tbuckley/cabot-search huggingface dataset:
Abstract 3030: Mutant p53-driven metastasis explored utilizing a traceable, conditional osteosarcoma model
Authors: Rasoul Pourebrahimabadi, Yun Zhang, Mark J. McArthur, Guillermina Lozano
Journal: Cancer Research (2017)

Abstract TP53 is the most frequently mutated gene in cancer and missense mutations in particular account for the majority of mutations. Mutant p53 proteins exert oncogenic Gain-of-Function (GOF) properties that contribute to increased migration and invasion in culture and metastasis in vivo. To elucidate how mutant p53 drives metastasis, we developed a traceable somatic osteosarcoma model that initiates with a single p53 mutation (p53R172H or p53R245W), or p53 loss specifically in osteoblasts using Osx-cre. To mark tumor cells, we utilized the mTmG allele which expresses membrane-targeted Tomato (mT) prior to Cre-mediated excision and membrane-targeted green fluorescent protein (mG) after excision so the tumor cells become GFP+ and the stromal cells remain RFP+. In this high penetrant, short latency mouse model, tumor micro-metastasis can be detected by GFP expression in the context of a normal stroma and immune system. The cohort has developed osteosarcoma with complete penetrance and an average survival of 304± 65 day. We observed metastasis in 55% of p53 mutant osteosarcomas which was significantly higher than 26% metastasis observed in p53 null tumors (p&amp;lt;0.01). In p53 mutant osteosarcomas, the metastasis rate was found significantly associated with low p53 copy number. Spectral karyotyping (SKY) on early passage cells derived from somatic p53 mutant tumors exhibited marked aneuploidy with modal chromosome numbers near tetraploid. To characterize the transcriptional profile associated with mutant p53 GOF, we analyzed and compared the RNA-Seq transcriptomes of eight tumors derived from p53R172H mutant mice with eight p53 null tumors. Comparative analysis of gene expression identified a signature of snRNA genes to be strongly associated with mutant p53 gain of function. Functional annotation of upregulated genes in mutant tumors was also highly enriched for chromatin modifying enzymes. These findings contribute to our understanding of the role of mutant p53 GOF in metastasis. Our long term goal is to study how tumor-stromal interactions affect tumor development and metastasis. This understanding will have broad translational significance in diagnosis and treatment of tumors with mutant p53. Citation Format: Rasoul Pourebrahimabadi, Yun Zhang, Mark J. McArthur, Guillermina Lozano. Mutant p53-driven metastasis explored utilizing a traceable, conditional osteosarcoma model [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 3030. doi:10.1158/1538-7445.AM2017-3030
Abstract 5086: Chronic radiation induced uPA expression mediates neuroblastoma cells survival
Authors: Manu Gnanamony, Karen Fernández, Jaime Libes, Julian Lin, Pushpa A. Joseph, Christopher S. Gondi
Journal: Cancer Research (2017)

Abstract Neuroblastoma accounts for more than 15% of cancer-related deaths of children in the United States. Despite aggressive treatment regimens, the long-term survival for these children remains less than 40%. The urokinase plasminogen activator (uPA) system plays a role in several critically important biology processes, such as cell adhesion, migration, proliferation and survival. This system includes uPA, a serine protease which converts a zymogen plasminogen into the active serine protease plasmin, its surface receptor uPAR/CD57, which binds uPA with high affinity, facilitates proteolytic activation/conversion of uPA precursor (single-chain uPA, scuPA) into the active two-chain uPA protease (tcuPA) and mediates uPA-induced activation of several intracellular signaling cascades, and protects against several inhibitors, e.g. PAI-1, among others. Recent findings demonstrate that dividing/proliferating cells translocate intact scuPA to the nucleus via the nucleocytoplasmic shuttle protein nucleolin. In this study we demonstrate that both SKNBE(2) and NB1691 neuroblastoma cells when exposed to chronic radiation suppresses nMYC gene copy number and induces the overexpression of cMYC and uPA expression levels without observable change in uPA gene copy number. Increased uPA expression was accompanied with increase in the mitochondrial mass (4 fold in both NB1691 and SKNBE (2) cells). Knockdown of uPA expression in chronic radiation cells using siRNA resulted in reduced cell survival. RT-PCR analysis shows that uPA knockdown resulted in reduced expression of cMYC and its target genes cyclin A and cyclin D1. Overexpression of uPA in both SKNBE(2) and NB1691 wildtype cells resulted in increased cMYC and cyclin D1 expression but not nMYC expression suggesting that cMYC may be specifically regulated by uPA. In conclusion, our study shows that uPA plays a vital role in survival of neuroblastoma cells treated with chronic radiation by associating with cMYC to compensate for loss of nMYC expression. Our study also implies that targeting uPA might be a viable option as a combination therapy in the treatment of high-risk neuroblastoma. Citation Format: Manu Gnanamony, Karen Fernández, Jaime Libes, Julian Lin, Pushpa A. Joseph, Christopher S. Gondi. Chronic radiation induced uPA expression mediates neuroblastoma cells survival [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 5086. doi:10.1158/1538-7445.AM2017-5086
Abstract 254: The potential of <i>Lactobacillus</i> probiotic treatments in colorectal cancer (CRC)
Authors: Imen Kahouli, Meenakshi Malhotra, Susan Westfall, Moulay Alaoui-Jamali, Satya Prakash
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the third leading cause of death worldwide. It is known to be a type of cancer that is preventable by changes in diet and lifestyle. Mounting evidence are supporting the role of gut microbiome in the etiology of CRC and emphasize on the potential of probiotics as biotherapeutics in the prevention and management of CRC. Lactobacillus probiotic bacteria were suggested to balance pathogenic and oncogenic microbial community in the colon and produce anti-tumorigenic and anti-inflammatory effects in healthy individuals at risk and CRC patients. There is a need, however, for studies that focus on identifying potent probiotic strains with activity against CRC and inhibit cancer growth. This report discusses and present findings about the formulation of novel probiotic Lactobacillus biotherapeutic for CRC based on anti-CRC proliferative effect, immune modulation and metabolic activity, in vitro and in vivo, using a genetically-induced animal CRC model. Results and metabolomic analysis demonstrated the potential acrion of probiotic treatment to change host and gut microbiome co-metabolic profiles, produce local and systemic anti-inflammatory effects, inhibit cancer-causing events, and improve overall gut health. Note: This abstract was not presented at the meeting. Citation Format: Imen Kahouli, Meenakshi Malhotra, Susan Westfall, Moulay Alaoui-Jamali, Satya Prakash. The potential of Lactobacillus probiotic treatments in colorectal cancer (CRC) [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 254. doi:10.1158/1538-7445.AM2017-254
Abstract 5292: Multitarget fecal miRNA test combined with fecal occult blood test and fecal miRNA test for colorectal cancer screening
Authors: Yoshikatsu Koga, Nobuyoshi Yamazaki, Yasuo Kakugawa, Takahisa Matsuda, Masaaki Ito, Yutaka Saito, Hiroshi Saito, Yasuhiro Matsumura
Journal: Cancer Research (2017)

Abstract Background &amp; Aims: The fecal immunochemical test (FIT) is used for colorectal cancer (CRC) screening worldwide. However, there are several issues of the false-positive and the false-negative. To overcome these problems, various molecular biological tests have been combined to FIT. In this context, multitarget fecal DNA test was approved by FDA in August 2014. In addition, multitarget fecal microbiota has been recently reported. We have reported the usefulness of fecal miRNA analysis to detect CRC. Here, we investigated the applicability of multitarget fecal miRNA test combined with FIT and fecal miRNA test using fecal RNA extracted from FIT residua. Methods: In this study, 57 patients with invasive CRC, 33 patients with advanced adenoma, and 60 healthy individuals were enrolled. Each participant collected 10 mg fecal samples using the FIT sampling container for 2 days. After FIT was performed, total RNA was extracted from the residuum and miRNA expression was analyzed by using real-time RT-PCR. The sensitivity and specificity of the multitarget fecal miRNA test combined with FIT and fecal miRNA test was analyzed by using the decision tree analysis. Results: Approximately 1μg RNA was extracted from 10 mg fecal sample. The expressions of miR-16, miR-92a, miR-106a, miR-142-3p, miR-223, and miR-451 in fecal samples were significantly higher in the patients with advanced neoplasm (including invasive CRC and advanced adenoma) than in the healthy individuals (P&amp;lt;0.05). The sensitivity and the specificity of the FIT alone were 74.4% (67/90) and 93.3% (56/60), whereas those of the multitarget fecal miRNA test were 93.3% (83/90) and 91.7% (55/60). Moreover the multitarget fecal miRNA test could detect 81.8% of patients with advanced adenoma (27/33). Conclusions: Multitarget fecal miRNA test combined with FIT and fecal miRNA test may be a useful new CRC screening method. Citation Format: Yoshikatsu Koga, Nobuyoshi Yamazaki, Yasuo Kakugawa, Takahisa Matsuda, Masaaki Ito, Yutaka Saito, Hiroshi Saito, Yasuhiro Matsumura. Multitarget fecal miRNA test combined with fecal occult blood test and fecal miRNA test for colorectal cancer screening [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 5292. doi:10.1158/1538-7445.AM2017-5292
Abstract 4733: Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung cancer
Authors: Hui Li, Lei Jia, Fan Yan, Pengbo Zhou
Journal: Cancer Research (2017)

Abstract Background: The Cullin-RING ubiquitin ligases 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human cancer patients. Methods: 352 lung cancer and 62 benign lung specimens of Asian origin were constructed into tissue microarrays (TMAs) of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B and their substrates was detected by immunohistochemistry (IHC), and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability. Results: Both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (PCUL4A&amp;lt;0.001, PCUL4B&amp;lt;0.001), and significantly associated with tumor size (PCUL4A&amp;lt;0.001, PCUL4B=0.002), lymphatic invasion (PCUL4A=0.004, PCUL4B&amp;lt;0.001), metastasis (PCUL4A=0.019, PCUL4B=0.006), and advanced TNM stage (PCUL4A&amp;lt;0.001, PCUL4B&amp;lt;0.001), which parallels gene amplification and abnormal activation of the canonical Wnt signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (P=0.01), and inversely correlated with XPC and p21, both of which are substrates of CUL4A (PCUL4A=0.019, PCUL4B=0.006). Higher levels of CUL4A or CUL4B are significantly associated with patients’ OS (PCUL4A&amp;lt;0.001, PCUL4B&amp;lt;0.001) and PFS (PCUL4A&amp;lt;0.001, PCUL4B=0.001). Conclusion: Our findings revealed that CUL4A and CUL4B are differentially associated with etiological factors for pulmonary malignancies and are independent prognostic markers for survival of distinct lung cancer subtypes. Citation Format: Hui Li, Lei Jia, Fan Yan, Pengbo Zhou. Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung 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 4733. doi:10.1158/1538-7445.AM2017-4733
Abstract 4758: Sensitization of nasopharyngeal carcinoma to radiotherapy by targeting GFPT1/TGF-β1 signaling pathways
Authors: Siqi Chen, Wei Gao, Jimmy Yu-Wai Chan, Thian-Sze Wong
Journal: Cancer Research (2017)

Abstract Background: Nasopharyngeal carcinoma (NPC) is a unique cancer with high susceptibility to radiation and mainstay treatment is radiotherapy. Effectiveness of NPC treatment is therefore dependent on the sensitivity of cancer cells to ionizing radiation treatment. Further, development of radio-resistant phenotype is a risk factor for distant metastasis and disease recurrence. Therefore, enhancing the degree of radiation sensitivity could improve prognosis and reduce the toxicity of radiotherapy with the use of lower radiation dose. Transforming growth factor β1(TGF-β1) expression is responsive to radiation treatment and the increase is important in the post-irradiation DNA repair. Tumor with low TGF-β1 level is more responsive to radiation treatment. Therefore, inhibiting TGF-β1 production can enhance the radiation damage to cancer cell DNA and also intensify the sensitivity of cancer cells to radiation. Our preliminary results indicate that TGF-β1 production in NPC is mediated by hexosamine pathway. Of which, GFPT1 (glucosamine-fructose-6-phosphate aminotransferase) is the rate-limiting enzyme. Purpose of the study: To enhance radiation sensitivity by targeting GFPT1/ TGF-β1 cascade in NPC. Experimental procedures: Radiation protective effects of TGF-β1 was examined by colony formation assay and Danio rerio (zebrafish) embryonic system. Production of TGF-β1 by activated hexosamine pathway in NPC was revealed by glucose and glucosamine treatment. Effects of GFPT1 silencing on radiosensitization are revealed by GFPT1 siRNA treatment followed by colony formation assay and gamma-H2AX formation assays. Results: Pretreatment of HONE1 cells with recombinant TGF-β1 protein enhanced the clonogenic ability of irradiated cells. TGF-β1 significantly increased the survival of zebrafish embryos after irradiation. Glucose and glucosamine treatment increased the expression of TGF-β1 protein in HONE1 cells. Silence of GFPT1 reduced TGF-β1 mRNA and protein expression in HONE1 cells. Silencing GFPT1 reduced the clonogenic capacity of head and neck cancer cells after radiotherapy and enhanced the degree of radiation-induced DNA double-strand breaks. Conclusions: Targeting GFPT1 enhances head and neck cancer cell sensitivity to radiation. GFPT1 inhibition can enhance the radiation sensitivity of head and neck cancer cells by inhibiting the expression of TGF-β1. Citation Format: Siqi Chen, Wei Gao, Jimmy Yu-Wai Chan, Thian-Sze Wong. Sensitization of nasopharyngeal carcinoma to radiotherapy by targeting GFPT1/TGF-β1 signaling pathways [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 4758. doi:10.1158/1538-7445.AM2017-4758
Abstract 765: Prognostic impact of Philadelphia chromosome in elderly acute lymphoblastic leukemia patients ineligible for hematopoietic stem cell transplantation
Authors: Ja Min Byun
Journal: Cancer Research (2017)

Abstract Elderly acute lymphoblastic leukemia (ALL) patients are often unfit for neither dose-intensive chemotherapy nor stem cell transplantation, thus their clinical outcomes have been dismal. The increased incidence of BCR-ABL translocation with increasing age also contributed to poor prognosis but, it was our conjecture that the introduction of potent tyrosine kinase inhibitors (TKI) targeting ABL, BCR-ABL translocation might not deliver negative prognostic impact in elderly ALL. Considering that many elderly Ph- ALL patients do not tolerate cytotoxic chemotherapy required for effective tumor control, we supposed that efficacy of ABL TKIs and their combination strategy with low dose cytotoxic chemotherapy would result in better survival for elderly Ph+ ALL compared to their Ph- counterparts. This study was a multicenter longitudinal cohort study of elderly de novo ALL (≥ 60 years) recruited from 11 hospitals in Korea from January 2005 to December 2015. We considered Ph+ if it was positive in at least one of three techniques: conventional cytogenetics, fluorescence in situ hybridization, or quantitative real-time polymerase chain reaction (qRT-PCR). Among the 96 patients enrolled, there were 50 Ph- ALL patients (52.1%) and 46 Ph+ ALL patients (47.9%). There were no differences between the 2 groups regarding age, sex distribution, performance status, and induction regimens. For treatment outcomes evaluation, the 5 Ph+ ALL patients not receiving TKI were eliminated and 41 Ph+ ALL patients treated with TKI were compared with 50 Ph- ALL patients (Table). Complete remission (CR) was attained in 27 (54.0%) of patients in the Ph- group versus 35 (85.4%) in the Ph+ group (P=0.001). The median RFS was significantly longer in the Ph+ group (3.1 months for Ph- vs. 8.9 months for Ph+, P=0.017). Induction death and induction failure occurred significantly more often in the Ph- group. The median OS was 6.3 months for Ph- group versus 10.3 months for Ph+ group (P=0.033). In conclusion, using real world data, this study reports the possible favorable impact of Ph+ in TKI-era for elderly patients. Citation Format: Ja Min Byun. Prognostic impact of Philadelphia chromosome in elderly acute lymphoblastic leukemia patients ineligible for hematopoietic stem cell transplantation [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 765. doi:10.1158/1538-7445.AM2017-765
Abstract LB-088: Role of histone demethylase JMJD1A in the generation of AR-V7
Authors: Lingling Fan, Fengbo Zhang, Martin Gleave, Xuesen Dong, Jianfei Qi
Journal: Cancer Research (2017)

Abstract Formation of androgen receptor (AR) splicing variant, AR-V7, has been shown to contribute to the resistance of prostate cancer to androgen deprivation therapy and development of castration-resistant prostate cancer (CRPC). We and others have reported that histone demethylase JMJD1A promotes the transcriptional activity of AR by functioning as an AR co-activator. Here, we identified a new role for JMJD1A in the expression of AR-V7 in prostate cancer cells. Knockdown of JMJD1A reduced the mRNA and protein level of AR-V7 but had little effect on the full-length AR (AR-FL). Re-expression of AR-V7 in the JMJD1A-knockdown cells partly restored the expression of select AR target genes and growth of prostate cancer cells under the androgen deprivation condition in vitro and in the mouse xenograft model. Our preliminary data show that JMJD1A promotes the alternative splicing of AR-V7 and we are currently investigating the splicing factor(s) regulated by JMJD1A for the AR-V7 formation. Together, our data reveal that JMJD1A enhances the castration-resistant growth of prostate cancer cells by promoting the alternative splicing of AR-V7. Note: This abstract was not presented at the meeting. Citation Format: Lingling Fan, Fengbo Zhang, Martin Gleave, Xuesen Dong, Jianfei Qi. Role of histone demethylase JMJD1A in the generation of AR-V7 [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 LB-088. doi:10.1158/1538-7445.AM2017-LB-088
Abstract 3992: Immune regulation of disseminated tumor cell clearance versus metastatic growth
Authors: Hasan Korkaya, Eunmi Lee, Raziye Piranioglu, Maria Ouzounova, Abdeljabar El-Andaloussi, Iskander Asm, Ahmet K. Korkaya, Gang Zhou, Ali Arbab, Paulo Rodriguez
Journal: Cancer Research (2017)

Abstract Metastatic disease is the end stage of extremely inefficient processes that entail overcoming multiple barriers including anti-tumor immunity. Although evidences from preclinical and clinical settings suggest that dissemination of malignant cells is an early process, majority of disseminated cells either eliminated or remain dormant in distant organs, while very few cells eventually develop successful metastasis. Therefore, it is widely accepted that dynamic and reversible tumor cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We provide evidence that monocytic and granulocytic subsets of myeloid derived suppressor cells (m-MDS, g-MDSC) infiltrated in primary 4T1 tumor and distant organs with different time kinetics regulate spatiotemporal tumor plasticity. Using co-culture experiments and syngeneic mouse models of murine 4T1 (metastatic) tumor, we demonstrated that tumor infiltrated m-MDSCs facilitate tumor cell dissemination from the primary site by inducing the EMT/CSC phenotype. In contrast, g-MDSCs infiltrated in the lungs support metastatic growth by reverting the EMT/CSC phenotype and thus promoting tumor cell proliferation. In contrast, less invasive EMT6 tumors fail to induce efficient pulmonary infiltration of g-MDSCs and results in clearance of disseminated tumor cells in the lungs. Gene expression analyses of tumors and MDCS subsets in primary tumor site and distant organs at different time points reveal mechanistic temporal regulation of in vivo tumor plasticity by m-MDSC and g-MDSC subsets in 4T1 tumor-bearing mice. However, the lung microenvironment of EMT6 tumor-bearing mice display a gene expression signature of anti-tumor immunity which predict better survival in breast cancer patients. In our functional studies, we demonstrate that EMT6 tumor-bearing animals efficiently eliminate disseminated tumor cells in the lungs. Furthermore, g-MDSCs isolated from 4T1-tumor bearing animals significantly enhance metastatic growth of already disseminated tumor cells. Consistent with the “seed and soil” hypothesis, our studies provide a molecular mechanism by which the immune system regulate spatiotemporal tumor plasticity and generation of permissive or anti-tumorigenic microenvironment in distant organs determining the fate of disseminated tumor cells. Citation Format: Hasan Korkaya, Eunmi Lee, Raziye Piranioglu, Maria Ouzounova, Abdeljabar El-Andaloussi, Iskander Asm, Ahmet K. Korkaya, Gang Zhou, Ali Arbab, Paulo Rodriguez. Immune regulation of disseminated tumor cell clearance versus metastatic growth [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 3992. doi:10.1158/1538-7445.AM2017-3992