bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2282: Rapid and accurate variant calling of FFPE samples with the genexus system
Authors: Casuga Iris , Gioia Jason , Au-Young Janice , Chan Frances , Huynh Milton , Crowe Michael 
Published: July 2021

Abstract
Next Generation Sequencing technology has enhanced oncology research by enabling the detection of relevant variants for clinical and drug discovery programs. The Oncomine Comprehensive Assay v3, a pan-cancer panel, used with the Ion Torrent Genexus System allows for formalin-fixed paraffin embedded (FFPE) samples to be examined across 161 unique genes in an automated workflow from sample to result in 30hrs. This study demonstrates ≥ 90% accuracy for detecting SNV/Indel/CNV and Fusion variants.
The Genexus System consists of two software linked instruments, the Genexus Purification System and the Genexus Integrated Sequencer. The purification system is used first to extract and quantify 6 FFPE sections from human colon and lung tissue for matching DNA & RNA pairs. The nucleic acid output plate from the purification instrument is directly transferred to the sequencer for library preparation and sequencing using the Oncomine Comprehensive Assay v3. Variant calling analysis of 6 DNA & RNA pairs are completed the following day. Results show that the variants were detected with ≥ 90% Sensitivity when compared to the Ion Torrent GeneStudio S5 System as an orthogonal method. All variants report p-values ≤ 10^-5 signifying more confidence that the variant call is correct. The Genexus System is a seamless solution for sample to variant calling results.
Citation Format: Iris Casuga, Jason Gioia, Janice Au-Young, Frances Chan, Milton Huynh, Michael Crowe. Rapid and accurate variant calling of FFPE samples with the genexus system [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 2282.
Abstract 2302: The mechanism of activation of monomeric B-Raf V600E
Authors: Maloney Ryan C. , Zhang Mingzhen , Jang Hyunbum , Nussinov Ruth 
Published: July 2021

Abstract
B-Raf V600E mutations are frequent in cancer, including over 50% of all melanoma. B-Raf, like many other kinases, undergoes structural changes as it transitions between the inactive and active conformations. Key among these changes are the movement of αC helix from an inactive “OUT” conformation to an active “IN” conformation, and the movement of the activation loop from a closed inactive conformation to an open active conformation. Yet even with the knowledge of what the inactive and active conformations are, questions remain concerning how the V600E mutation activates B-Raf. In particular, we seek to understand why B-Raf V600E is constitutively active in its monomeric state while wild type B-Raf requires dimerization. Here, we investigate the differences between the wild type and mutant B-Raf monomers using molecular dynamics (MD) simulations. We included ATP in the nucleotide binding pocket to more fully explore how it is positioned within B-Raf. Our results show that the 1 µs simulations are too short to capture large conformational changes, however some of the simulations show a transient formation and breaking of the key salt-bridge between Lys483 and Glu501, which gives insight into the movement of the αC helix between the OUT and IN conformations. In addition, the dihedral angles around the DFG motif move towards a more active configuration for B-Raf V600E, while those of the wild type adopt a more inactive orientation. These simulations aid in our understanding of the dynamics of activation in B-Raf V600E.
Citation Format: Ryan C. Maloney, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of activation of monomeric B-Raf V600E [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 2302.
Abstract 2304: Regulation of the oncogenic tyrosine kinase ACK1 through ubiquitin-dependent mechanism
Authors: Balasooriyage Eranga Roshan Balasooriya Loku , Owen Jacob , Gashler Jack , Muir Colin , Pennington Katie , Moody James , Andersen Joshua L. 
Published: July 2021

Abstract
ACK1 is an oncogene in the ACK family of non-receptor tyrosine kinases (NRTK). In humans, ACK1 is located on chromosome 3q29, a region that is frequently amplified in a variety of cancers including prostate, lung and breast. The ACK kinase family has a unique domain arrangement with, most notably, a putative ubiquitin association (UBA) domain at their C-termini. In the present study, we focus on understanding the ubiquitin-binding nature of the ACK1 UBA and its role in kinase regulation. Structural modeling and sequence analysis suggest that the ACK1 UBA diverges from many other UBAs but shares similarities with the ACK family kinase, TNK1. We found that the ACK family UBA has a remarkably high affinity for diverse poly-ubiquitin linkages with dissociation constants in the low nanomolar range. Our preliminary data suggest that a non-covalent interaction between the UBA and ubiquitin is necessary for ACK kinase activation in cell culture systems. Furthermore, our preliminary data suggest this interaction is sufficient to induce ACK1 activation in vitro. In support of the idea that the UBA is important for ACK1 activation, we identified a variety of cancer patient mutations that disrupt the ACK1 UBA, which we are currently testing for oncogenic activity. Lastly, we have identified small molecule inhibitors of ACK with low nanomolar IC50 values in ACK1-driven cells. Altogether, our data suggest a model of ACK1 activation that involves direct, non-covalent interaction with ubiquitin and potential therapeutic approaches to inhibit ACK1 in cancer.
Citation Format: Eranga Roshan Balasooriya Loku Balasooriyage, Jacob Owen, Jack Gashler, Colin Muir, Katie Pennington, James Moody, Joshua L. Andersen. Regulation of the oncogenic tyrosine kinase ACK1 through ubiquitin-dependent mechanism [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 2304.
Abstract 2328: Interrogating the anti-cancer effects of co-enzyme Q10 (CoQ10) identifies metabolic and mitochondrial apoptotic responses as primary mechanisms in squamous cell carcinoma model
Authors: Narain Niven R. , Kazerounian Shiva , Khatu Shivani , Diers Anne R. , McCook John , Gesta Stephane , Kirsner Robert S. , Berman Brian , Sarangarajan Rangaprasad 
Published: July 2021

Abstract
Targeting mitochondrial function as a therapeutic modality in cancer has been extensively investigated. BPM 31510 is a proprietary drug-lipid nanoconjugate formulation enabling delivery of supra-physiological concentrations of oxidized CoQ10 specifically into mitochondria. In this study, the anti-cancer properties of CoQ10 in squamous cell carcinoma (SCC) and its mechanism of action were investigated in in vivo xenograft and in vitro model systems. Nude mice were inoculated with a squamous carcinoma cell line isolated from tongue, SCC-25, and treated with a topical formulation containing 1.5% or 5% CoQ10. Treatment was associated with a dose-dependent delay in the detection of palatable tumors (14 ± 3 days vehicle control, 27 ± 7 days 1.5% cream, 39 ± 9 days 5% cream), (p&lt;0.05). Histology and immunostaining analysis demonstrated a decrease in expression of VEGF in the treatment groups (p&lt;0.05). The anti-cancer mechanism of action of CoQ10 was further investigated by interrogating the influence of CoQ10 exposure on molecular profiles using SCC-25 cells in vitro. Cell based assays, mRNA-based RT-PCR assays, and protein-based antibody chip microarrays confirmed an apoptotic response as a major anti-cancer effect in SCC-25 cells in response to CoQ10 exposure. The change in anti- and pro-apoptotic markers (Bcl-2 and caspase families) was independently confirmed by western blotting. In addition, global proteomic analysis revealed alterations in key metabolic proteins in the Pentose Phosphate Pathway (PPP). For example, expression of Transaldolase 1, an enzyme involved in the cellular protection against oxidative stress, resistance/susceptibility to apoptosis, and SCC tumor development and progression, was reduced 1.5 fold at both 6 and 24 hour time point in response to CoQ10 treatment. Together, the data suggests that CoQ10 influences cancer metabolism and redox pathway in activating apoptosis in SCC cancer model.
Citation Format: Niven R. Narain, Shiva Kazerounian, Shivani Khatu, Anne R. Diers, John McCook, Stephane Gesta, Robert S. Kirsner, Brian Berman, Rangaprasad Sarangarajan. Interrogating the anti-cancer effects of co-enzyme Q10 (CoQ10) identifies metabolic and mitochondrial apoptotic responses as primary mechanisms in squamous cell carcinoma model [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 2328.
Abstract 2329: ONC212-induced impairment of oxidative phosphorylation is synergistic with glycolysis inhibition in treatment of pancreatic cancer in vitro and in vivo
Authors: Louie Anna Donovan , Ferrarini Isacco , Zhou Lanlan , El-Deiry Wafik S. 
Published: July 2021

Abstract
ONC212 is a fluorinated imipridone shown to have preclinical efficacy against multiple cancers, including pancreatic cancer. One of the binding targets of ONC212 is the mitochondrial peptidase, ClpP, but its role in the anticancer activity of ONC212 is incompletely understood. Understanding the effects of ONC212 on the bioenergetics of pancreatic cancer could facilitate understanding and amplification of its anti-tumor effects. On extracellular flux analysis, ONC212 impairs mitochondrial ATP production and oxidative phosphorylation in multiple pancreatic cancer lines. However, pancreatic adenocarcinoma uses both glycolysis and mitochondrial function to meet its energy demands. Some pancreatic cancer cell lines are resistant to ONC212 inhibition of oxidative phosphorylation alone, but co-treatment with glycolytic inhibitor 2-deoxy-D-glucose (2-DG) synergizes with ONC212 and increases tumor cell death in vitro. Suppression of ClpX, the regulatory binding protein of ClpP, occurs with ONC212 treatment and was used as a biomarker of ONC212 activity. This suppression was demonstrated in multiple pancreatic cancer lines in vitro and in vivo. In a xenograft mouse tumor model of pancreatic cancer using both the ONC212 resistant Bxpc3 pancreatic cancer cell line and the more sensitive HPAF-II cell line, the combination of ONC212 and 2-DG treatment significantly decreased tumor growth and reduced the intertumoral variability. Immunohistochemistry also revealed increased apoptotic markers in these tumors. There was no significant toxicity from dual treatment in mice, which suggests that tumor energy deprivation from dual inhibition of oxidative phosphorylation and glycolysis via ONC212 and 2-DG has a therapeutic window and should be explored further as a potential combination therapy. In addition, if this effect holds true across other models and cancer types, baseline mitoATP percentage could be used as a functional biomarker of sensitivity to ONC212.
Citation Format: Anna Donovan Louie, Isacco Ferrarini, Lanlan Zhou, Wafik S. El-Deiry. ONC212-induced impairment of oxidative phosphorylation is synergistic with glycolysis inhibition in treatment of pancreatic cancer in vitro and in vivo [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 2329.
Abstract 2334: Discovery of selective inhibitors of carbamoyl phosphate synthetase I (CPS1) to modulate cancer relevant metabolic pathways
Authors: Yao Shihua , Nguyen Tuong-Vi , Rolfe Alan , Agrawal Anant A. , Ke Jiyuan , Peng Shouyong , Colombo Federico , Yu Sean , Bouchard Patricia , Wu Jiayi , Huang Kuan-Chun , Bao Xingfeng , Omoto Kiyoyuki , Selvaraj Anand , Yu Lihua , Ioannidis Stephanos , Vaillancourt Frédéric H. , Zhu Ping , Larsen Nicholas A. , Bolduc David M. 
Published: July 2021

Abstract
Carbamoyl Phosphate Synthetase 1 (CPS1) catalyzes the first and rate-limiting step in ammonia detoxification through the urea cycle, generating carbamoyl phosphate from ammonia, bicarbonate and ATP. CPS1 is overexpressed in several cancers, including LKB1-deficient non-small cell lung carcinoma (NSCLC), where its activity has been proposed to support tumor growth by generating carbamoyl phosphate for use in pyrimidine synthesis. In other cancers, CPS1 has been reported to remove toxic ammonia from growing tumors to allow for sustained growth. Currently, no small molecule inhibitors of CPS1 have been identified, limiting researcher's ability to dissect the involvement of CPS1 function in cancer biology.
We describe here the discovery of the first known small molecule inhibitors of CPS1. From a high throughput screen, we identify two chemical series, which achieve inhibition of CPS1 by blocking bicarbonate phosphorylation in the first step of carbamoyl phosphate synthesis. Biochemical experiments reveal inhibition of bicarbonate phosphorylation occurs through competition between inhibitor and ATP. High-resolution co-crystal structures demonstrate that these novel inhibitors bind to a previously unidentified allosteric pocket located between the integrating domain and carbamate synthetase domain of CPS1. This allosteric mechanism of action allows for highly selective CPS1 inhibition, with no inhibition of CPS2 observed. Analogs with increased potency were developed, which are able to inhibit CPS1 cellular activity, blocking both urea production and the CPS1-mediated pyrimidine biosynthetic pathway in cultured cells. These novel CPS1 inhibitors are valuable, first-in-class tools for probing CPS1 biology. We will also discuss the opportunity to utilize these novel inhibitors of CPS1, along with genetic approaches, to probe the functional roles of CPS1 in LKB1-deficient NSCLC.
Citation Format: Shihua Yao, Tuong-Vi Nguyen, Alan Rolfe, Anant A. Agrawal, Jiyuan Ke, Shouyong Peng, Federico Colombo, Sean Yu, Patricia Bouchard, Jiayi Wu, Kuan-Chun Huang, Xingfeng Bao, Kiyoyuki Omoto, Anand Selvaraj, Lihua Yu, Stephanos Ioannidis, Frédéric H. Vaillancourt, Ping Zhu, Nicholas A. Larsen, David M. Bolduc. Discovery of selective inhibitors of carbamoyl phosphate synthetase I (CPS1) to modulate cancer relevant metabolic pathways [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 2334.
Abstract 2346: Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel
Authors: Labanca Estefania , Bizzotto Juan , Yang Jun , Sanchis Pablo , Shepherd Peter , Paez Alejandra , Antico-Arciuch Valeria , Anselmino Nicolas , Lage-Vickers Sofia , Hoang Anh , Tituts Mark , Efstathiou Eleni , Cotignola Javier , Logothetis Christopher , Vazquez Elba , Navone Nora , Gueron Geraldine 
Published: July 2021

Abstract
Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis. Using PCa patient-derived xenografts (PDXs) we assessed the metabolic changes after castration of tumor-bearing mice. We found that relapsed tumors had a significant increase in fatty acids and ketone body content compared with baseline. We confirmed that critical ketogenic/ketolytic enzymes (ACAT1, OXCT1, BDH1) were significantly augmented after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. Increased ACAT1 and OXCT1 was also observed for a subset of PCa patients that relapsed with low AR and ERG expression. These factors were associated with decreased biochemical relapse and progression free survival. In summary, our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.
Citation Format: Estefania Labanca, Juan Bizzotto, Jun Yang, Pablo Sanchis, Peter Shepherd, Alejandra Paez, Valeria Antico-Arciuch, Nicolas Anselmino, Sofia Lage-Vickers, Anh Hoang, Mark Tituts, Eleni Efstathiou, Javier Cotignola, Christopher Logothetis, Elba Vazquez, Nora Navone, Geraldine Gueron. Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel [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 2346.
Abstract 235: Identifying potential drug targets using patient-derived, tissue specific, gene regulatory networks
Authors: Forbes Andre Neil , Xu Duo , Khurana Ekta 
Published: July 2021

Abstract
Recent developments in sequencing have allowed consortiums like ENCODE and ROADMAP to probe the epigenome of normal and cancer cell lines. Applying these approaches in a broad fashion to patient data has been difficult but a pioneering TCGA study using ATAC-Seq, an assay for probing open chromatin and thus regulatory regions, provides an opportunity to analyze cancer patient epigenomes for key regulators and potential drug targets.
Utilizing this TCGA dataset, we identify the regulatory targets of open chromatin regions as assayed by ATAC-Seq and RNA-Seq across 371 patients on a patient-specific basis. We subsequently utilize transcription factor (TF) footprinting to identify regions bound by 850 TF &TF-families in each patient. The final output of this approach identifies which TF regulates individual genes for every patient. Using a combination of network metrics and TF abundance, we can identify known and rare subtypes of multiple cancers with similar underlying networks. We next identify a set of TFs with greater importance and predicted activity within each cluster of samples relative to others. To expand the set of potentially druggable genes, we use data from the Achilles/DepMap project to identify a set of genes whose essentiality is most highly correlated with the set of critical TFs for each cluster, i.e. “coessential genes”. We next combine our list with two datasets, the list of known druggable genes and the Drug Interaction Database to identify compounds that target this gene set. We prioritize genes highly correlated with our key TFs' essentiality, are not pan-cancer essential genes or targeted by drugs with high inferred toxicity. We identify a set of neuroendocrine-like cancers in lung and stomach adenocarcinoma, rare disease subtypes in their representative cancers. Further investigation finds these samples expressing high levels of known neuroendocrine markers synaptophysin and PCSK1. Within well-studied cancers like breast and colon adenocarcinoma we identify separate ER+ and ER- sample clusters as well as MSI-H samples as separate and featuring different key TFs than MSI-L and MSS clusters. Our drug candidate pipeline identified known targeted drugs in breast cancer such as Tamoxifen and Fulvestrant, non-specific chemotherapies like doxorubicin in addition to the novel candidates Nelfinavir and Indinavir as potential therapeutic agents. In summary we identify key TFs in multiple cancers and novel drugs for targeting those TFs or downstream effectors.
Citation Format: Andre Neil Forbes, Duo Xu, Ekta Khurana. Identifying potential drug targets using patient-derived, tissue specific, gene regulatory networks [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 235.
Abstract 2351: Multiomics integration elucidates onco-metabolic modulators of drug resistance in lymphoma
Authors: Singh Satishkumar , Choueiry Fouad , Hart Amber , Sircar Anuvrat , Zhu Jiangjiang , Sehgal Lalit 
Published: July 2021

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton's tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure. Upon reaching drug tolerance, B-cell NHL cells proliferate faster, which suggests increased metabolic activity. In this study, we explored the onco-metabolic regulators of ibrutinib -resistant activated B-cell (ABC) DLBCL using a ‘multi-omics' analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomics (gene expression analysis). We performed unbiased statistical analyses to uncover dysregulated metabolic pathways among the proteomic and transcriptomic datasets. Overlay of the analyses identified two significantly altered metabolic pathways at both the metabolic and transcript level. Gene-metabolite integration revealed interleukin 4 induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in the production of various amino acids. We showed for the first time that a metabolic shift from glycolysis towards oxidative phosphorylation in these lymphomas is activated via the BTK-PI3K-AKT-IL4I1 axis and can be targeted therapeutically. These findings from our unbiased analyses highlight the role of metabolic dysregulation during drug resistance development. Furthermore, our work demonstrates that a multi-omics approach can be a powerful and unbiased strategy to uncover genes and pathways that drive metabolic dysregulation in cancer cells.
Citation Format: Satishkumar Singh, Fouad Choueiry, Amber Hart, Anuvrat Sircar, Jiangjiang Zhu, Lalit Sehgal. Multiomics integration elucidates onco-metabolic modulators of drug resistance in lymphoma [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 2351.