bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract GMM-054: AN INVESTIGATION OF THE EFFECTS OF THE ATYPICAL PKC-ζ INHIBITOR ζ-STAT ON CLEAR CELL CARCINOMA OVARIAN CANCER PROLIFERATION AND INVASION
Authors: Smalley Tracess , Patel Rekha , Acevedo-Duncan Mildred 
Published: June 2021

Abstract
Ovarian cancer is the most lethal gynecological cancer diagnosis. There is no efficient screening process for ovarian cancers and the average stage of diagnosis is stage III. The most common ovarian cancer diagnosis is epithelial ovarian carcinomas, which constitute for 85-90% of prognosis; of this percent, clear cell ovarian carcinoma (CCOC) represents 5% of incidence. CCOC presents unique pathological features and has a high reoccurrence rate after treatment. An overexpression of atypical PKCs (PKC-ζ and PKC-ι/λ) has been observed in various malignant cells lines and are linked to pathways for cellular proliferation and invasion. In this investigation, ovarian cell lines (TOV21G and ES-2) were treated with the atypical PKC-ζ inhibitor ζ-Stat and assayed to determine the effects on proliferation and cellular invasion. These assays included protein quantification, cell proliferation, and wound healing. Mouse xenograph experiments were also performed to determine the effects of ζ-Stat on TOV21G tumor growth in vivo. Our data shows that ζ-Stat decreases the proliferation of clear cell carcinoma ovarian cancer cells and decreases wound healing. Our results also show that tumor growth in athymic female mice is decreased when treated with ζ-Stat and that mouse body weight is maintained. This suggests that PKC-ζ is a novel target in carcinogenesis and inhibition of this protein decreases the rate of proliferation.
Citation Format: Tracess Smalley, Rekha Patel, Mildred Acevedo-Duncan. AN INVESTIGATION OF THE EFFECTS OF THE ATYPICAL PKC-ζ INHIBITOR ζ-STAT ON CLEAR CELL CARCINOMA OVARIAN CANCER PROLIFERATION AND INVASION [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-054.
Abstract NT-104: SYNERGISTIC COMBINATION OF MORTALIN-TARGETING AND P53 REACTIVATOR DRUGS FOR OVARIAN CANCER
Authors: Ramraj Satish Kumar , Benbrook Doris M. 
Published: June 2021

Abstract
PURPOSE: TP53 gene missense mutations represent the most common genetic defect in fallopian tube (FT) lesions and high grade serous ovarian cancer (HGSOC) and cause of drug resistance. We hypothesized that drugs with complementary p53 protein-targeted mechanisms (SHetA2 drug release of p53 from mortalin binding, PRIMA-1MET drug reactivation of p53 transcription activity) synergistically kill ovarian cancer cells without harming normal cells.
EXPERIMENTAL DESIGN: SHetA2-mediated cytoplasmic to nuclear/mitochondrial p53 translocation was studied in wildtype and mutant p53 ovarian cancer cell lines using Western blot analysis of subcellular-enriched fractions and fluorescent microscopic imaging of immunocytochemistry. Human FT epithelial cells (hFTSECs) were used as healthy controls. The p53 reactivator drugs PRIMA-1 and PRIMA-1MET were combined with SHetA2 to study drug interactions and mechanisms using Western blot, rtPCR, cytotoxicity, reactive oxygen species (ROS) and ATP assays.
RESULTS: SHetA2 induced p53 nuclear and mitochondrial accumulation in ovarian cancer cell lines, but not in hFTSECs. Both mortalin and p53 expression altered SHetA2 cytotoxicity in ovarian cancer cells. Modest effects of PRIMA-1MET on cell lines inversely correlated with SLC7A11 expression, a known biomarker of PRIMA-1MET sensitivity. SHetA2 induced SLC7A11 in the presence of wildtype or missense mutant p53, but inhibited SLC7A11 in the absence of p53. SHetA2 and PRIMA-1MET were synergistic-to-strongly synergistic in ovarian cancer cells with mutant p53, synergistic with wildtype p53, additive with null p53 and antagonistic in hFTSECs. Elevated apoptosis, p53 transcription activity and ROS in combination with reduced ATP were associated with this mutant p53-dependent synergy.
CONCLUSION: Altogether, our findings identified the SHetA2 and PRIMA-1MET combination as a promising new therapeutic strategy for the treatment of HGSOCs with missense mutant p53.
GRANT SUPPORT: Supported by the US National Cancer Institute grant R01 CA196200 and Foundation for Women's Cancer- Ovarinnovate: Ovarcome Research Excellence Award.
Citation Format: Satish Kumar Ramraj, Doris M. Benbrook. SYNERGISTIC COMBINATION OF MORTALIN-TARGETING AND P53 REACTIVATOR DRUGS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-104.
Abstract NT-112: APTAMER CONJUGATED NANOPARTICLES FOR TARGETED DRUG DELIVERY
Authors: Thiviyanathan Varatharasa , Pi Fengmei , Zhang Hui , Li Hui , Wang Hongyu , Guo Peixuan , Sood Anil 
Published: June 2021

Abstract
Targeted Delivery of therapeutic drugs and imaging agents, using nanoparticles, shows great promise in diverse fields, including the diagnostics and treatment of cancer. Monoclonal antibodies (mAbs) that have been traditionally used for detecting specific proteins can also be used as targeting moieties. However, due to their intrinsic characteristics such as immunogenicity, batch-to-batch variation and instability, antibodies have several limitations for in vivo applications. Nucleic acid based aptamers are emerging as attractive alternatives for mAbs. We have developed single-stranded DNA aptamers, which can specifically recognize and bind to ovarian cancer endothelial cells. Using mass-spectroscopy based proteomics, we have identified Annexin A2 as the protein target for the selected aptamers. These aptamers can act as homing devices to deliver therapeutic drugs and/or imaging agents specifically to ovarian cancer cells. Using a highly stable, three-way junction (3WJ) motif from the phi29 packaging RNA as a scaffold, we made a multi-functional RNA nanoparticle that can harbor therapeutic drugs, imaging agent, siRNA and the targeting ligand. The aptamer-containing multi-functional RNA nanoparticle is used to deliver Doxorubicin to Annexin A2 positive ovarian cancer cells, while the control nanoparticles failed to deliver. After systemic injection in mice, the DNA/RNA hybrid nanoparticles remained intact and strongly bound to tumors with little accumulation in healthy organs 6 hour post-injection. The aptamer-3WJ-Sph1/Dox intercalates selectively enhanced toxicity to Annexin A2 positive ovarian cancer cells in vitro, demonstrating the potential of the constructed DNA/RNA hybrid nanoparticles to enhance the therapeutic efficiency of Doxorubicin at low doses for ovarian cancer treatment. The use of the aptamer-3WJ RNA nanoparticle will benefit ovarian cancer patients by reducing the side effects of cancer chemo-therapeutics and increasing its local concentration in the tumor microenvironment after systemic administration. Our ultimate goal is the development of patient-optimized aptamer-nanoparticle delivery systems for chemotherapy and molecular diagnostics imaging.
Citation Format: Varatharasa Thiviyanathan, Fengmei Pi, Hui Zhang, Hui Li , Hongyu Wang, Peixuan Guo, Anil Sood. APTAMER CONJUGATED NANOPARTICLES FOR TARGETED DRUG DELIVERY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-112.
Abstract NT-114: CATALYTIC SUBUNITS SWITCH DRIVES RESISTANCE TO EZH2 INHIBITORS IN ARID1A-MUTATED CELLS
Authors: Wu Shuai , Fatkhutdinov Nail , Fukumoto Takeshi , Bitler Benjamin G. , Park Pyoung Hwa , Kossenkov Andrew V. , Trizzino Marco , Gardini Alessandro , Speicher David W. , Zhang Rugang 
Published: June 2021

Abstract
The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells. SMARCA4 decease dominates over SMARCA2 increase in the switch. SMARCA4 loss leads to suppression of apoptotic pathways through upregulating anti-apoptotic genes such as BCL2 in the EZH2 inhibitor resistant cells. EZH2 inhibitor resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263. ABT263 is sufficient to overcome resistance to EZH2 inhibitor and synergistic with EZH2 inhibitor in vivo in ARID1A-inactivted ovarian tumour mouse models. Together, these data establish that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 underlies the acquired resistance to EZH2 inhibitors and BCL2 inhibition alone or in combination with EZH2 inhibition represents a novel strategy to overcome and/or prevent EZH2 inhibitor resistance in ARID1A-mutated cancers. Given that the SWI/SNF subunits are among the most frequently mutated genes in human cancers and EZH2 inhibitors are in the clinical trials for tumor with mutations in the SWI/SNF complex, we expect our findings to have far-reaching implications for developing cancer epigenetic therapeutics.
Citation Format: Shuai Wu, Nail Fatkhutdinov, Takeshi Fukumoto, Benjamin G. Bitler, Pyoung Hwa Park, Andrew V. Kossenkov, Marco Trizzino, Alessandro Gardini, David W. Speicher, Rugang Zhang,. CATALYTIC SUBUNITS SWITCH DRIVES RESISTANCE TO EZH2 INHIBITORS IN ARID1A-MUTATED CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-114.
Abstract NT-121: AN ANTI-AMPHIREGULIN ANTIBODY AS POTENTIAL TREATMENT FOR OVARIAN CANCER
Authors: Zmora Einav , Lindzen Moshit , Yarden Yosef 
Published: June 2021

Abstract
The ErbB family of receptors consists of four receptors, which bind with eleven ligands. These EGF-like ligands can be classified according to their affinity to EGFR: EGF, TGFα, HB-EGF and betacellulin are considered high affinity ligands, whereas AREG, EREG and EPGN are considered low affinity ligands. The literature reports that AREG is a type II cytokine which plays a role in inflammation, its expression is known to contribute to tissue repair and regeneration due to its ability to promote cell survival and proliferation. Furthermore, AREG is expressed by activated Th2 cells, mast cells, eosinophils, basophils and M1 macrophages.
Profiling the repertoire of EGF-like ligands in ascites fluids collected from 43 ovarian cancer patients, we found that 86% expressed high levels of AREG. These findings lead us to generate an anti-AREG antibody active against both human and murine AREG. Efficacy of this antibody was tested in several in vivo experiments using anti-AERG alone or in combination with chemotherapy (cisplatin). A murine anti-EGFR antibody was used as a positive control. Our results showed a significant prolongation of the lifespan of mice treated with an anti-AREG antibody, postponing the advancement of the disease compared to the control untreated group, or the groups treated with an anti-EGFR antibody or with chemotherapy only.
One of our next goals is to establish a model that is completely murine. We are using immunocompetent C57 black female mice, the ID8 cell line which is an ovarian cancer mouse cell line and our antibody, which blocks the murine form of AREG. We hope that in this way we would be able to evaluate the involvement of the immune system. The knowledge we will gain about the efficacy and toxicity of an anti-AREG approach may not be available from humanized models.
Citation Format: Einav Zmora, Moshit Lindzen, Yosef Yarden. AN ANTI-AMPHIREGULIN ANTIBODY AS POTENTIAL TREATMENT FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-121.
Abstract TMIM-077: MYXOMA VIRUS ENHANCES TREATMENT BENEFIT OF CHEMOTHERAPY AND DENDRITIC CELL IMMUNOTHERAPY IN OVARIAN CANCER PRECLINICAL MODEL
Authors: Conrad Steven J , Nounamo Bernice , Cannon Martin , Liu Jia 
Published: June 2021

Abstract
Myxoma virus (MYXV) is a poxvirus with oncolytic and immunotherapeutic potential in many cancer models, including ovarian cancer (OC). Moreover, MYXV synergizes with chemotherapy including cisplatin for OC treatment. In this study, we used a p53-/- ID8 mouse model that closely portrays human high-grade serous OC to test MYXV virotherapy. We combined MYXV regime with cisplatin treatment and an innovative Th17-inducing dendritic cell (Th17-DC) vaccine currently being tested in clinical trials with OC patients. For DC immunotherapy, bone marrow-derived DC were pulsed with peptides from Sp17, a cancer testis antigen highly expressed in human OC and the ID8 mouse model. For MYXV virotherapy, we examined both wild-type and a replication-defective MYXV that is engineered without an essential viral immunomodulator called M062 (M062R-null MYXV). We found that inoculation with replication-competent MYXV improves survival when administered before cisplatin therapy. Interestingly, when the replication-defective M062R-null MYXV was used, improved survival was observed with virotherapy after the cisplatin treatment. We further found that M062R-null MYXV treatment provided long-lasting survival in combination with cisplatin and Th17-DC immunotherapy. Related studies showed that M062R-null MYXV infection in murine and primary human OC cells stimulated robust type I IFN expression and pro-inflammatory cytokines. Moreover, M062R-null MYXV activates type I IFN in macrophages and expression of inflammatory cytokines (e.g., CXCL-10 and IL-6). In conclusion, we propose that MYXV virotherapy provokes a type I interferon response and inflammatory cytokines that modulate the tumor microenvironment and enhance protective immune responses to Th17-DC vaccination for OC treatment.
Citation Format: Steven J Conrad, Bernice Nounamo, Martin Cannon, Jia Liu. MYXOMA VIRUS ENHANCES TREATMENT BENEFIT OF CHEMOTHERAPY AND DENDRITIC CELL IMMUNOTHERAPY IN OVARIAN CANCER PRECLINICAL MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-077.
Abstract A25: Hectd3 protects against colitis and colon cancer development through maintenance of homeostatic immune environment in the gut
Authors: Zuniga Ashley , Parthasarath Upasana , Cho Jonathan , Drashansky Theodore , Helm Eric , Lorentsen Kyle , He Zhen , Jobin Christian , Avram Dorina 
Published: June 2021

Abstract
Colorectal cancer (CRC) remains one of the most common and deadliest malignancies in USA, including in Florida. CRC includes hereditary, sporadic, and colitis-associated cancer (CAC). CAC often shows rapid progression, poor response to treatment, and high mortality. In CAC, tumors are formed in the context of chronic inflammation, but ultimately the immune populations in colonic tumors acquire a suppressive phenotype. Among such populations, myeloid-derived suppressive cells (MDSCs), consisting of polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs, accumulate in the tumors and promote a tumor-suppressive microenvironment, together with tumor-associated macrophages. Numerous questions remain unanswered in regard to the biology and regulation of myeloid-suppressive populations in CAC. We found that the levels of the ubiquitin ligase Hectd3 were reduced in human inflamed ulcerative colitis (UC) tissues and in colonic tumors versus healthy matched colonic tissues. Hectd3 KO mice developed more severe dextran sodium sulfate (DSS)-induced colitis and larger and more numerous colonic tumors in the azoxymethane (AOM)/DSS model of CAC. Bone marrow chimera experiments demonstrated that both the hematopoietic and nonhematopoietic compartments play roles in the phenotype, in DSS colitis and in AOM/DSS CAC model. During DSS-induced colitis we found that genes for several proinflammatory cytokines were upregulated in the colons of Hectd3 KO mice, including IL6, IL11 and G-CSF, as well for Lipocalin-2, associated with inflammation. However, in the colonic tumors of Hectd3 KO mice, the CD11b+ CD11c- myeloid cells were elevated and showed increased Arginase 1 and iNOS levels and frequencies, suggestive of a suppressive phenotype. We hypothesize that absence of Hectd3 promotes a highly inflammatory phenotype in the colon, and further an immune-suppressive phenotype in the colonic tumors through regulation of specific signaling pathways in myeloid populations.
Citation Format: Ashley Zuniga, Upasana Parthasarath, Jonathan Cho, Theodore Drashansky, Eric Helm, Kyle Lorentsen, Zhen He, Christian Jobin, Dorina Avram. Hectd3 protects against colitis and colon cancer development through maintenance of homeostatic immune environment in the gut [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A25.
Abstract A44: High-efficiency electroporation of nonexpanded T cells and NK cells for CAR-T and CAR-NK
Authors: Chen Jian , Xia Xiaofeng 
Published: June 2021

Abstract
CAR-T cells are currently manufactured for clinical use by infection of human T cells with viral vectors containing the CAR gene. T lymphocytes have to be stimulated and expanded ex vivo because the viral vectors infect fresh natural lymphocytes very poorly. NK cells are also commonly expanded ex vivo before they are subject to electroporation. Possibly influenced by virus infection protocols, T cell and NK cell electroporation is often done after they are ex vivo expanded. We developed a novel electroporation technology that corrected many physics mistakes in the field. We can now achieve very high transfection efficiency for fresh T cells while maintaining cell survival. For Sleeping Beauty transposon-based CAR expression, we found that over a period of two to three weeks the efficiency can get to 60% to 90% with fast cell proliferation. The protein expression time after electroporation is very short. For simple GFP plasmids we can observe GFP expression after only 30 minutes. Similarly, for NK cells, we were able to achieve 42% transfection efficiency with fresh nonexpanded NK cells. We further compared post-electroporation cell proliferation potential between nonexpanded fresh T cells and stimulated/expanded T cells. It turned out that although fresh T cells are smaller in volume, they are much better than expanded T cells in survival after electroporation. Expanded NK cells also showed much higher cytotoxicity than fresh NK cells after electroporation. With our new electroporation technology, CAR-T and CAR-NK can now be manufactured quicker and better. Our new protocols focusing on fresh T cells and fresh NK cells would be a great help for the field.
Citation Format: Jian Chen, Xiaofeng Xia. High-efficiency electroporation of nonexpanded T cells and NK cells for CAR-T and CAR-NK [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A44.
Abstract A47: The immunoproteosome mediates resistance to natural killer cell killing
Authors: Pasion Joyce , Wendel Hans Guido 
Published: June 2021

Abstract
We identified the immunoproteosome as a mediator of resistance to natural killer (NK) cell killing through a genome-wide activation CRISPR screen. The immunoproteosome is a modified proteolytic complex composed of a catalytic 20S core and a regulatory 11S component. An essential function of the immunoproteosome is to degrade intracellular proteins that are eventually presented as antigens on the cell surface by the major histocompatibility complex (MHC) I. We validated several subunits that play a critical role in regulating responses to NK cells, specifically, PSMA1, PSMB6 and PSME1, which encode the alpha subunit of the 20S catalytic proteosome, the beta subunit of the 20S proteosome, and the alpha subunit of the 11S regulator, respectively. While several studies have reported that proteasome inhibitors sensitize cancer cells to NK cell killing, the exact mechanisms of these inhibitors are not well understood. Our data indicate that these proteasome components may be attractive targets to improve cancer cell response to NK cell-based therapies.
Note: This abstract was not presented at the conference.
Citation Format: Joyce Pasion, Hans Guido Wendel. The immunoproteosome mediates resistance to natural killer cell killing [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A47.
Abstract A68: A casein kinase 2 inhibitor disorders myeloid cell differentiation by blocking CCAAT/enhancer-binding protein-alpha signaling pathway in tumor microenvironment
Authors: Hashimoto Ayumi , Gao Chan , Mastio Jerome , Kossenkov Andrew , Abrams Scott I. , Purandare Ashok V. , Desilva Heshani , Wee Susan , Hunt John , Jure-Kunkel Maria , Gabrilovich Dmitry I. 
Published: June 2021

Abstract
Myeloid cells are major components of the tumor microenvironment, which are known to suppress antitumor immunity. Casein kinase 2 (CK2), a serine/threonine protein kinase with diverse intracellular protein substrates, regulates several signaling pathways involved in tumor progression and cell differentiation. We examined the efficacy of a novel CK2 inhibitor on modulating the myeloid cells in the tumor microenvironment. Although CK2 inhibitors BMS-595 and BMS-211 moderately inhibited the tumor growth in LLC, 4T1, MC38 and CT26 tumor-bearing mice, these inhibitors drastically enhanced the antitumor efficacy of anti-CTLA4 antibody with 60% to 90% of complete rejection. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and macrophages in spleens, and tumor-associated macrophages (TAM) were found to be decreased in LLC tumor-bearing mice treated with BMS-595 for 2 weeks. Murine hematopoietic progenitor cells (HPC) from bone marrow and human progenitor cells from cord blood were cultured with BMS-595 to evaluate the differentiation. BMS-595 treatment dramatically decreased the proportion of granulocytic cells, and this decrease was not caused by the direct killing nor apoptosis. Therefore, the genes regulated by transcription factors, IRF8, C/EBPα and C/EBPβ, which are involved in PMN-MDSC differentiation, were evaluated. Many genes controlled by C/EBPα were downregulated by the BMS-595 treatment in HPCs. Active p42 subunit of C/EBPα was revealed to be reduced by the BMS-595 treatment in HPCs, which are inversely correlated with the increased level of dominant negative p30 subunit of C/EBPα, in both the cytoplasm and nucleus of HPCs. Our results suggest that CK2 inhibition leads to a reduction of immune-suppressive PMN-MDSC and TAM by inhibiting C/EBPα activity, resulting in an enormous augmentation of antitumor efficacy of immunotherapy.
Citation Format: Ayumi Hashimoto, Chan Gao, Jerome Mastio, Andrew Kossenkov, Scott I. Abrams, Ashok V. Purandare, Heshani Desilva, Susan Wee, John Hunt, Maria Jure-Kunkel, Dmitry I. Gabrilovich. A casein kinase 2 inhibitor disorders myeloid cell differentiation by blocking CCAAT/enhancer-binding protein-alpha signaling pathway in tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A68.