Alshad S. , Elenius Klaus 
Published: July 2021

Abstract
Hundreds of somatic ERBB4 mutations have been described in cancer tissues with very limited information about their functional significance. However, analyses of individual mutants have indicated that activating ERBB4 mutations, such as ERBB4 K935I, do exist. Understanding the functional consequences of ERBB4 mutations is needed in order to assess the relevance of targeting ERBB4 in human cancers with matched therapies such as neratinib. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that binds to and potently inhibits ERBB4 kinases activity in-vitro, and is currently approved clinically for the treatment of early stage and metastatic HER2+ breast cancers.
We set up to address the transforming potential of individual ERBB4 variants by selecting 18 mutations (Table 1) from cBioPortal data (www.cbioportal.org) using the following criteria: 1) the mutations were recurrent, 2) they were analogous to activating mutations described for other oncogenic ERBB family members and/or 3) their position at receptor dimerization interfaces suggested functional relevance.
Retroviral pBABE-puro-gateway vector was used to achieve functional, but still near-physiological expression levels of ERBB4 in different cell backgrounds. A screen for optimal cellular background to assess the transforming potential of ERBB4 variants indicated that 1) IL-3 independent growth of mouse lymphoid Ba/F3 cells, 2) focus formation analysis of mouse NIH-3T3 fibroblasts, and 3) ligand-induced proliferation of human mammary epithelial MCF-10A provided read-outs with robust differences when the effects of the positive control mutant ERBB4 K935I was compared to wild-type ERBB4. These models are now being used to address the transforming potential of the 18 mutations (Table 1).
Table 1.Somatic ERBB4 mutations chosen for functional analyses.R106CE452KR711CL798RG870RK1223TS303FR524CG741EV840IG907ES1289AR393WR544WS774GR847HR992CR1304W
Citation Format: Peppi Suominen, Deepankar Chakroborty, Kari J. Kurppa, Irmina Diala, Lisa D. Eli, Alshad S. Lalani, Klaus Elenius. Characterizing the oncogenic activity of ERBB4 mutations and their sensitivity to neratinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2420.
Abstract 243: Identification of novel epitopes of NY-ESO-1 for solid malignancies by Kiromic proprietary search engine Diamond
Authors: Piccotti Lucia , Mirandola Leonardo , Chiriva-Internati Maurizio 
Published: July 2021

Abstract
Adoptive cell therapy has been proven a powerful approach for the cure of cancer and other diseases. In particular, the selection of appropriate immunogenic targets has been key to positive outcomes in clinical settings. The availability of RNA-Seq analysis, the accessibility to large data repositories such as TCGA and GTEx, and the creation of new bioinformatic tools have accelerated the process of neoantigen discovery. However, most of the current algorithms are encumbered by the intrinsic complexity of predicting antigen immunogenicity. Diamond™ is a novel artificial intelligence and cognitive machine and deep learning platform to predict peptide processing, HLA binding, and T cell activation. To validate the predictive value of DIAMOND algorithms, the meta-analyses of expression data of cancer-testis antigen New York Esophageal Squamous Cell Carcinoma 1 (NY-ESO-1) and predictions for the immunogenic peptides were compared to experimental data in the literature. In agreement with published clinical observations, DIAMOND metanalysis showed NY-ESO-1 genic overexpression in skin cutaneous melanoma, lung adenocarcinoma, and sarcoma. Moreover, DIAMOND predicted an MHC binding affinity of 0.289 with Supertype A2 for a new NY-ESO-1 peptide, which has been successfully targeted in clinical trials for patients with HLA-A*02:01, as well as it mirrored published data in its prediction of peptide affinity binding in NY-ESO-1–specific MHC II–restricted T cell receptors. Taken together these data support DIAMOND as a reliable platform for the discovery of new immunogenic targets for cancer therapy.
Citation Format: Lucia Piccotti, Leonardo Mirandola, Maurizio Chiriva-Internati. Identification of novel epitopes of NY-ESO-1 for solid malignancies by Kiromic proprietary search engine Diamond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 243.
Abstract 2433: Core regulatory circuits of clear cell ovarian and kidney cancers
Authors: Scott Marla Elizabeth , Nameki Robbin , Abbasi Forough , Fonseca Marcos Abraao de Souza , (Ivetth) Corona de la Fuente Rosario , Lawrenson Kate 
Published: July 2021

Abstract
Clear cell ovarian and kidney cancers are rare but aggressive cancers characterized by resistance to traditional chemotherapies. The transcriptional drivers of these tumors are poorly understood, but the histologic similarities suggest that a subset of common factors may drive differentiation of the clear cell phenotype, agnostic of anatomic origin. Master transcription factors (MTFs) are the essential transcriptional regulators that create interconnected auto-regulatory circuits critical for tumor cell survival. Candidate MTFs can be identified due to their characteristic high level, tissue-specific expression, functional essentiality in tumor models, and participation in interconnected core regulatory transcriptional circuits. We collated 5 high grade serous ovarian cancer, 5 clear cell ovarian cancer, 5 papillary renal cell cancer and 11 clear cell renal cell cancer primary tissue and 27 cell line data sets for clear cell ovarian and kidney cancers, and non-clear cell tumors of the same organs. We integrated gene expression, super-enhancer landscapes and global maps of open chromatin to identify candidate MTFs specific to clear cell tumors. This identified known Hepatocyte nuclear factor-1-beta (HNF1B), commonly over-expressed in &gt;90% of clear cell cancers and other novel candidates, including RARA, which encodes retinoic acid receptor alpha. Clear cell kidney and ovarian cancer cell lines are often co-dependent on sustained expression of HNF1B and RARA for survival, suggesting perturbed retinoic acid signaling represents a novel therapeutic target for clear cell tumors. Transcriptional inhibitors provide a novel therapeutic target for many cancers that may otherwise be chemoresistant. Clear cell lines are particularly sensitive to general transcriptional inhibitors in in-vitro models; functional analyses are ongoing to determine the role of RARA, HNF1B and other factors in explaining these responses.
Citation Format: Marla Elizabeth Scott, Robbin Nameki, Forough Abbasi, Marcos Abraao de Souza Fonseca, Rosario (Ivetth) Corona de la Fuente, Kate Lawrenson. Core regulatory circuits of clear cell ovarian and kidney cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2433.
Abstract 2441: Polysome profiling suggests VHL-dependent translational control in clear cell renal cell carcinoma
Authors: Vassalakis Julia A. , Zequi Stenio C. , Bezerra Stephania M. , da Costa Walter H. , Larsson Ola , Topisirovic Ivan , Hajj Glaucia N. 
Published: July 2021

Abstract
ccRCC is the most common type of renal carcinoma with 80% of incidence among all types of kidney neoplasms. Most cases are localized in the kidney and potentially curable after nephrectomy however about 30% of patients will relapse with distant metastasis. Metastatic patients comprehend one third of all cases and, despite the advances in therapies, they still have low response rates. The identification of molecular mechanisms associated with ccRCC is essential to understand disease progression and treatment resistance. Genes frequently mutated in ccRCC affect the activation of signaling pathways including the mTOR pathway which can cause an unbalance in translational control. Another frequent mutation is in the tumor suppressor gene VHL which regulates response under hypoxia. Hypoxia affects gene expression by both translational and transcriptional controls that contributes to tumor formation and disease progression. Here we aim to understand how translational control can contribute to ccRCC development. We evaluated the activity of mTOR pathway and translational control in cell lines and PDX models with VHL mutation through polysome profiling. We observed lower global translational rates in both VHL mutated models suggesting an important role in translational control. Differentially translated genes identified from polysome associated RNA show a specific translational signature in response to VHL deletion. For human tumors, a cohort of 118 cases was selected between metastatic and non-metastatic patients available at A.C. Camargo Cancer Center Tumor Tissue Biobank. Polysome profiling was performed for all cases and show that increased translational rates are associated with reduced overall and progression-free survival.
Citation Format: Julia A. Vassalakis, Stenio C. Zequi, Stephania M. Bezerra, Walter H. da Costa, Ola Larsson, Ivan Topisirovic, Glaucia N. Hajj. Polysome profiling suggests VHL-dependent translational control in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2441.
Abstract 2450: A systemic approach to decipher the interactome of RET receptor isoforms
Authors: Kheitan Samira , Pedersen Annika E. , Hyndman Brandy D. , Drecun Luka , Saraon Punit , Stagliar Igor , Mulligan Lois M. 
Published: July 2021

Abstract
The REarranged during Transfection (RET) receptor tyrosine kinase is pivotal for normal tissue development, but is also an oncogene driver involved in several human cancers. Alternative splicing at the 3' end of the RET gene leads to expression of two conserved protein isoforms, RET9 and RET51, that differ in their subcellular localization and protein trafficking, as well as their functional roles in tumorigenesis and metastatic processes. Importantly, RET9 and RET51 have unique C-terminal phospho-tyrosine binding sites, suggesting that they may also differ in their interactomes. We used a combination of cell-based screening and in silico approaches to identify novel potential interaction partners of RET isoforms. We performed a Mammalian Membrane Two-Hybrid (MaMTH) screen using a library of SH2 domain-containing adaptor and signaling proteins, to identify interactions with each RET isoform. We complemented these studies by using sequence homology detection models (HMM, PSSM), based on SH2 domain sequences known to interact with RET, to rank the SH2 library members and predict novel interactions. Independently, we compared published consensus binding sequences for each SH2 domain library member with predicted RET phosphotyrosine motifs to identify potential interactors. Predicted interactions were validated in co-immunoprecipitation assays. We confirmed previously known interactions of RET with SH2 domain proteins including SHC1, GRB2 and GRB10, and identified additional novel RET-binding proteins, a subset of which showed differential interactions that were mediated through RET isoform-specific docking sites. Our results suggest that combinations of distinct interaction partners may contribute to RET isoform-specific functions. Together, our research has developed a systematic approach to map and characterize RET isoform interactions. Our data suggest that no single method identified all confirmed RET interactions, and that a combination of multiple approaches improves characterization of growth factor receptor interactomes.
Citation Format: Samira Kheitan, Annika E. Pedersen, Brandy D. Hyndman, Luka Drecun, Punit Saraon, Igor Stagliar, Lois M. Mulligan. A systemic approach to decipher the interactome of RET receptor isoforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2450.
Abstract 2452: Metformin administration in hypoglycemia compromises cancer cell viability in glioblastoma initiating cells
Authors: Cianci Francesca , Cazzoli Riccardo , Verduci Ivan , Minucci Saverio , Mazzanti Michele 
Published: July 2021

Abstract
Cancer cells show higher energy and biomolecules requirements than healthy cells, making the targeting of cancer metabolic dysfunctions an appealing therapeutic approach. Unfortunately, tackling the tumor metabolism is a daunting task, due to the ability of cancer cells to re-organize their metabolism switching between glycolysis and oxidative phosphorylation. Cancer metabolic plasticity and re-programming is partially supported by altered ionic channels expression and activity, our laboratory has described Chloride Intracellular Channel 1 (CLIC1) as a marker of malignancy in tumor cells and a possible therapeutic target. CLIC1 is a metamorphic protein able to switch between cytoplasmic and transmembrane forms (tmCLIC1), the latter characterized by chloride conductance. TmCLIC1 was found to be overexpressed in several solid tumors where supports cancer proliferation and growth, while it is mainly absent in healthy cells. Recently, it has been demonstrated that tmCLIC1 activity is affected by biguanide compounds, in particular metformin. Metformin was recently repurposed as an anticancer drug with unclear mechanisms. We demonstrated that in hypoglycemia, metformin displays increased toxic effect on cancer cells, inducing apoptosis. Metformin inhibits Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), and hypoglycemia upregulates PP2A subunit B56δ targeting the Glycogen Synthase Kinase 3 Beta (GSK3b). Metformin treatment in combination with hypoglycemia leads to de-phosphorylation of GSK3b protein resulting in degradation of induced myeloid leukemia cell differentiation protein (MCL-1), a pro-survival protein, and cell death (Elgendy et al., Cancer Cell 2019). In primary glioblastoma cell lines enriched in tumor-initiating-cells (GSCs), metformin has proven to be effective in reducing cell growth without affecting viability (Gritti et al., Oncotarget 2014). Here, we are going to show studies trying to establish whether CLIC1 is a component of the established PP2A-mediated signaling network. Our work aims to clarify metformin molecular mechanism of action and to assess a new potential therapeutic approach for solid tumors in which tmCLIC1 is found to be overexpressed.
Citation Format: Francesca Cianci, Riccardo Cazzoli, Ivan Verduci, Saverio Minucci, Michele Mazzanti. Metformin administration in hypoglycemia compromises cancer cell viability in glioblastoma initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2452.
Abstract 2454: Vitamin D-mediated anti-cancer activity involves iron homeostatic balance disruption and oxidative stress induction in breast cancer
Authors: Bajbouj Khuloud , Shafarin Jasmin , Sahnoon Lina , Al-Ali Abeer , Muhammad Jibran Sualeh , Guraya Salman Y. , Hamad Mawieh 
Published: July 2021

Abstract
Background: Vitamin D deficiency has long been associated with increased risk of breast cancer (BC). Moreover, increased cellular iron content is emerging as a biomarker of BC metastasis. Although the connection between vitamin D and cellular iron content in BC remains ambiguous, recent studies have shown that vitamin D exerts some of its anti-cancer effects by modulating the expression of key iron regulatory genes (IRGs). Herein, we addressed the question of whether vitamin D signaling plays a role in cellular iron homeostasis and whether this has a effects on breast cancer cell survival and growth.
Experimental Methods: Bioinformatics analysis from publicly available transcriptomic data set has been utilized to profile the expression status of key IRGs in vitamin D-treated breast cancer cells. Additionally, hormonal-responsive (MCF-7) and triple negative (MDA-MB-231) BC cells were treated with 1α,25-dihydroxyvitamin D3 (calcitriol; the vitamin D active form) and evaluated for labile iron content, expression of IR proteins, oxidative stress, and cell survival.
Results and Discussions: Bioinformatics analysis revealed that several IRGs including hepcidin, ferroportin, ferritin and transferrin receptor as well as genes related to metabolic cellular stress are differentially expressed in BC cells. Vitamin D treatment resulted in cellular iron depletion and differentially affected the expression of key IR proteins. Moreover, vitamin D induced oxidative stress and altered the redox balance in treated cells by reducing catalase protein levels and increasing the expression of several stress-related markers including γ-H2AX, hypoxia-inducible factor 1 alpha and hemoxygenase 1. Consecutively, BC cell survival was significantly decreased in vitamin D-treated cells.
Conclusion: Collectively, data presented here demonstrate that vitamin D disrupts iron homeostasis, augments oxidative damage and reduces BC cell survival and growth.
Citation Format: Khuloud Bajbouj, Jasmin Shafarin, Lina Sahnoon, Abeer Al-Ali, Jibran Sualeh Muhammad, Salman Y. Guraya, Mawieh Hamad. Vitamin D-mediated anti-cancer activity involves iron homeostatic balance disruption and oxidative stress induction in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2454.
Abstract 2457: NANOG bindsPRC2 to reprogram metabolismandpromotelabel-retaining populationin experimental mouse and clinical carcinoma
Authors: Yeh Da-Wei , Hernandez Juan Carlos , Machida Keigo 
Published: July 2021

Abstract
Background: Alcohol and HCV synergistically promote hepatocarcinogenesis. Our previous studies indicated that this synergistic effect of HCV and alcohol was mediated by TLR4, which increases the expression of NANOG, a transcription factor important for the stemness of TICs. Our recent studies further indicated that NANOG could repress mitochondrial oxidative phosphorylation (OXPHOS) genes to support the self-renewal and drug resistance of tumor-initiating stem cell-like cells (TICs), leading to relapse and metastasis (Chen et al., Cell Metabolism). In addition, approximately 39% of HCV-alcohol-associated HCCs have mutations in ARID1A, a component of the chromatin remodeling complex SWI/SNF.
Hypothesis: The efficacy of the combined FAOi and PRC2 inhibition (PRC2i) therapy relies on activation of cell death signaling.
Aims: We (1) tested if NANOG together with the PRC2 complex inhibits OXPHOS and generates TICs in the presence of ARID1A mutations; (2) tested if specific genetic alterations and NANOG cooperate to generate different classes of TICs for the development of HCC; (3) tested if ARID1A mutations with NANOG induction generate TICs.
Methods: We transduced LPCs with a lentiviral vector that expresses mCherry and used the CRISPR/Cas9 system to target Arid1a or Ctnnb1. EZH2, SUZ12 and EED were silenced in patient-derived TICs (with or without ARID1A mutations). Surviving cells are subjected to the spheroid formation assay on ultra-low attachment plates for analysis of their self-renewal ability.
Results: Mutant Arid1a HCCs with Nanog overexpression caused HCC metastasis to the lung. The humanized FRG mice subjected to alcohol feeding and/or HCV infection developed HCCs, especially in the CTNNB1 or ARID1A mutant hepatoblast groups, six months post-HCV infection and/or alcohol feeding. HCV-infected humanized livers in these mice contained HCV RNA, but not in the UV-irradiated HCV infected group.
Conclusion: ARID1A gene loss promotes sorafenib-resistance phenotype and self-renewal through PRC2 complex genes. We demonstrated that sorafenib induced cytochrome c release from mitochondria to cause apoptosis of TICs, that restoration of OXPHOS was overexpressed in TICs. The studies established a novel therapy to overcome the chemoresistance of TICs for HCC treatment.
Citation Format: Da-Wei Yeh, Juan Carlos Hernandez, Keigo Machida. NANOG bindsPRC2 to reprogram metabolismandpromotelabel-retaining populationin experimental mouse and clinical carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2457.
Abstract 2466: Stochastic loss of GLUL expression correlates with STK11-loss-dependent glutamine addiction and may impact anti-PD1 therapy resistance in NSCLC
Authors: Lenahan Sean M. , Sarausky Hailey M. , Seward David Joseph 
Published: July 2021

Abstract
Our work aims to delineate the molecular interactions linking somatic disruption of Serine-Threonine Kinase 11 (STK11) with anti-PD1 therapy resistance in KRAS-driven lung adenocarcinoma (LUAD). Data presented here suggests glutamine synthetase (GLUL) may modulate this phenotype. Immune checkpoint inhibitors (ICIs), including anti-PD1 monoclonal antibody therapy, represent a promising therapeutic option for non-small cell lung cancer (NSCLC) patients. Unfortunately, efficient use of these drugs is hampered by an inability to accurately predict which patients will respond. Clinical observations have correlated anti-PD1 therapy resistance in KRAS-driven LUAD with somatic STK11 disruption, but the mechanism(s) responsible remains unknown. To investigate this connection we knocked out STK11 in three different human KRAS-driven LUAD cell lines and performed RNA-seq analysis to identify STK11-loss-dependent differentially expressed genes. Intriguingly, GLUL expression was reproducibly lost in a subset of KRAS-driven/STK11 null clones across two different human lung adenocarcinoma cell lines. GLUL is an enzyme that converts glutamate to glutamine. Glutamine is a critical metabolite supplying carbon and nitrogen necessary for amino acid, nucleotide, and lipid synthesis. Additionally, glutamine plays an important role in redox homeostasis, chromatin organization, and intra-tumoral signaling. Glutamine dependency is a common phenotype across many solid tumor types, and has previously been linked with STK11-deficiency in the context of polycystic kidney disease. Our current work suggests loss of GLUL expression correlates with an altered tumor-intrinsic response to nutrient stress in KRAS-driven LUAD culminating in immune evasion and anti-PD1 therapy resistance. Ongoing experiments aimed to define the relationship between STK11 loss and GLUL expression suggest this phenomenon is stochastic in nature and may provide tumor cells with a selective advantage. In conclusion, understanding the biology underlying the molecular connection between STK11 and GLUL may reveal reliable biomarkers for anti-PD1 therapy response and suggest a method for restoring sensitivity to current therapies.
Citation Format: Sean M. Lenahan, Hailey M. Sarausky, David Joseph Seward. Stochastic loss of GLUL expression correlates with STK11-loss-dependent glutamine addiction and may impact anti-PD1 therapy resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2466.