bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 801: A zebrafish model of NF1-mutant melanomas that lack activating mutations of BRAF or NRAS
Authors: He Shuning , Mansour Marc R. , Layden Hillary M. , Rodig Scott J. , Patton E. Elizabeth , Look A. Thomas 
Published: July 2017

Abstract
Cutaneous melanoma is the most lethal type of skin cancer, with ~76,380 newly diagnosed melanoma and ~10,130 melanoma-associated deaths per year in the US. Thus, there is a need for improved understanding of the molecular pathogenesis and more effective targeted therapies for this devastating disease. The recent work of The Cancer Genome Atlas Network has defined melanoma as an RTK/RAS-driven solid tumor that can be classified into four genomic subtypes: BRAF-mutant, RAS-mutant, NF1-mutant, and triple-wild-type. This landmark study highlighted the important role of the previously understudied NF1 tumor suppressor in melanoma pathogenesis, especially for the 9% of melanoma patients who have acquired inactivating NF1-mutations, but lack hotspot mutations that activate BRAF or RAS. To date, animal models have not been developed for the NF1-mutant subtype of melanoma, which has significantly impaired the development of novel therapeutic strategies for this subtype. Here we report the first zebrafish model for NF1-mutant melanoma, which we generated by combining the loss of nf1 with loss of both pten and p53. The resultant compound mutant zebrafish develop aggressive melanomas from the age of 7 weeks and the tumor penetrance is 80% by the age of 18 weeks. We demonstrate further that these high-risk zebrafish melanomas were exclusive of hotspot mutations of braf and nras. Sustained inhibition of both MEK and PI3K suppressed tumor progression in vivo, whereas inhibition of MEK or PI3K alone was insufficient to suppress the growth of these tumors. Surprisingly, single agent therapy with rapamycin, an MTOR inhibitor, proved even better for short- and long-term suppression of tumor cell growth in nf1/pten-mutant melanomas. Thus our model appears ideal for the testing of drugs that will prove uniquely active for the significant subset of NF1-mutant, BRAF/NRAS-wildtype human melanomas.
Citation Format: Shuning He, Marc R. Mansour, Hillary M. Layden, Scott J. Rodig, E. Elizabeth Patton, A. Thomas Look. A zebrafish model of NF1-mutant melanomas that lack activating mutations of BRAF or NRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 801. doi:10.1158/1538-7445.AM2017-801
Abstract 802: Loss of function of Arid1a synergizes with MYCN in neuroblastoma pathogenesis
Authors: Shi Hui , Tao Ting , Kadoch Cigall , Look Thomas 
Published: July 2017

Abstract
ARID1A is a key component of the SWI/SNF-A (BAF) chromatin-remodeling complex that is known to modulate chromatin structure and gene transcription. Recent exome and whole-genome resequencing has identified SWI/SNF as the most frequently mutated chromatin remodeler in human cancers, and ARID1A as the most highly mutated component among the SWI/SNF subunits, primarily in solid tumors. In high-risk neuroblastoma, ARID1A is mutationally inactivated in one allele in ~1% of patient tumors. In addition, ARID1A is deleted in one allele in at least 85% of cases with chromosome 1p deletions, which is the most common deletion found in neuroblastoma. Thus, ARID1A appears to function as a haploinsufficient tumor suppressor in a substantial fraction of high-risk neuroblastomas. The arid1a gene is duplicated in zebrafish, and the two genes are hence named arid1aa and arid1ab. We targeted each allele of the two genes using CRISPR/Cas genome editing system and recovered stable lines with loss-of-function mutations in each arid1a gene. arid1ab but not arid1aa homozygous mutation showed embryonic lethality. We bred these lines with a transgenic zebrafish line expressing high levels of MYCN in the peripheral sympathetic nervous system driven by the dopamine beta-hydroxylase promoter. Loss of one copy of either arid1aa or arid1ab dramatically accelerated the onset and increased the penetrance of MYCN-induced neuroblastoma. Loss of additional copies of arid1aa or arid1ab accelerated the tumor onset even futher, with the most rapid onset in compound heterosygotes of both genes. The compound heterosygotes showed increased fraction of sympathoadrenal cells in active cell cycle compared to the MYCN transgenic fish with wild type arid1a allales. Our long-term goal is to use the zebrafish model to elucidate the mechanisms underlying the highly dose-dependent tumor suppressor role of this component of the BAF chromatin remodeling complex in neuroblastoma, as a first step toward designing targeted therapies synthetic lethal with reduced expression levels of ARID1A.
Citation Format: Hui Shi, Ting Tao, Cigall Kadoch, Thomas Look. Loss of function of Arid1a synergizes with MYCN in neuroblastoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 802. doi:10.1158/1538-7445.AM2017-802
Abstract 804: Zebrafish as a model organism to study human pancreatic CSC's
Authors: Sanchez Laura E. , Sainz Pablo Cabezas , Sainz Bruno , Muinelo Laura , Lopez Rafael 
Published: July 2017

Abstract
Zebrafish is establishing itself as a powerful animal model for understanding human disease, including cancer. Xenotransplantation of human cancer cells into zebrafish is becoming an attractive research tools for studying cancer behaviour, both for established lines and primary tumours, however, its utility as a model for cancer stem cells (CSCs) is still in its infancy. In addition, only when the differences between primary tumours and established cancer cell lines are minimized will we be truly one step closer to developing biologically relevant personalized medicine platforms for cancer. To address these two limitations, we set out to achieve a deeper behavioral understanding of pancreatic CSCs inside the zebrafish embryo. The main methodology of this study was focused on the xenotransplantation of human primary pancreatic ductal adenocarcinoma (PDAC) cells (185 scd line) into zebrafish embryos using two different conditions: adherent cells (non-CSCs) vs sphere-derived cells (CSCs). Marked with a lipophilic dye, cells were injected into zebrafish embryos and incubated at 36ºC during 48h/72h to assess the proliferation of the injected cells. Self-developed Matlab software was used to analyze the intensity and area of the injected cells in order to give a ‘proliferation ratio’. Results obtained indicated that the sphere-derived cells proliferated and migrated at a higher rate than adherent cells. This is likely due to the different CSC content present between the two conditions tested: adherent pancreatic 185 cells contain 1% CSCs versus the 15% enrichment of CSCs in sphere-derived 185 cells. Apart from the differential CSC content, we also hypothesize that the 3D environment afforded by the yolk sac of the zebrafish embryo additionally favors the expansion of CSCs. Importantly, similar results were obtained with CSCs isolated via FACsorting, using autofluorescence as a marker for CSCs. This work not only contributes to the behavioral understanding of pancreatic CSCs using the zebrafish model organism but more importantly concludes that 1) PDAC CSC proliferation and migration can be studied in zebrafish, 2) the zebrafish model represents a potentially powerful surrogate model for the study of PDAC CSC biology in vivo, and 3) this model can potentially be adapted for to test chemotherapeutics that specifically target PADC CSCs, the cell type considered to be the most chemoresistant and tumorigenic in pancreatic cancer.
Citation Format: Laura E. Sanchez, Pablo Cabezas Sainz, Bruno Sainz, Laura Muinelo, Rafael Lopez. Zebrafish as a model organism to study human pancreatic CSC's [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 804. doi:10.1158/1538-7445.AM2017-804
Abstract 807: A novel immunodeficient rat for modeling human cancer
Authors: Noto Fallon K. , Arey Angela , McClain Christopher , Zhang Wei , Yeshi Tseten 
Published: July 2017

Abstract
Animal models of human cancer offer the potential to study human tumor growth kinetics, genetic variance among human cancers, and provide in vivo platforms for drug efficacy testing. In particular, immunodeficient mouse models have been invaluable in modeling a wide range of human cancers. However, some cancer lines don’t grow well in the available mouse models or show variability in growth kinetics from mouse to mouse, making drug efficacy studies difficult due to differences in tumor size at the onset of treatment. These challenges are also seen in patient derived xenograft (PDX) models, in addition to long timeframes to obtain sufficient mice with PDX tissue growth for drug efficacy studies. Mice are also limited in tumor growth potential with regard to humane endpoints and small size also limits the volume of blood that can be collected for analysis. An immunodeficient rat model could provide a solution to some of these issues. A rat model would allow for larger tumor size, easier surgical manipulation, and greater volume of tissue and blood sampling for downstream analysis. In addition, large tumors from rats could be serially transplanted into mice for drug efficacy testing and could provide a large number of transplanted mice in a shorter period of time compared with serially transplanting from mouse to mouse.
We have created an immunodeficient rat model with a functional deletion of the Rag2 gene. This knockout, created using spermatogonial stem cells, lacks mature B and T cells. To assess the capability of the Rag2 knockout rat to accept human xenografts, we transplanted 2 commercially available human cancer cell lines into our animals. The human REH acute lymphocytic leukemia cell line was transplanted via intravenous injection and the human glioblastoma cell line U87MG was transplanted subcutaneously. Both cell lines survived in the Rag2 knockout rat and resulted in the growth of tumors comprised of human cells. Studies are underway to characterize the Rag2 knockout rat’s ability to grow other human cell lines, including those that do not grow well in mice, and PDX tissues.
Citation Format: Fallon K. Noto, Angela Arey, Christopher McClain, Wei Zhang, Tseten Yeshi. A novel immunodeficient rat for modeling human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2017-807
Abstract 816: Molecular and genomic characterization of a newly established male breast cancer cell line
Authors: Vaclova Tereza , Maguire Sarah , Pugh Matthew , Barry Peter , Orr Nick 
Published: July 2017

Abstract
Although the majority of breast cancers affect women, approximately 1% of cases occur in men. At present comparatively little is known about the molecular mechanisms that influence male breast cancer predisposition and tumorigenicity. This is largely due to the current unavailability of an established cell line model in which to study male breast cancer. Development of in vitro models of the disease is therefore warranted, not least because growing evidence indicates that it is sufficiently different from female breast cancer such that extrapolating knowledge from one to the other may be misleading.
Here we report the establishment and characterisation of a male breast cancer cell line derived from a primary tumor arising in a 61-year old male patient. We used 3T3-J2 mouse fibroblast co-culture in the presence of a ROCK inhibitor to conditionally reprogram epithelial cells from freshly resected tumor tissue. Once established, the cell line showed a rapid proliferation rate and growth in full conditioned media without the support of mouse fibroblasts. Immunohistochemical profiling demonstrated expression of epithelium-specific antigens AE1/AE3, breast epithelial marker CK7 and confirmed estrogen receptor positivity in concordance with the primary tumor. Germline sequencing detected no pathogenic germline predisposition mutations in either BRCA1 or BRCA2. There was no evidence of somatic mutation in any of the established female breast cancer driver genes. Somatic whole genome sequencing of early and late passages indicated a paucity of structural aberration and little evidence for obvious accumulation of gross genetic alterations.
In conclusion, we have established a novel in vitro model for studying male breast cancer. That the cell line genome displays minimal evidence of significant acquired genetic changes arising due to reprogramming suggests that it will be of value in future studies of the biology of male breast cancer.
Citation Format: Tereza Vaclova, Sarah Maguire, Matthew Pugh, Peter Barry, Nick Orr. Molecular and genomic characterization of a newly established male breast cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 816. doi:10.1158/1538-7445.AM2017-816
Abstract 82: MiR-206-mediated c-MET suppression modulates BCRP/ABCG2 levels in NRF2-silenced cancer cells
Authors: Choi Bo-hyun , Ryoo In-geun , Kim Donghyeok , Lee Sujin , Kwak Mi-Kyoung 
Published: July 2017

Abstract
Breast cancer resistance protein (BCRP/ABCG2), a xenobiotic efflux transporter, is responsible for anticancer resistance in tumors. NF-E2-related factor 2 (NRF2) is a critical transcription factor in cellular defense system by regulating the expression of antioxidant and detoxifying enzymes; however, its overexpression is often associated with tumor resistance to chemotherapy. In the present study, we demonstrate that NRF2 modulation affects the expression of hepatocyte growth factor receptor (HGFR/c-MET) and consequently suppresses BCRP/ABCG2 activity in cancer cells. Interfering RNA-mediated stable inhibition of NRF2 in both ovarian carcinoma SKOV3 and renal carcinoma A498 cell lines reduced the expression of c-MET and this was accompanied by BCRP/ABCG2 down-regulation. The treatment of cells with pharmacological or genetic inhibitor of c-MET decreased BCRP/ABCG2 level and subsequently increased intracellular accumulation of doxorubicin and Hoechst 33342, indicating a link between c-MET and BCRP/ABCG2 activity. As a potential molecular mechanism of altered c-MET expression, miR-206 was identified as a predictive regulator of c-MET. As experimental evidence, transient and stable expressions of miR-206 in SKOV3 and A498 cells repressed c-MET and BCRP/ABCG2 levels. In addition, NRF2-knockdown cancer cells expressed higher levels of miR-206 compared to the control cells, and the treatment of NRF2 knockdown cells with the miR-206 inhibitor could restore c-MET and BCRP/ABCG levels. Collectively, our results showed that the NRF2 silencing-mediated miR-206 regulation could suppress BCRP/ABCG2 levels through c-MET modulation, which is providing an additional evidence of chemosensitization of tumor cells by NRF2 inhibition.
Citation Format: Bo-hyun Choi, In-geun Ryoo, Donghyeok Kim, Sujin Lee, Mi-Kyoung Kwak. MiR-206-mediated c-MET suppression modulates BCRP/ABCG2 levels in NRF2-silenced cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 82. doi:10.1158/1538-7445.AM2017-82
Abstract 825: Cetixumab enhanced apoptosis effects of radiation on human prostate cancer cell line PC-3
Authors: Chang Chia-lun , Wu Szu-Yuan 
Published: July 2017

Abstract
Prostate cancer is a leading cause of cancer death in men in developed countries. Radiotherapy is the main treatment to prostate cancer. Dose escalation of irradiation with image guide rasdiotherapy and intensity modulated radiotherapy were used with more and more evidences in prostate cancer patients and bring in longer PSA-free survival time. Although the evolution of radiation techniques bring better outcomes, but modern modalities were not avaliable in non-western world. Radiation enhancement is still an improtant issus in prostate cancer in non-western world, especially in androgen independnt prostate cancer. The epidermal growth factor receptor (EGFR) network has rich targets for prostate cancer killing. The chimeric monoclonal antibody Cetuximab (IMC-A12, Erbitux®) binds to EGFR and prevents its intracellular signaling. Currently, it is approved for treatment of wild-type KRAS colon and head and neck cancer. The effect and mechanisms of Erbitux and radiotherapy are still not clear. In this study, we evaluated the effects of combining the EGFR inhibition and radiation on PC-3 prostate cancer cells. PC-3 cells were treated with various doses(1,2.5,5 and 10 ug/ml) of anti-EGFR antibody (CETUXIMAB) and irradiation(5, 7.5 Gy). The results revealed that 5 and 10 ug/ml of CETUXIMAB significnatly reduced the colony formation. The cell cycle analysis revealed that CETUXIMAB significnatly enhanced the radiation induced G2/M phase arrest and subG1 peak increasing. The Hoechst staining and DNA laddering analysis revealed radiation and CETUXIMAB combined use will induced more apoptotic bodies or DNA fragmentation than radiation alone use. By using a apaptosis protein array, we found that several apaptosis related protein (Catalase, cIAP-1, Clusterin, Fas, HIF-1α, HSP27, HSP60, HSP70, SMAC and Survivin) were significantly downregulated in radiation and CETUXIMAB combined group. Taken together, our results demonstrated that Erbitux enhanced apoptosis effects of radiation on PC-3.
Citation Format: Chia-lun Chang, Szu-Yuan Wu. Cetixumab enhanced apoptosis effects of radiation on human prostate cancer cell line PC-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 825. doi:10.1158/1538-7445.AM2017-825
Abstract 826: Nrf2 confers radioresistance by regulating cancer stem trait in lung cancer cells
Authors: He Xiaoqing , Chi Alex , Wang Liying , Rojanasakul Yon 
Published: July 2017

Abstract
Lung cancer is the leading cause of cancer-related death accounting for more than 1.3 million deaths worldwide annually. Despite advances in treatment, the five-year survival rate is 2% if the cancer has metastasized to other organs. The major cause of poor prognosis of advanced lung cancer is multi-resistance to chemo/radio therapy. Therefore, it is crucial to understand the underlying mechanisms of chemo/radio resistance and develop therapeutic strategies to overcome the resistance. Transcription factor Nrf2 is a key regulator of cytoprotective genes which facilitate cellular defense against harmful insults. We found that Nrf2 and its downstream target NQO1 are highly upregulated in lung cancer patient tumor tissues as well as in lung cancer cell lines compared to adjacent normal tissues or normal cell lines. We hypothesized that the upregulated Nrf2 may be responsible for radio/chemo resistance and malignancy in lung cancer. RNA interference studies showed that knockdown of Nrf2 substantially increased the sensitivity of human lung cancer H460 and A549 cells to radiation-induced cell death. Knockdown of Nrf2 also decreased tumor sphere formation, suggesting its role in cancer stem cell (CSC) regulation which may be responsible for the radioresistance. Analyses of CSC markers including ALDH and Oct4 in control and Nrf2-knockdown H460 and A549 cells support this finding. Together, our results indicate an essential role of Nrf2 in the control and regulation of CSCs and radioresistance. Since CSCs are widely believed to be responsible for cancer chemoresistance and relapse, our novel finding on the role of Nrf2 in radiation resistance may aid in the design of novel therapeutic strategies for resistant cancers.
Citation Format: Xiaoqing He, Alex Chi, Liying Wang, Yon Rojanasakul. Nrf2 confers radioresistance by regulating cancer stem trait in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 826. doi:10.1158/1538-7445.AM2017-826
Abstract 83: Irinotecan resistance in type 2 interleukin-1 receptor overexpressed colorectal cancer cells is overcome by inhibitor of MEK
Authors: Mar Ai-Chung , Chu Chun-Ho , Lee Te-Chang 
Published: July 2017

Abstract
We have previously demonstrated that the expression of interleukin-1 receptor type II (IL1R2) is closely associated with the advanced staging and distant metastasis in patients with CRC. We also found that enhanced expression of IL1R2 played certain roles to resist the targeted therapeutics, regorafenib, in CRC cells. Whether IL1R2 expression is associated with the resistance to chemotherapeutics is unclear. Irinotecan, a water-soluble and semisynthetic derivative of camptothecin, is one of widely used first- and second-line chemotherapeutics for treatment of patients with metastatic colorectal cancer (CRC). Herein, we first demonstrated that enhanced expression of IL1R2 resulted in increased resistance of CRC cells to irinotecan using IL1R2 ectopically expressed HCT116 and DLD-1 cells, which were IL1R2 low expressing CRC cells, and IL1R2 silenced HT29 cells, which were IL1R2 high expressing CRC cells. Since we have shown that IL1R2 may activate MEK/ERK signaling by inhibition of PP2A, we further revealed that a specific inhibitor of MEK, CI-1040, could overcome the irinotecan resistance in IL1R2-overexpressing DLD-1 and HT29 cells. Our result showed that the combination of irinotecan and CI-1040 synergistically suppressed the cell growth in high IL1R2 expressing CRC cells but less significant in low IL1R2 expressing cells. We also confirmed that treatment of IL1R2-overexpressing CRC cells with CI-1040 significantly suppressed the pERK, a downstream target of MEK. These results support that IL1R2 mediates through activation of MEK/ERK signaling to cause irinotecan resistance in human CRC cells. The investigation how IL1R2 induces irinotecan resistance is ongoing. Accordingly, we may suggest that combined treatment of irinotecan and MEK-ERK inhibitor is a potential therapeutic strategy against IL1R2 overexpression related irinotecan resistant CRC.
Citation Format: Ai-Chung Mar, Chun-Ho Chu, Te-Chang Lee. Irinotecan resistance in type 2 interleukin-1 receptor overexpressed colorectal cancer cells is overcome by inhibitor of MEK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 83. doi:10.1158/1538-7445.AM2017-83