bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A004: Developing ovarian cancer xenograft in mouse model to see FSHR-mediated anticancer effect of Moringa oleifera root extract
Authors: Basu Chinmay Kumar 
Published: August 2018

Abstract
Introduction: Sex hormones play an important role in ovarian cancer as novel redirected T-cell-based immunotherapy targeting human follicle-stimulating hormone receptor (FSHR)is tried. Moringa olifera root extract has shown efficacy in cancer cell as well as in hormonal milieu of ovary and reproductive organ. Hence, the aim of the present study was to study the anticancer effect of Moringa oleifera on human OAW 42 & MCF-7 cell line through its putative FSHR antagonistic role. Methods: The colorimetric MTT metabolic activity assay was used to see cell viability. Western blot analysis was performed to check its effect in apoptosis. Clonogenic assay was carried out to see the effect of Moringa root extract on cancer cell proliferation. Cell cycle analysis was done based on incorporation of Propidium Iodide into DNA (BD Cycletest™ Plus DNA Kit). Analyses of the samples were carried out flow cytometrically using BD LSRFortessaTM SORP (San Jose, CA) cell analyzer and BD FACSDiva v8.0.1 software.On day 35, mice were sacrificed and histopathologic analysis of the ovaries was carried out following standard protocol followed by IHC for detection of FSHR. Result: The dose-dependent analysis on viability of OAW-42 and MCF-7 cells by MTT assay showed 50% lethal toxicity (IC-50) of MRE (Moringa root extract) to be 250µg/ml and 200µg/ml, respectively, with synergestic effect of Moringa extract with both cisplatin and paclitaxol in OAW-42 cell line. Moringa extract at its IC-50 value showed visible effect in case of cleaved caspase-9. In clonogenic assay approximately 40% reduction of colony formation was observed. Flow cytometric data showed that after 24 hours and 48 hours of treatment with MOL root extract at its IC-50 dose, DNA content progressively increased in the sub G0 phase. However, approximately 3% upregulation and 11.4% downgulation of PI intensity at G0/G1 phase was also observed. Profuse expression of FSHR and its downstream target cMyc in the stroma of carcinoma control mice compared to control or Moringa-treated mice. Conclusion: We can conclude that MRE is a promising candidate for treatment of ovarian cancer by an FSHR-mediated pathway either alone or in combination with traditional chemotherapeutic drugs like cisplatin and paclitaxol at a sublethal dose of their toxicity.
Citation Format: Chinmay Kumar Basu. Developing ovarian cancer xenograft in mouse model to see FSHR-mediated anticancer effect of Moringa oleifera root extract [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A004.
Abstract A007: Establishment and characterization of the MDA-MB-175 breast tumor xenograft model
Authors: Wick Michael J. , Groves Megan , Moriarty Alyssa , Guerra Marcus , Rundle Melissa , Rasco Drew , Patnaik Amita , Tolcher Anthony W. , Papadopoulos Kyriakos P. 
Published: August 2018

Abstract
Background: The MDA-MB-175 cell line is widely used in vitro for targeted drug development in breast cancers with ERBB 2/3 receptor and heregulin signaling. However, lack of an accessible, matched xenograft has limited in vivo analysis of potential therapies. To better utilize this cell line as a tool for receptor targeting drug development, we established the MDA-MB-175 xenograft model in athymic nude mice. The resulting model was characterized and compared with the parent line using immunohistochemistry and genomic analysis. In vivo studies were performed using the xenograft model comparing various ERBB2 and ERBB3-targeting agents. Materials and Methods: The MDA-MB-175 xenograft model was established and serially passaged in athymic nude mice for in vivo studies. Receptor expression was determined using immunohistochemistry and RNA in-situ hybridization and compared with the parent line. For the in vivo study of ERBB2/3 targeting therapies, trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib were evaluated as monotherapies, along with a trastuzumab/lapatinib combination group. Dosing was initiated on Day 0 and continued for four weeks at which time tumor regrowth was followed. The study was ended on Day 60 and drug response reported at Day 28 and Day 60 as %T/C values and %Tumor Regressions (%TR). Results: Immunohistochemistry on the cell line and model reported intensity values of (2+) for ERBB2 and ERBB3 receptor expression. In vivo the following %T/C were reported on Day 28: trastuzumab=50%,lapatinib=62%, pertuzumab= -96% (100% TR), T-DM1=-19% (50% TR), neratinib=-88% (100% TR) and trastuzumab/lapatinib=72%. Day 60 results reported regrowth in neratinib and T-DM1 groups. Conclusion: We have established a reproducible xenograft model of the MDA-MB-175 cell line that is sensitive to pertuzumab, T-DM1, and neratinib, but neither trastuzumab nor lapatinib alone or in combination in vivo.
Citation Format: Michael J. Wick, Megan Groves, Alyssa Moriarty, Marcus Guerra, Melissa Rundle, Drew Rasco, Amita Patnaik, Anthony W. Tolcher, Kyriakos P. Papadopoulos. Establishment and characterization of the MDA-MB-175 breast tumor xenograft model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A007.
Abstract A009: Evaluation of hormonal therapy in a panel of prostate patient-derived xenograft models and comparison to standard cell line models
Authors: Papadopoulou Nektaria , Woolley Louise , Wainwright Louise , Harris Lucy , Wrigley Jane , King Jason , Collins Anne , Kumari Rajendra 
Published: August 2018

Abstract
Background: Prostate cancer is the second most common cancer worldwide for males, and the fourth most common cancer overall, with more than 1 million new cases diagnosed. However, progress toward understanding the biology of prostate cancer and the development of new therapies has been hampered by the lack of in vivo models that adequately represent the spectrum of benign, latent, aggressive, and metastatic forms of the human disease. Here we report the validation of a panel of patient-derived xenograft (PDX) models and their utilization in preclinical studies alongside cell line models of prostate cancer that are routinely used. Methods: Prostate cancer samples obtained from patients undergoing surgery were collected with ethical consent, disaggregated, and established subcutaneously in Rag-2 knockout mice (The Jackson Laboratory) to generate PDX models. Tumor material was diagnosed on the basis of operative histology and immunohistochemistry (IHC for PSA, androgen receptor expression). Subcutaneous tumor growth of prostate models was evaluated 3 times a week by measuring the tumor in two dimensions using electronic calipers for the duration of the study, and tumor volumes were estimated. For orthotopic PC3M, tumor growth was checked once weekly by bioluminescent imaging (BLI). Briefly, the mice were injected (s.c.) with 150mg/kg D-Luciferin prior to imaging, anesthetized following administration of D-Luciferin, and placed into the imaging chamber (Spectrum CT) and imaged for luminescence (ventral view). Results: We have established a bank of transplantable prostate cancer PDX. Two models were reported to be hormone sensitive and 2 models represented castrate-resistant prostate cancer (CRPC), one of which has a TMPRSS-ETS fusion. In comparison, cell-derived LNCaP requires testosterone to grow whereas the bioluminescent PC3M CRPC orthotopic model develops metastasis in the liver, lungs, lumbar lymph nodes, fore limbs, and hind limbs, representing the late stage of cancer. The tumor response to standard-of-care agents such as docetaxel, abiraterone, and enzalutamide will be reported. Conclusions: We have characterized both cell- and patient-derived prostate cancer xenograft models that will provide a clinically relevant platform spanning the different stages of the disease for preclinical drug evaluation.
Citation Format: Nektaria Papadopoulou, Louise Woolley, Louise Wainwright, Lucy Harris, Jane Wrigley, Jason King, Anne Collins, Rajendra Kumari. Evaluation of hormonal therapy in a panel of prostate patient-derived xenograft models and comparison to standard cell line models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A009.
Abstract B008: PD-1/PDL-1 blockade remarkably regulates abundance of gut commensal microbiota in a murine syngeneic tumor model
Authors: Yang WenQing , Ding Jian , Gu Xiangchao , Chen Fei , Zhang Juan , Shi Qian 
Published: August 2018

Abstract
Microbiota has been linked to immune surveillance of tumor progression and tumor growth in cancer patients as well as in cancer mouse models. Recent research reveals that gut microbiota has the potential to act as a biomarker to predict responders or even as an alternative treatment approach. Therefore, several gut microbes discovered in this invention (e.g., Akkermansia, Adlercreutzia, Coprococcus) could possibly be used as a biomarker to predict PD-1 antibody efficacy or could combine with PD-1 antibody in preclinical and clinical settings. Considering the complexity of intestinal microorganisms, a larger panel or wider spectrum of microbiota species may be involved in this process. The current study was designed to explore the possibilities of identifying multiple strains of intestinal microbiota that may be involved in antitumor effects of immune-checkpoint inhibitors, using preclinical tumor models. Gut microbiota changes were determined before and after a series of anti-PD-1 mAb treatments had been administered. Sixteen-S (16S) rRNA-seq was performed using feces collected at 4 time points. The results indicate that significant antitumor activity was found to be associated with gut microbiota changes of a large panel of microbiota, including a few strains with robust upregulation or downregulation. Upon further characterization and confirmation, these findings could lead to identification of one or more microbiota strains that could have biomarker potentials for cancer immunotherapy.
Citation Format: WenQing Yang, Jian Ding, Xiangchao Gu, Fei Chen, Juan Zhang, Qian Shi. PD-1/PDL-1 blockade remarkably regulates abundance of gut commensal microbiota in a murine syngeneic tumor model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B008.
Abstract B019: Developing new ceramide analogs against AIDS-related lymphoma
Authors: Dai Lu , Foroozesh Maryam , Qin Zhiqiang 
Published: August 2018

Abstract
The Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including primary effusion lymphoma (PEL), a subtype of highly aggressive non-Hodgkin lymphoma (NHL). PEL preferentially arises in immunocompromised patients, e.g., AIDS patients, but lacks of effective therapeutic options. Ceramide serves as a central mediator in sphingolipid metabolism and is referred to as a “tumor suppressor lipid”; however, its functional role in PEL survival and therapeutic value remain largely unknown. Our previous work demonstrated that targeting sphingolipid metabolism by either sphingosine kinase 2 (SphK2) inhibitor or exogenous ceramides induced significant PEL apoptosis and suppressed tumor progression. Recently, we have synthesized a series of new ceramide analogs with better stability and solubility. Our first screening indicated that at least 2 new compounds effectively inhibited PEL cell growth, through the complex mechanisms including induction of tumor cell apoptosis, cell cycle arrest, intracellular ceramide production, and viral lytic gene expression. By using an immunodeficiency mice xenograft model, we found that these selective ceramide analogs significantly repressed PEL progression in vivo. Ongoing work includes the identification of global gene profile affected by these new compounds within PEL cells using the NGS technology. We hope these new ceramide analogs can be developed as promising therapeutic strategies for prolonging the survival time of PEL patients and/or improving their life quality.
Citation Format: Lu Dai, Maryam Foroozesh, Zhiqiang Qin. Developing new ceramide analogs against AIDS-related lymphoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B019.
Abstract B029: Deletion of mesothelin impairs intraperitoneal growth of pancreatic cancer
Authors: Alewine Christine Campo , Rudloff Michael , Arons Danielle , El-Behaedi Salma , Zhang Xianyu , Avula Leela 
Published: August 2018

Abstract
The mesothelin (MSLN) protein is expressed in at least 85% of pancreatic adenocarcinomas but not on cells of the healthy pancreas nor in the parenchyma of other vital organs. Due to this differential expression, MSLN has been used as a target for various antibody-based treatments and cancer vaccines. The physiologic role of MSLN is unknown. The MSLN gene encodes for a precursor protein, which is cleaved to produce the mature MSLN protein. Previous reports have suggested that overexpression of MSLN precursor protein may increase tumorigenicity and metastatic potential of pancreatic adenocarcinoma. Here, we have used CRISPR-Cas9 gene editing to delete MSLN from the KLM-1 pancreatic cancer cell line (ΔMSLN) and have examined the growth of these cells compared to mock deleted cells (Mock). The ΔMSLN and Mock cells grew at the same rate both in cell culture and as subcutaneous tumors in nude mice, but had significantly impaired growth when inoculated into the mouse intraperitoneal cavity. Lentivirus transduction was used to restore expression of MSLN in ΔMSLN cells. Transduction of full-length WT MSLN, but not a Y318A mutant, restored intraperitoneal growth. Interestingly, reintroduction of mature MSLN instead of the precursor protein did not restore growth even though it was appropriately expressed on the cell surface. In summary, we have demonstrated that MSLN enhances the growth of pancreatic cancer within the peritoneal cavity and defined key regions of MSLN important for this activity.
Citation Format: Christine Campo Alewine, Michael Rudloff, Danielle Arons, Salma El-Behaedi, Xianyu Zhang, Leela Avula. Deletion of mesothelin impairs intraperitoneal growth of pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B029.
Abstract B036: Synthetic DNA-encoded monoclonal antibody delivery (DMAbTM) of anti-CTLA4 antibodies induces tumor shrinkage in vivo
Authors: Duperret Elizabeth , Trautz Aspen , Patel Ami , Kim Joseph , Muthumani Kar , Weiner David B. 
Published: August 2018

Abstract
Antibody-based immune therapies targeting the T-cell checkpoint inhibitors CTLA4 and PD1 have made incredible advances in cancer therapy. In particular, the combination of CTLA4 and PD1 blockade (using ipilimumab and nivolumab, respectively) was recently shown to be the most effective immune therapy for improving progression-free survival in advanced melanoma patients. However, this immune therapy combination strategy is extraordinarily expensive due to high manufacturing costs of monoclonal antibodies, with an estimated annual cost of almost one million dollars per patient. In this study, we focused on the development of a DNA-encoded monoclonal antibody (DMAbTM) approach for delivery of anti-CTLA4 monoclonal antibodies in vivo. With this technology, formulated DMAbTM plasmids are injected into the muscle with electroporation, allowing for muscle cells to produce and secrete the DMAbTM for a prolonged period of time without the need for repeated administration. In proof-of-concept studies in mice, we show that delivery of a DMAbTM plasmid for a monoclonal antibody targeting mouse CTLA4 (clone 9D9) elicits high serum expression (peak expression of 7.9µg/mL in immune-competent C57Bl/6 mice with one injection of DNA). This anti-mouse CTLA4 DMAbTM is capable of inducing tumor regression in A/J mice that were implanted with the immunogenic Sa1N tumor cell line without repeated administration. Furthermore, this anti-mouse CTLA4 DMAbTM is capable of synergizing with a DNA vaccine targeting the tumor antigen TERT in slowing tumor growth for the nonimmunogenic TC-1 tumor cell line. We also examined DNA delivery of the anti-human CTLA4 antibodies ipilimumab and tremelimumab. For these anti-human CTLA4 DMAbsTM, we achieved steady-state levels of approximately 75µg/mL and 50ug/mL for ipilimumab and tremelimumab, respectively, in mice, which is greater than the mean trough levels of ipilimumab achieved in patients (21.8µg/mL serum concentration for 3mg/kg dose). These anti-human CTLA4 DMAbsTM produced in vivo bind to human CTLA4 protein and induce T-cell activation in a functional assay ex vivo. These results demonstrate the feasibility of delivering immune checkpoint blockade monoclonal antibodies using DNA for cancer immune therapy. Future studies will explore combination therapies with CTLA4 DMAbsTM and chemotherapy.
Citation Format: Elizabeth Duperret, Aspen Trautz, Ami Patel, Joseph Kim, Kar Muthumani, David B. Weiner. Synthetic DNA-encoded monoclonal antibody delivery (DMAbTM) of anti-CTLA4 antibodies induces tumor shrinkage in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B036.
Abstract B086: Targeting Auger electrons to cellular nuclei via PARP-1
Authors: Winters Harrison D. , Mach Robert H. , Mankoff David A. , Pryma Daniel A. , Makvandi Mehran 
Published: August 2018

Abstract
Introduction: Auger-emitting radionuclides have promising therapeutic properties due to their high linear energy transfer with nanometer ranges in tissue, although they have proven challenging to work with since they must be targeted to cellular nuclei to directly cause DNA damage. In the present study, we sought to utilize PARP-1 as a molecular target for the delivery of Auger electrons to induce local DNA damage without altering PARP-1 enzymatic activity. PARP-1 is an abundantly expressed nuclear protein involved in the DNA damage response and the primary target of emerging therapeutics for the treatment of homologous recombination deficient (HRD) ovarian cancers. Methods: In vitro cytotoxicity studies were performed by treating BRCA1-deficient ovarian carcinoma cell lines (UWB1.289 and OVCAR8) with various doses of [125I]KX1 or [123I]KX1, a PARP inhibitor analogue. To understand the specificity of KX1, the same treatments were given to matching cell lines that either were engineered to have a restored HR status via BRCA1 expression (UWB1.289 BRCA1-restored), or PARP1 knockout via CRISPR/cas9 genome editing (OVCAR8 PARP1-knockout). Next, cellular immunofluorescence was performed and DNA damage was assessed by measuring GH2AX, 53BP1, PAR, and PARP-1 levels at 2 or 24 hours after treatment with [125I]KX1 or [123I]KX1. Results: Cytotoxicity data revealed a dose-dependent reduction in cell viability in both BRCA1 HRD cell lines after treatment with either Auger emitter. Cell death in UWB1.289 BRCA1-restored and OVCAR8 PARP1-knockout cell lines was reduced when compared to identical treatments in parent cell lines. Immunofluorescence analysis showed a dose-dependent increase in GH2AX and 53BP1 foci as early as 2 hours post treatment in OVCAR8. Similar to the cytotoxicity data, GH2AX foci formation was reduced in OVCAR8 PARP1-knockout. Interestingly, treatment with radiolabeled [123I]KX1 did not reduce cellular ribosylation (PAR) as seen with the treatment of a commercially available PARP inhibitor, but resulted in an increase from control. Conclusions: Auger-emitting radionuclides delivered to nuclei via PARP-1 can cause significant DNA damage. Reduced cytotoxicity and GH2AX foci observed after treating OVCAR8 PARP1-knockout cell lines demonstrated that both Auger emitters caused DNA damage as a result of specifically targeting PARP-1. Furthermore, these agents did not inhibit the enzymatic activity of PARP-1 and may have the potential to elicit neoantigenicity through DNA damage without altering the proinflammatory pathways regulated by ribosylation.
Citation Format: Harrison D. Winters, Robert H. Mach, David A. Mankoff, Daniel A. Pryma, Mehran Makvandi. Targeting Auger electrons to cellular nuclei via PARP-1 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B086.
Abstract B207: Obesity and p16INK4A downregulation activate breast adipocytes and promote their pro-tumorigenicity
Authors: Alkhalaf Huda H. 
Published: August 2018

Abstract
Obesity is increasingly recognized as a risk factor for breast cancer development. However, the molecular basis of obesity-related breast carcinogenesis remains elusive. In this study, we have shown that obesity reduces the level of the tumor suppressor p16INK4A protein in breast adipocytes, which showed active features and strong pro-carcinogenic potential both in vitro and in orthotopic tumor xenografts, as compared to mature adipocytes from lean women. Furthermore, obesity triggered epithelial-to-mesenchymal transition (EMT) in breast ductal epithelial cells. Interestingly, specific downregulation of p16INK4A increased the expression/secretion levels of various adipokines including leptin, and activated breast adipocytes from lean women. Consequently, like breast adipocytes from obese women, p16-deficient adipocytes induced EMT in normal primary breast luminal cells in a leptin-dependent manner and enhanced tumor growth. Additionally, we have shown that p16INK4A negatively controls leptin at the mRNA level through miR-141 and miR-146b-5p, which bind the leptin mRNA at specific sequence in the 3’UTR. These results show that obesity activates breast stromal adipocytes through p16 downregulation, which upregulates leptin and promotes pro-carcinogenic processes.
Citation Format: Huda H. Alkhalaf. Obesity and p16INK4A downregulation activate breast adipocytes and promote their pro-tumorigenicity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B207.