bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1165: Complementary diagnostics for precision targeting of cellular pathways
Authors: Siddaway Robert , Nobre Liana , Johnson Monique , Milos Scott , Ryall Scott , Sheth Javal , Tabori Uri , Hawkins Cynthia 
Published: July 2021

Abstract
Precision medicine aims to tailor treatment to an individual patient through understanding the molecular basis of their disease. Targeted therapies have the potential to optimize responses and minimize side effects, while also offering savings to the healthcare system through tailoring treatment and avoiding futile therapies. Regimes are usually designed through identifying DNA-level alterations in the tumour and selecting drugs tailored to that mutation. However, cancer is not a one-pathway disease: not all patients with a particular mutational profile will respond to the same treatment, and patients without a canonical pathway-activating alteration will be excluded from potentially life-saving treatment. To address this, we developed a NanoString assay that combines proteomic and transcriptomic profiling of 4 key cancer-related, actionable pathways (MAPK, PI3K, NF-κB and JAK/STAT). Using RNA-Seq data from gold standard cell lines with defined changes in each pathway we generated minimal sets of genes indicative of pathway activation, and integrated this with total and phospho protein measurements to show pathway activation levels. The combined panel was run on a series of isogenic cell lines and glioma samples with both known and unknown driving alterations. Overall, pathway activation is more variable than would be predicted based on DNA alterations alone, with alternate pathway activation emerging as a potential new target and implying that consideration of proteomic and/or transcriptomic-level information will be important for future therapeutic decision-making.
Citation Format: Robert Siddaway, Liana Nobre, Monique Johnson, Scott Milos, Scott Ryall, Javal Sheth, Uri Tabori, Cynthia Hawkins. Complementary diagnostics for precision targeting of cellular 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 1165.
Abstract 1176: CHD4 predicts aggressiveness in PTC patients and promotes cancer stemness and EMT in PTC cells
Authors: Poyil Pratheeshkumar , Siraj Abdul K. , Divya Sasidharan Padmaja , Parvathareddy Sandeep Kumar , Diaz Roxanne , Begum Rafia , Al-Obaisi Khadija , Thangavel Saravanan , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: July 2021

Abstract
Papillary thyroid carcinoma (PTC) is the most common histologic subtype, accounting for nearly 90% of thyroid cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of PTC has not been investigated. Immunohistochemistry was performed to assess CHD4 protein expression in PTC using a tissue microarray. We also performed in vitro analysis to investigate the role of CHD4 in regulating cancer stemness and EMT in PTC cells. CHD4 overexpression was observed in 45.3% (650/1436) of PTCs, and was associated with aggressive clinico-pathological parameters and worse outcome. Functional analysis using PTC cell lines showed that forced expression of CHD4 promoted cell proliferation, spheroid growth, migration, invasion, and progression of epithelial to mesenchymal transition (EMT) in PTC cells whereas its knockdown reversed the effect. Methylation of E-cadherin was associated with loss of expression in CHD4 expressing cells, while CHD4 depletion reactivated E-cadherin expression. Most importantly, knockdown of mesenchymal transcriptional factors, Snail1 or Zeb1, attenuated the spheroid growth in CHD4 expressing PTC cells, showing a potential link between EMT activation and stemness maintenance in PTC. These findings suggest that CHD4 might be a promising therapeutic target in the treatment of patients with an aggressive subtype of PTC.
Citation Format: Pratheeshkumar Poyil, Abdul K. Siraj, Sasidharan Padmaja Divya, Sandeep Kumar Parvathareddy, Roxanne Diaz, Rafia Begum, Khadija Al-Obaisi, Saravanan Thangavel, Saif S. Al-Sobhi, Fouad Al-Dayel, Khawla S. Al-Kuraya. CHD4 predicts aggressiveness in PTC patients and promotes cancer stemness and EMT in PTC 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 1176.
Abstract 1181: Neratinib induces synthetic lethality with PARP inhibitors in triple negative breast cancer cells in vitro and in vivo
Authors: Xing Chuan , Zhang Zhuo , Manna Deborah Della , Diala Irmina , Eli Lisa , Lalani Alshad S. , Yang Eddy Shih-Hsin 
Published: July 2021

Abstract
Background: We previously showed preclinical and clinical activity of combined inhibition of EGFR and PARP with lapatinib and veliparib in triple negative breast cancer (Nowsheen et al. PLoS One 2012;7(10):e46614; Reasor et al. J Clin Onc 2018; 36(15_suppl):1095), due to an induced homologous recombination repair defect with EGFR inhibition sensitizing cells to PARP inhibition. In this study, we tested the in vitro and in vivo activity of the irreversible pan-HER tyrosine kinase inhibitor, neratinib, with the PARP inhibitor olaparib or niraparib.
Methods: Human triple negative breast cancer (TNBC) cells MDA-MB231 (BRCA wt), MDA-MB453 (BRCA wt), and MDA-MB436 (BRCA1 mutant) and Mouse TNBC 4T1 cells (BRCA wt) were used. Cell proliferation and colony formation assays were performed to assess the in vitro activity of various concentrations of neratinib and olaparib. Markers of DNA damage were measured via gamma-H2AX western blot analysis. In vivo effects of combination treatments on tumor metastasis were tested using intracardiac injection of tumor cells labelled with luciferase and mice were monitored for survival.
Results: Combining neratinib with olaparib or niraparib significantly decreased proliferation compared to either agent alone in MDA-MB231, MDA-MB453, MDA-MB436 and 4T1 cells. Similar results were observed using colony formation assays. Cytotoxicity was associated with increased gamma-H2AX levels, indicating persistent DNA damage. Mice treated with 20mg/kg/day of neratinib and 100mg/kg/day of olaparib after MDA-MB231-Luc intracardiac injection exhibited reduced tumor metastases compared to either agent alone, resulting in better survival (p=0.0088).
Conclusions: Combining neratinib with PARP inhibition induces synthetic lethality resulting in increased anti-tumor activity in TNBC in cell lines and in xenografts. Future clinical trials testing these combinations are warranted.
Citation Format: Chuan Xing, Zhuo Zhang, Deborah Della Manna, Irmina Diala, Lisa Eli, Alshad S. Lalani, Eddy Shih-Hsin Yang. Neratinib induces synthetic lethality with PARP inhibitors in triple negative breast cancer cells 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 1181.
Abstract 1200: Long-duration term TTFields treatment of glioblastoma cells induces cell death
Authors: Castiglione Stefania , Ranucci Matteo , Cannavale Gaetano , Cianci Francesca , Verduci Ivan , Mazzanti Michele 
Published: July 2021

Abstract
Glioblastoma is the most aggressive among brain tumors. Radiotherapy and chemotherapy, as adjuvanttreatments after surgical removal of the tumor mass, are often accompanied by undesirable symptoms. Evenwith these available treatment options, patient prognosis is extremely poor. The only approved treatmentoption demonstrating improved life expectancy in the last twenty years has been the application of TumorTreating Fields (TTFields). However, despite different therapeutic actions, tumor relapse occurs inexorably inmost patients. It is essentially unanimously agreed upon that tumor recurrence is due to a small populationof cells named glioblastoma stem cells (GSCs). GSCs represent a restricted cellular subpopulation in the tumormass composed mainly of bulk cells. The main characteristic of GSCs is their tumorigenic capacity even if asmall number of cells are left after surgery. Our working hypothesis is based on evidence that TTFieldsexposure destabilizes the mitotic spindle of rapidly dividing cells to elicit cell death. Thus, TTFields stimulationshould preferentially target bulk cells due to their higher proliferation rates compared to GSCs. Preliminaryexperiments performed using glioblastoma primary cultures obtained from patients' biopsies demonstratedthe presence of two different cell populations. In glioblastoma primary cultures maintained in stem-cellselective medium, more than 90% of glioblastoma cells did not exhibit stemness characteristics. After 72hours of TTFields stimulation, cell death was ascertained in approximately 50% of cells. The remaining viablecells were more than 20% positive for three different stemness markers. Long duration TTFields treatmentexperiments (144 and 288 hours) showed that TTFields at 200 kHz is able to increase the percentage of GSCin glioblastoma cells, yet did exhibit a propensity to reestablish cellular proliferation.In conclusion, long duration TTFields (200 kHz) treatment demonstrated efficacy by inducing cell death anddelaying glioblastoma cell expansion. However, to prevent glioblastoma relapse it is important to combineTTFields with different combination partners that specifically target glioblastoma stem cells.
Citation Format: Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci, Michele Mazzanti. Long-duration term TTFields treatment of glioblastoma cells induces cell death [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 1200.
Abstract 1201: Amentoflavone inhibits cell growth and metastasis in colorectal cancer was associated with the suppression of KIAA1199
Authors: Ku Hsiang-Ju , Tan Zhao-Lin , Chiang I-Tsang , Chang Yuan , Hsu Fei-Ting 
Published: July 2021

Abstract
Amentoflavone (AF), a kind of diflavonoid compound, which was used as a traditional folk medicine thousands years ago. AF had been proven to prevent cells degeneration, aging, and could also induce cell cycle arrest and apoptosis in various human cancer cells to achieve anti-tumor effects. Cell migration-induced hyaluronic acid binding protein (CEMIP, KIAA1199), an oncogene protein, has been confirmed to be associated with the abnormal expression of epithelial-mesenchymal transition (EMT) markers. Several studies also reported that the inhibition of KIAA1199 can suppress the proliferation of colorectal cancer (CRC). At present, there is no study identify whether AF can inhibit the growth of colorectal cancer by regulating KIAA1199. The aim of this study was to investigate the anticancer effect and mechanism of AF in colorectal in vitro and in vivo. First, we indicated that the cytotoxic effect was induced by AF in human and mouse CRC (CT26 & HT29) cells. The fewest colony formation was found in AF treated group, which represent the suppression of proliferation. Cell cycle was arrest at G1 by AF treatment which was evaluated by flow cytometry. Then, the migration and invasion suppression was also found in amentoflavone treatment group by wound healing and invasion/migration transwell assay. Furthermore, real-time polymerase chain reaction detection and Western blotting results indicated that KIAA1199 related genes, such as E-cadherin, N-cadherin, Vimentin and Fibronectin were all downregulated by amentoflavone. In animal experiments, the CRC tumors volume were reduced in AF treatment groups. In summary, AF can achieve therapeutic effects in colorectal cancer by inhibiting cell proliferation, migration/invasion ability and EMT potential via suppression of KIAA1199.
Citation Format: Hsiang-Ju Ku, Zhao-Lin Tan, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu. Amentoflavone inhibits cell growth and metastasis in colorectal cancer was associated with the suppression of KIAA1199 [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 1201.
Abstract 1202: ERG344: A novel IRG1 inhibitor for the treatment of colon cancer
Authors: Papathanassiu Adonia E. , Lodi Francesca , Vu Hong A. , Lambrechts Diether 
Published: July 2021

Abstract
Immune responsive gene 1 (Irg1) is an LPS-inducible gene within macrophages (MF) whose protein product is responsible for the synthesis of itaconate from aconitate through a break in the TCA cycle. Although primarily present in proinflammatory macrophages, IRG1 expression has been linked with certain cancers (glioblastoma, ovarian carcinoma) and its tumor-driven upregulation in peritoneal resident macrophages (pResMF) has been shown to contribute to peritoneal tumor growth. Here, we report Irg1 gene expression at the single cell level (scRNAseq) in samples obtained from colorectal cancer patients (n=7; ~11,000 single cells). Transcriptomic analysis showed that Irg1 was primarily expressed by cancer cells, although other tumoral cell types also showed substantial levels of the gene. To determine if IRG1 is a druggable target in cancer, we synthesized a series of small MW inhibitors and selected ERG344 for in vivo testing based on its ability to inhibit itaconate synthesis in a rat glioblastoma cell line (C6) engineered to stably express Irg1. The IC50 value of inhibition was ~150 μM. In vivo, ERG344 suppressed tumor growth and increased survival probability in a syngeneic colon cancer model (CT26). Drug administration was initiated when the tumors reached an average tumor volume of ~100 mm3 and involved daily ERG344 doses of 0.2 mg/kg ip or 0.3 mg/kg po. Complete tumor regressions (~17%) were observed in the same model when ERG344 was administered ip at 3 mg/kg. Immunophenotyping of CT26 tumors treated with either vehicle or 0.2 mg/kg ERG344 ip indicated that IRG1 inhibition renders the tumor microenvironment less immunosuppressive by decreasing the frequency of monocytic myeloid suppressor cells (m-MDSCs), increasing the frequency of cytotoxic CD8+ T cells, and decreasing the CD8+ expression of the negative co-stimulatory molecule PD-1. To determine if ERG344 is also able to reduce pResMF-driven peritoneal tumor growth, murine melanoma B16F15 cells were injected into the peritoneal cavity of C57BL/6 mice treated with vehicle or 1 mg/kg ERG344 (n=8/group). Seven days after tumor inoculation, mice treated with ERG344 showed reduced tumor growth in the peritoneal cavity, which led to increased survival probability of the animals. The studies collectively suggest that IRG1 is a novel target for the treatment of primary and metastatic tumor growth in colorectal cancer and highlight the therapeutic potential of ERG344.
Citation Format: Adonia E. Papathanassiu, Francesca Lodi, Hong A. Vu, Diether Lambrechts. ERG344: A novel IRG1 inhibitor for the treatment of colon 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 1202.
Abstract 1208: Identifying a novel glycolytic inhibitor for treatment of aggressive prostate cancer
Authors: Stoyanova Tanya Ivanova 
Published: July 2021

Abstract
Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. Chalcones are a major class of widely occurring natural products that are intermediates in plant flavonoid isoflavonoid synthesis. They are characterized by an α,β-unsaturated carbonyl structure with two aromatic rings and commonly act as free-radical scavengers.
Herein, we describe a chalcone derivative, SU086, as an anticancer agent for prostate cancer. Proteomic and metabolomic profiling demonstrate that SU086 impairs glycolysis, a critical pathway for cancer growth and survival. SU086 inhibited prostate cancer cell growth, migration, and invasion in vitro. Moreover, SU086 significantly delayed the tumor growth of cell line-derived xenograft models of CRPC as well as patient-derived xenografts (PDXs) in vivo, and the proliferation of primary human prostate cancer patient-derived tissues ex vivo. Furthermore, SU086 strongly synergized with standard of care second-generation anti-androgens, enzalutamide and abiraterone, in inhibiting prostate cancer cell growth in vitro and tumor growth in vivo.
Our study identifies SU086 alone or in combination therapy settings as a novel treatment for aggressive prostate cancer. We demonstrate that SU086 represents a highly effective therapeutic strategy for both AR-sensitive and AR-insensitive prostate cancers and may potentially be applicable across multiple cancer types.
Citation Format: Tanya Ivanova Stoyanova. Identifying a novel glycolytic inhibitor for treatment of aggressive prostate 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 1208.
Abstract 1215: Targeting TIP1 with a novel radiosensitizing antibody-drug conjugate (ADC) enhances the therapeutic efficacy of radiation for non-small cell lung carcinoma treatment
Authors: Lewis Calvin , Singh Abhay K. , Thotala Dinesh , Hallahan Dennis E. , Kapoor Vaishali 
Published: July 2021

Abstract
Tax-interacting protein 1 (TIP1) is a multifunctional protein involved in cellular motility, cellular adhesion, migration, cancer cell protection from ionizing radiation, and metastasis. We found that TIP1 is a radiation inducible antigen that is translocated to the cancer cell surface. Antibody-drug-conjugates (ADCs) are emerging as promising anti-cancer immunoconjugates. ADCs carry antitumor payloads and allow site-specific targeting of cancer with increased cytotoxicity and decreased side effect profiles as compared to conventional chemotherapy. Monomethyl auristatin E (MMAE) is a potent radiosensitizing microtubule inhibitor with enhanced cancer cytotoxicity in combination with radiotherapy. We developed ADCs against radiation-inducible TIP1 for lung cancer treatment in combination with radiation. Out of the various anti-TIP1 antibodies, we prioritized the lead antibody that shows high affinity to TIP1 protein on the cancer cell surface and in vivo irradiated lung cancers. Our lead antibody, 7H5 undergoes endocytosis in cancer cells in vitro. We conjugated 7H5 to VcMMAE. Hydrophobic interaction chromatography (HIC) was performed to determine drug-to-antibody ratio (DAR). We obtained an average DAR of 3.7. Cytotoxic potential of 7H5-VcMMAE was evaluated in A549 and H1299 NSCLC cells. Cells were exposed to 7H5-VcMMAE or 7H5-antibody alone at various doses. At 10nM concentration, ~70% reduction in viable cells was observed following 7H5-VcMMAE treatment compared to 7H5 alone in both A549 (p=0.0032) and H1299 cells (p=0.0010). 7H5-VcMMAE sensitized A549 and H1299 cells to radiation as observed by significantly decreased (p&lt;0.001) surviving fraction compared to 7H5 alone. In vivo therapeutic efficacy of the 7H5-VcMMAE was determined using mice bearing hind-limb human NSCLC tumors. The ADC showed a prolonged delay in tumor growth and improved tumor control was achieved with IR + 7H5-VcMMAE in A549 and H1299 hind-limb tumor models. Furthermore, mice in all groups displayed no toxicity associated with treatment. Our study suggests that targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy to enhance therapeutic efficacy in lung cancer. This novel approach of targeting cancer using ADCs to radiation-inducible antigens will lead to clinical trials in lung cancer patients treated with radiotherapy.
Citation Format: Calvin Lewis, Abhay K. Singh, Dinesh Thotala, Dennis E. Hallahan, Vaishali Kapoor. Targeting TIP1 with a novel radiosensitizing antibody-drug conjugate (ADC) enhances the therapeutic efficacy of radiation for non-small cell lung carcinoma treatment [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 1215.
Abstract 1219: Deep mutational scanning of PDE3A identifies residues required for DNMDP response
Authors: Wu Xiaoyun , Papanastasiou Malvina , Schnitzler Gavin , Garvie Colin , Hoyt Stephanie , Zhang Terry , Mullahoo James , Baker Andrew , McGaunn Joseph , Kaplan Bethany , Lee Sooncheol , Lange Martin , Carr Steven , Yang Xiaoping , Piccioni Federica , Cherniack Andrew , Meyerson Matthew , Greulich Heidi 
Published: July 2021

Abstract
PDE3A-SLFN12 complex formation is induced by a class of compounds, now called “velcrins”, exemplified by the small molecule, DNMDP. Cancer cells that express elevated levels of PDE3A and SLFN12 are sensitive to a velcrin-mediated cytotoxic response, which is independent of PDE3A inhibition. However, the details of complex formation have not yet been revealed. We solved the crystal structure of PDE3A with a series of ligands bound to the active site and found that PDE3A exists as a dimer, and velcrin binding does not cause any obvious structural changes in the PDE3A protein structure. Hydrogen-deuterium exchange (HDX-MS) experiments with velcrin-bound PDE3A in the absence and presence of SLFN12 identified three regions of PDE3A that are shielded from solvent as a result of velcrin-induced SLFN12 binding. Two of these regions are near the velcrin binding site, and the third region lies at the PDE3A homodimerization interface. In order to further investigate the structural relationship between PDE3A, DNMDP, and SLFN12, we took a deep-mutation scanning (DMS) approach to identify residues of PDE3A that impact DNMDP sensitivity. A library of PDE3A alleles was developed in which the sequence encoding amino acids 668-1141, including the PDE3A catalytic domain, was substituted with a codon for every other possible amino acid or a stop codon in the context of the full-length cDNA. The library was transduced into PDE3A-knockout GB1 glioblastoma cells and assessed for survival in the presence of DMSO or DNMDP. Corroborating the HDX-MS data, we identified three regions of PDE3A in which missense mutations abrogated DNMDP response: the active site, the homodimerization surface, and an alpha helix containing amino acid F914. We confirmed that mutations of F914 and the homodimer interface retain the ability to bind resin-conjugated compound but fail to complex with SLFN12. Taken together, the HDX and DMS results suggest that PDE3A dimerization is required to stabilize velcrin-induced SLFN12 binding and implicate the alpha helix containing F914 as the SLFN12 binding interface of PDE3A.
Citation Format: Xiaoyun Wu, Malvina Papanastasiou, Gavin Schnitzler, Colin Garvie, Stephanie Hoyt, Terry Zhang, James Mullahoo, Andrew Baker, Joseph McGaunn, Bethany Kaplan, Sooncheol Lee, Martin Lange, Steven Carr, Xiaoping Yang, Federica Piccioni, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Deep mutational scanning of PDE3A identifies residues required for DNMDP response [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 1219.