bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1035: VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity
Authors: Wang Jieqiong 
Published: June 2022

Abstract
Pancreatic cancer is the most lethal malignant neoplasms across the world with the lowest overall five-year survival rate (9%). TP53 is mutated in ~70% of pancreatic ductal adenocarcinomas (PDACs). Hotspot p53 mutants promote cancer cell proliferation, metastasis and metabolism through their gain-of-function (GOF). Among the p53 “hotspot” mutations, R273 is the most frequent mutation position (~12%) with R273H as the most commonly mutated codon (~8%) in PDACs. However, the mechanisms underlying regulation of mutant p53s’ GOF in PDACs remain incompletely understood. In our attempt to address this question, we recently identified the ATPase valosin-containing protein (VCP)/p97 as a novel mutant p53-binding protein by performing immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) analysis. VCP bound to p53-R273H via the DNA-binding domain. VCP inhibition either by genetic depletion or pharmacological inhibition by CB-5083 resulted in the increase of MDM2-mediated ubiquitination and degradation of p53-R273H. VCP did so by binding to MDM2 and disturbing its interaction with mutant p53. As a result, VCP protected mutant p53 from degradation and enhanced its GOF in cancer development. Ablation of VCP retarded PDAC cell growth in vitro and in vivo. Our further studies also unveiled the negative regulation of wt p53 by VCP in cancer cells. Together, these results demonstrate that VCP can strengthen mutant p53’s oncogenic function by stabilizing it and negating wt p53 function, suggesting VCP as a resistant factor for chemotherapy against PDACs and thus a potential therapeutic target of the mutant p53-harboring pancreatic cancers as well as of the wt p53-containing cancer cells.
Citation Format: Jieqiong Wang. VCP/p97 promotes pancreatic cancer growth by enhancing mutant p53 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1035.
Abstract 1040: Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma
Authors: Sarnella Annachiara , Ferrara Ylenia , Auletta Luigi , Albanese Sandra , Alterio Vincenzo , Winum Jean-Yves , Supuran Claudiu T , Cerchia Laura , De Simone Giuseppina , Zannetti Antonella 
Published: June 2022

Abstract
The head and neck squamous carcinomas (HNSSCs) are the sixth most common cancer worldwide. Given the heterogeneous nature of HNSCC, this carcinoma results in higher resistance to chemoradiotherapy. Recent evidence highlight the importance of the hypoxic microenvironment in contributing to cisplatin resistance. Therefore, the aim of this study was to investigate the role played by hypoxia-induced protein carbonic anhydrase 9 (CA9) in supporting HNSCC cisplatin resistance. Furthermore, we purpose to investigate the ability of CA9 inhibitor, SLC-0111, a small molecule already used in Phase I clinical trial, to sensitize HNSSC cells to chemotherapy in vitro and in vivo. We analyzed the expression of CA9 in a public data set of 103 HNSCC samples and 22 oral cavity normal tissues and in two HNSSC cell lines (FaDu; SCC-011). HNSCC cells grown in 2D and 3D models under hypoxic conditions (1% O2) showed increased levels of CA9 and greater resistance to cisplatin than cells grown under normoxic conditions. The addition of CA9 inhibitor SLC-0111 to cisplatin sensitized cells to the chemotherapeutic agent and caused a reduction of colony number, spheroid formation, tumor cell, and spheroid migration and invasiveness. Furthermore, the combination therapy hampered activation of STAT3, AKT, ERK, and EMT program whereas it induced apoptosis. Notably, the combined treatment caused inhibition of tumor growth and induction of apoptosis in HNSCC subcutaneous xenografts, as assessed by high-frequency ultrasonography and fluorescent molecular tomography (FMT) with NIR-Annexin V, respectively, at a higher extent than single agents. In addition, FMT with NIR-Prosense revealed a stronger reduction of lymph nodes metastases when mice bearing orthotopic xenografts were treated with cisplatin plus SLC-0111 with respect to a single treatment. Our findings taken together demonstrate the crucial role played by CA9 in promoting cisplatin resistance in HNSCC and the efficacy of SLC-0111 to sensitize tumor cells and xenografts to chemotherapy.
Citation Format: Annachiara Sarnella, Ylenia Ferrara, Luigi Auletta, Sandra Albanese, Vincenzo Alterio, Jean-Yves Winum, Claudiu T Supuran, Laura Cerchia, Giuseppina De Simone, Antonella Zannetti. Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1040.
Abstract 1070: Dual inhibition of AR and β-catenin induces cell death in abiraterone-resistant prostate cancer
Authors: Atawia Ibrahim M. , Kushwaha Prem P. , Verma Shiv S. , Lin Spencer , Shankar Eswar , Abdel-Gawad Osama , Gupta Sanjay 
Published: June 2022

Abstract
Abiraterone acetate has been clinically approved for treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite exhibiting improved survival outcomes, almost all patients with advance-stage disease relapse, progressing to a more aggressive and lethal castration-resistant prostate cancer. Our pathway-related analysis and characterization of gene expression identified activation of the β-catenin pathway in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and β-catenin and their crosstalk between distinct signaling pathways causes activation of AR target genes and regulatory networks for which overcoming innate or acquired resistance remains a major challenge. Here we show that co-targeting AR and β-catenin induces cell death in abiraterone-resistant prostate cancer. For these studies, we generated abiraterone-resistant C4-2B cells (C4-2B-Abi) by growing them in progressive concentration of abiraterone 5-20µM to develop resistance and maintained in 5µM abiraterone in the culture medium for &gt;20 generations. Treatment of C4-2B-Abi cells individually with abiraterone (20µM) and ICG001 (2µM) for 72 h exhibited a partial suppressive effect in cell growth compared to C4-2B parental cell line. A combination of abiraterone and ICG001 (20µM + 2µM) exhibited marked cell growth inhibition with significant increase in G1-phase cell cycle arrest, inhibition of migration and invasion in C4-2B-Abi cells, compared to the parental counterpart. Furthermore, combination treatment led to significant reduction in cell proliferation as assessed by PCNA along with reduction in the protein expression of AR, AR-v7, CDC20, PSA, β-catenin and its downstream targets, cyclinD1 and c-Myc, which were more prominent in C4-2B-Abi cells, compared to parental C4-2B cells. Co-targeting AR and β-catenin potentiated cell death in C4-2B-Abi cells as evident by increased PARP cleavage. Together, our data identify activation of the β-catenin pathway as a major mechanism contributing to abiraterone resistance and demonstrate that combined treatment with abiraterone and ICG001 appears to be an effective regimen for treatment of abiraterone-resistant cancer cells. This opens new therapeutic modality for advance-stage castration-resistant prostate cancer patients.
Citation Format: Ibrahim M. Atawia, Prem P. Kushwaha, Shiv S. Verma, Spencer Lin, Eswar Shankar, Osama Abdel-Gawad, Sanjay Gupta. Dual inhibition of AR and β-catenin induces cell death in abiraterone-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1070.
Abstract 108: Insulin-like growth factor binding protein 4 exerts differential effects on breast cancer cell proliferation based on the expression status of pregnancy-associated plasma protein A
Authors: Flynn Keenan L. , Houston Kevin D. 
Published: June 2022

Abstract
Insulin-Like Growth Factor Binding Protein 4 (IGFBP-4) is one of six binding proteins involved in sequestering insulin-like growth factors 1 and 2 (IGFs). IGFBP-4 expression is induced by estrogen receptor α (ERα), and its classical function is to prevent activation of IGF-1 receptor (IGF-1R) by sequestration of IGF-1. However, the aggressive triple-negative breast cancer cell line MDA-MB-231 shows high expression of IGFBP-4 along with its protease, pregnancy-associated plasma protein A (PAPP-A). Further, inhibition of IGFBP-4 in MDA-MB-231 cells is sufficient to reduce migration. To better understand the function of IGFBP-4 as a pro-cancer or anti-cancer protein, its anti-proliferative effects in ERα positive cells must be reconciled with its pro-migratory effects in triple negative cells. The role of IGFBP-4 in proliferation across four breast cancer cell lines representing ERα positive and triple negative subtypes was investigated. Stable transfection with IGFBP-4 expression construct in the MCF-7 and T-47D cell lines, which have silenced the PAPP-A gene, shows a reduction in proliferation. Further, MCF-7 parental cells cultured in conditioned media containing IGFBP-4 also show reduced proliferation, suggesting that the anti-proliferative effect of IGFBP-4 is associated with the absence of PAPP-A. Stable IGFBP-4 transfection of triple-negative MDA-MB-468 cell line, which has low extracellular IGFBP-4 when compared to MDA-MB-231 but does express PAPP-A, was sufficient to increase proliferation. Taken together, these results support the conclusion that proliferative effects of IGFBP-4 are dependent upon the expression status of PAPP-A.
Citation Format: Keenan L. Flynn, Kevin D. Houston. Insulin-like growth factor binding protein 4 exerts differential effects on breast cancer cell proliferation based on the expression status of pregnancy-associated plasma protein A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 108.
Abstract 1084: FlexBodies: Targeting intracellular tumor antigens with T cell redirecting bispecific antibodies
Authors: Haber Lauric , McKay ryan , Finney jennifer , castaneda stephen , spitler kristen , Rizvi sahar , Hwang aidan , Bray kevin , Ramos willy , Krueger pamela , delfino frank , Meagher Craig , huang tammy , shen yang , olson william , Lin john , smith eric 
Published: June 2022

Abstract
Bispecific antibodies engineered to recruit T cells as a means to kill tumor cells are a promising new class of therapeutics in the field of oncology. A challenge for this class of agents is the requirement for cell surface expressed tumor specific targets, as a large number of tumor-specific antigens are only expressed intracellularly. One strategy to access these targets is to take advantage of the natural processing and presentation of intracellular antigens in the context of the major histocompatibility complex (MHC). However, this requires the development of therapeutics that can be active against targets with a very low surface density. Here, we describe the generation and characterization of Flexbodies, a novel format bispecific antibody engineered to target MHC-peptide tumor neoantigens. We demonstrate that the orientation of the targeting arms and the valency of these reagents allow specific T-cell activation and potent cytotoxic activity against cell lines expressing endogenous level of peptide antigens. This bispecific format has the potential to become an important new tool to expand the range of tumors able to be specifically targeted with t-cell redirecting biologics.
Citation Format: Lauric Haber, ryan McKay, jennifer Finney, stephen castaneda, kristen spitler, sahar Rizvi, aidan Hwang, kevin Bray, willy Ramos, pamela Krueger, frank delfino, Craig Meagher, tammy huang, yang shen, william olson, john Lin, eric smith. FlexBodies: Targeting intracellular tumor antigens with T cell redirecting bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1084.
Abstract 1086: PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma
Authors: Del Pozo Vanessa , Robles Andrew J. , Fontaine Shaun , Liu Qianqian , Michalek Joel E. , Houghton Peter J. , Kurmasheva Raushan 
Published: June 2022

Abstract
Introduction: The Ewing family of sarcomas is the fourth most common highly malignant childhood cancer. Current standard therapy is relatively ineffective for relapsed and metastatic Ewing sarcoma predominantly due to development of resistance to chemotherapeutics. Nanoparticle-formulated drugs are reported to increase uptake into tumor tissue, while reducing drug access to normal tissues, because of reduced permeability of normal vasculature. This potentially leads to lower dose exposure in normal tissues and reduced toxicity. The purpose of this study was to evaluate the antitumor activity of the PEGylated poly(ADP) ribose polymerase 1/2 (PARP1/2) inhibitor talazoparib combined with the DNA alkylating agent temozolomide (TMZ) in Ewing sarcoma xenograft models and other pediatric cancers.
Method:. We evaluated the preclinical efficacy of PEGylated talazoparib (PEG~TLZ), alone or in combination with TMZ, in Ewing sarcoma and glioblastoma patient derived xenograft (PDX) models. Additional solid tumor models, such as rhabdomyosarcoma, Wilms tumor, malignant rhabdoid tumor, osteosarcoma, and synovial sarcoma were evaluated using a novel single mouse testing approach. PEG~TLZ was administered as a single administration intraperitoneally to mice bearing subcutaneous tumors at a single dose of 5 - 20 µmol/kg alone, or at 10 µmol/kg on day 1 combined with TMZ administered orally at 40 mg/kg starting on day 3 or 4 for 5 consecutive days.
Results: Mice bearing Ewing sarcoma and MGMT-deficient glioblastoma xenografts tolerated PEG~TLZ+TMZ with minimal toxicity and achieved maintained complete response (MCR). The time-separated drug administration schedule of the single dose of PEG~TLZ followed by the 5-day TMZ treatment demonstrated objective responses in Ewing sarcoma, rhabdoid tumor, rhabdomyosarcoma, and glioblastoma PDX models.
Conclusion: We evaluated the range of PEG~TLZ+TMZ activity among pediatric solid tumor panels using conventional and single-mouse testing approaches, and demonstrated that PEG~TLZ combined with delayed TMZ administration enhances the therapeutic window of the treatment compared to free TLZ. From the clinical standpoint, the single intravenous administration of PEG~TLZ could be advantageous for treating infants and young children.
Citation Format: Vanessa Del Pozo, Andrew J. Robles, Shaun Fontaine, Qianqian Liu, Joel E. Michalek, Peter J. Houghton, Raushan Kurmasheva. PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1086.
Abstract 111: Head and neck cancer cells can differentiate and resemble their tissue of origin
Authors: Oppel Felix , Shao Senyao , Gendreizig Sarah , Kühnel Philipp , Przybycin Vivien , Hain Carsten , Schmidt Pascal , Schürmann Matthias , Goon Peter , Niehaus Karsten , Kalinowski Jörn , Sudhoff Holger 
Published: June 2022

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with a mortality rate of about 50%. It represents the sixth most common type of malignant tumor in the world. Risk factors include tobacco and alcohol usage and infection with the human papilloma virus (HPV). HPV-negative HNSCCs frequently display areas of cornification evident by keratin pearls in the tumor tissue. Cornification represents a natural differentiation path of keratinocytes in the normal epidermis and oral mucosa. To investigate the mechanisms of HNSCC cell differentiation we have established spheroid cell cultures from patient-derived HNSCC and parotid gland adenoid cystic carcinoma (ACC) tissue that grow in suspension under serum-free conditions. The use of a specific differentiation medium induced striking adhesion, loss of proliferation, and differentiation in tumor cells. Spheroid cells grew as single cell clones under serum-free conditions with a cloning efficiency of 40-60%, which was fully diminished under differentiating conditions. HNSCC cells cornified as indicated by the formation of lamellar bodies in the cytoplasm of adherent cells and an upregulation of cornification markers SPRR3 and involucrin. ACC cells upregulated parotid gland differentiation markers including α-amylase. RNA-seq analysis in HNSCC cells confirmed an upregulation of signaling pathways associated with cornification and epithelial cell differentiation. Conversely, pathways regulating the three-dimensional organization of the genome were downregulated upon differentiation. This was accompanied by the formation of ATRX-positive heterochromatin foci in the nucleus of differentiated ACC and HNSCC cells resembling those previously described to arise during therapy-induced senescence. Moreover, gas chromatography mass spectrometry analysis revealed a lack of essential amino acids including leucine to be implicated in the differentiation process. Altogether, our spheroid model of HNSCC and ACC cells is suitable to analyze the mechanisms underlying tumor cell differentiation and might lead to new therapeutic approaches that can drive long-term repopulating HNSCC and ACC cells into differentiation.
Citation Format: Felix Oppel, Senyao Shao, Sarah Gendreizig, Philipp Kühnel, Vivien Przybycin, Carsten Hain, Pascal Schmidt, Matthias Schürmann, Peter Goon, Karsten Niehaus, Jörn Kalinowski, Holger Sudhoff. Head and neck cancer cells can differentiate and resemble their tissue of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 111.
Abstract 1112: Detection ofHMGB1 and extracellular ATP for the assessment of immunogenic cell death
Authors: Somberg Richard L. , Kupcho Kevin , Niles Andrew , Cali James 
Published: June 2022

Abstract
Immunogenic cell death (ICD) is a form of apoptosis that kills susceptible populations of cancer cells while teaching the immune system to attack the remaining resistant cells. Chemotherapeutics which induce ICD elicit their immune response by inducing tumor cells to display or release damage-associated molecular patterns (DAMPs). There are two key biomarkers for ICD:  1) during the apoptotic process, tumor cells secrete ATP (extracellular ATP or eATP) and 2) during secondary necrosis, tumor cells release HMGB1 (high mobility group box 1). Because the dying tumor cells display these DAMP molecules, they stimulate the recruitment of dendritic cells (DCs) into the tumor bed and ultimately “teach” cytotoxic T-lymphocytes (CTLs) to respond to these tumor specific antigens. These primed CTLs will then kill additional tumor cells through a direct cytotoxic response. Therefore, therapeutics which provoke an ICD response offer a therapeutically desirable outcome for cancer therapy. Current assay methods such as ELISA assays and flow cytometry for measuring these ICD biomarkers are laborious and involve multiple transfer and wash steps. We have developed homogeneous (no wash), single addition assays for measuring the two principle ICD biomarkers. The eATP assay uses optimized luciferase detection chemistry that is applied directly to live cells to measure ATP release over 24 hours. The HMGB1 assay uses a complementary luciferase fragment-labeled antibody approach to measure protein concentration. We demonstrated the use of these two assays with model systems for inducing Immunogenic Cell Death with human and murine cell lines including U2OS, EL4, and U937 cells. The potency and response magnitude of ICD-inducing compounds including doxorubicin, idarubicin and mitoxantrone differs depending on the model cell line used. Further, the timing of extracellular ATP release and HMGB1 release differs between cell lines and inducers. Improved assays to measure two markers of Immunogenic Cell Death will expedite the discovery and development of inducers of Immunogenic Cell Death, including small molecule therapeutics, oncolytic viruses, radiation therapy and other novel therapeutics, by streamlining the workflow, increasing sample throughput and providing real time live cell data.
Citation Format: Richard L. Somberg, Kevin Kupcho, Andrew Niles, James Cali. Detection ofHMGB1 and extracellular ATP for the assessment of immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1112.
Abstract 114: Progesterone via integrin αvβ3 induces cell proliferation in PR-negative breast cancer cells
Authors: Lin Hung-Yun , Huang Tung-Yung , Chang Tung-Cheng , Chen Han-Yu , Huang Haw-Ming , Lee Sheng-Yang , Li Zi-Lin , Chu Hung-Ru , Whang-Peng Jacqueline , Wang Kuan 
Published: June 2022

Abstract
Background: Progesterone (P4) stimulates reproductive functions such as ovulation and the initiation and maintenance of pregnancy. P4 regulates biological activities via its nuclear receptor. However, it is not fully understood mechanisms involved in P4 functions in PR-negative cells. Anchor protein integrin αvβ3 plays a vital role in cancer growth and metastasis.
Methods: We investigated the effect of P4 in PR-positive breast cancer MCF-7 cells and PR-negative breast cancer MDA-MB-231 cells. The protein and RNA expression changes induced by P4 were both analyzed in two cell lines. At the same time, the anti-integrin αvβ3 antibody and RGD peptide were employed for investigating the role of integrin αvβ3 in P4 regulation.
Results: P4 inhibited the proliferation in MCF-7 cells but stimulated cell growth in MDA-MB-231 cells. In addition to ERK1/2 activation, P4 stimulated the phosphorylation at Y397 and Y925 in focal adhesion kinase (FAK), a vital kinase in integrin ανβ3 signal pathway that modulated by co-treatment with anti-integrin αvβ3 antibody or RGD peptide. P4 activated the gene expression of integrin ανβ3, CCND1, PCNA, and MMP-9 in MDA-MB-231 cells. P4 also induced PD-L1 and CCND1 accumulation.
Conclusions: Progesterone via integrin αvβ3-mediated signal transduction regulates gene expression, cell proliferation, and migration in TNBC cells. It is the first time to demonstrate that P4 binds with the cell surface anchor protein, integrin αvβ3, to stimulate cancer cell proliferation in PR-negative breast cancer cells.
Keywords: Progesterone, Progesterone receptor, Integrin αvβ3, Breast cancer, Cell proliferation
Citation Format: Hung-Yun Lin, Tung-Yung Huang, Tung-Cheng Chang, Han-Yu Chen, Haw-Ming Huang, Sheng-Yang Lee, Zi-Lin Li, Hung-Ru Chu, Jacqueline Whang-Peng, Kuan Wang. Progesterone via integrin αvβ3 induces cell proliferation in PR-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 114.