tbuckley/cabot-search huggingface dataset:
Abstract 2848: Identifying and targeting competing endogenous RNA (ceRNAs) networks to inhibit lung metastasis in triple negative breast cancer
Authors: Pelin Ersan, Unal Tokat, Erol Eyupoglu, Umar Raza, Yasser Riazalhosseini, Can Alkan, Denis Thieffry, Daniel Gautheret, Ozgur Sahin
Journal: Cancer Research (2017)

Abstract Introduction: Triple negative breast cancer (TNBC), the most aggressive breast cancer subtype, has high incidence rate of lung metastasis. Not only protein coding transcripts, but also non-coding transcriptome, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have active roles in cancer progression and metastasis. Additionally, lncRNAs can act as sponges for miRNAs. Here, we aimed i) to construct the first mRNA-miRNA-lncRNA competing endogenous RNA (ceRNA) network controlling metastasis in TNBC, and ii) to prevent lung metastasis by targeting identified central candidate genes. Material/Method: We established primary tumor and human-in-mouse (HIM) and mouse-in-mouse (MIM) lung metastasis models using TNBC cell lines in nude and Balb/c mice, respectively. We visualized both primary and metastatic tumors using in vivo imaging system, harvested tumors and performed both RNA and small RNA sequencing. We obtained differentially expressed miRNAs, mRNAs and lncRNAs between primary and metastatic tumors. Using several bioinformatics tools, we did enrichment analyses, miRNA target predictions, and network construction. Identified central lncRNAs were overexpressed or knocked down and will be tested in in vitro and vivo metastasis-related assays. Results and Conclusions: We obtained 45 and 91 miRNAs which were differentially expressed between primary and metastatic tumors in HIM and MIM models, respectively. A miRNA family with an established role in metastasis as well as several other miRNAs was identified as highly differentially expressed in the same direction in both models. Moreover, 1127 and 3350 mRNAs, and 85 and 111 lncRNAs were differentially expressed in HIM and MIM models, respectively. Metastasis-related processes based on differentially expressed mRNAs were enriched in the data. We then integrated these three layers of data, functional enrichments, pathway maps and target predictions to construct the first ceRNA network controlling lung metastasis in TNBCs. Currently, we are testing the functional roles of candidate lncRNAs in in vitro and in vivo metastasis assays. Ultimately, our study will uncover novel lncRNAs that can be used as potential targets and/or biomarkers in breast-to-lung metastasis. Funding: This study is supported by TUBITAK-CNRS Bilateral Grant with project number 214S364. Citation Format: Pelin Ersan, Unal Tokat, Erol Eyupoglu, Umar Raza, Yasser Riazalhosseini, Can Alkan, Denis Thieffry, Daniel Gautheret, Ozgur Sahin. Identifying and targeting competing endogenous RNA (ceRNAs) networks to inhibit lung metastasis in triple negative breast 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 2848. doi:10.1158/1538-7445.AM2017-2848
Abstract 1961: Downregulation of proteasome activity promotes epithelial-mesenchymal transition
Authors: Daniel A. Garcia, Asoka Banno, Eric D. Van Baarsel, Patrick J. Metz, Christella E. Widjaja, Stephanie H. Kim, Jack D. Bui, Jing Yang, John T. Chang
Journal: Cancer Research (2017)

Abstract The epithelial-mesenchymal transition (EMT) is a developmental program that is aberrantly activated in cancer cells, producing an invasive phenotype that can lead to metastases. Inducers of EMT are largely known and have been widely studied. However, the mechanisms that regulate the link between extracellular stimuli and EMT phenotypes remain poorly understood. Preliminary evidence from our laboratory suggests that downregulation of proteasome activity may be responsible, in part, for driving EMT. Using immortalized human mammary epithelial (HMLE) cells as a model, we show that (1) EMT is associated with decreased proteasome activity and increased polyubiquitinated substrates, (2) pharmacologic inhibition of proteasome activity leads to increased EMT phenotypes and functionality, and (3) pharmacologic inhibition of proteasome activity leads to increased EMT via stabilization of the TGF-β signaling pathway. Together, these data suggest that proteasome activity may be an unappreciated regulator of EMT. Citation Format: Daniel A. Garcia, Asoka Banno, Eric D. Van Baarsel, Patrick J. Metz, Christella E. Widjaja, Stephanie H. Kim, Jack D. Bui, Jing Yang, John T. Chang. Downregulation of proteasome activity promotes epithelial-mesenchymal transition [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 1961. doi:10.1158/1538-7445.AM2017-1961
Abstract 78: Highly efficient antibody drug conjugation with a novel photoactivation strategy
Authors: Elisabeth Gardiner, Karin Forster, Robert McKenzie
Journal: Cancer Research (2017)

Abstract Meditope SnAP (site-specific novel antibody platform) technology is a novel way to target molecules to antibodies in a site specific, non-destructive fashion. A “meditope” is a proprietary peptide that can bind a meditope-enabled antibody in a unique site and in such a way that antigen binding is not compromised. This specific peptide antibody interaction can be readily employed for site-specific covalent conjugation of cytotoxic payloads to any meditope-enabled antibody. To facilitate covalent conjugation, the meditope peptide has been rationally designed with a photoactivatable side chain and the generation of the antibody-drug conjugate (ADC) occurs in a highly efficient manner following the specific binding of the meditope to the enabled antibody. To test the hypothesis that photoactivation would be an efficacious and homogenous way to make an ADC, meditope-enabled ADCs were designed and tested in vitro and in vivo. Toxin conjugation was tested, as was efficiency of covalent interaction following short-term exposure of the antibody peptide conjugates to a nondestructive wavelength of 340 nM. Photoactivation proved to be a highly efficient and scalable way to make an ADC. Payload stability was confirmed in vivo with multiple toxins and in vivo potency of two unique ADCs were tested in an EGFR positive gastric cancer xenograft as well as a HER2 positive ovarian cancer xenograft. The meditope-enabled photogenerated anti-HER2 ADC was benchmarked against conventionally conjugated T-DM1 and showed equivalent efficacy, but with the site-directed conjugated meditope ADC using less toxin. Meditope-directed photoactivated-controlled conjugation can be readily extended to any meditope-enabled antibody, resulting in a novel way to develop ADCs. This methodology, with its high efficiency, speed and homogeneity has evident advantages for the development of antibody-drug conjugates. Citation Format: Elisabeth Gardiner, Karin Forster, Robert McKenzie. Highly efficient antibody drug conjugation with a novel photoactivation strategy [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 78. doi:10.1158/1538-7445.AM2017-78
Abstract 3565: Recurrently detected germline mutation of FLT3 (D358V) associated with prevalence of hematopoietic malignancy and prognosis of AML patients
Authors: SEULKI SONG
Journal: Cancer Research (2017)

Abstract FLT3 is most frequently mutated gene in acute myeloid leukemia patients. While somatic mutation of FLT3 is well known, germline mutation of FLT3 and predispose to AML remain poorly understood. Here we identify a germline FLT3 p.D358V affected prognosis of AML patients. We performed whole exome sequencing (WES) using 76 patients’ saliva sample to detect FLT3 germline mutation in buccal epithelial cell and demonstrate FLT3 p.D358V mutation for 6 patients among 76 patients. The frequency of FLT3 p.D358V mutation in AML patients is significantly higher in general population (p=9.50E-07), suggesting association of FLT3 mutation with AML predisposition. Asian population especially carried this locus more than other ethic population. When we compared between AML patients and general population of Asian, the chi-square p-value was 0.07 and odd ratio was 2.26. Overall survival was significantly reduced in patients who had FLT3 p.D358V mutation (p=0.03) and disease free survival was show a tendency of reducing in the patients with FLT3 p.D358V mutation. Citation Format: SEULKI SONG. Recurrently detected germline mutation of FLT3 (D358V) associated with prevalence of hematopoietic malignancy and prognosis of AML patients [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 3565. doi:10.1158/1538-7445.AM2017-3565
A retrospective review of metastatic or recurrent uterine sarcomas treated with ifosfamide and doxorubicin (IMA)
Authors: N. Guler, D. Hizli, S. Sarici, R. Ocalan, M. Kose, S. Aksoy
Journal: Journal of Clinical Oncology (2006)

15053 Background: The prognosis of metastatic uterine sarcoma is poor with median survival reported between 4 to 26 months. We evaluated the efficacy and toxicity of ifosfamide (I) mesna (M) and doxorubicin (A) (IMA) chemotherapy regimen retrospectively in patients (pts) with metastatic, or recurrent uterine sarcomas. Methods: Eligible patients had measurable recurrent or metastatic disease, ECOG PS &lt; 2, had adequate renal, hepatic and hematologic functions. The IMA regimen was ifosfamide 2500 mg/m 2 days 1–3, mesna 2500 mg/m 2 days 1–3, doxorubicin 60 mg/m 2 day 1, repeated every 21 days. Patients were evaluated for response for each two cycles. Results: Thirty-five pts (17 leiomyosarcoma [LMS], 6 malignant mixed mesodermal tumor [MMMT], 5 endometrial stromal sarcoma, 4 carcinosarcoma, and 3 adenosarcoma) were enrolled in this study. The median age was 49 yrs (range, 18–72). Two pts were lost to follow up after the first cycle; one patient had ifosfamide encephalopathy on the third day of the first cycle. Thirty-two pts were assessable for response, toxicity, and survival. Nine pts had prior chemotherapy and 4 pts had radiotherapy. Most frequent metastatic sites were peritoneum, lung and liver. Median period of time from the diagnosis to starting IMA regimen was 14.5 months. A total of 132 cycles of chemotherapy were introduced and for each patient median number of chemotherapy cycles were 4 (range, 1–6). We observed CR in 2 pts; PR in 15 pts. Objective RR was % 48.6 (95% CI, 32% to 67%). Of 17 pts with LMS, 1 CR and 6 PRs were observed. The median progression-free survival time of the responders was 12.0 months. The median progression-free survival time of all patients was 7.0 months. NCI-CTC grade 3 or 4 leucopenia, neutropenia, thrombocytopenia, and anemia occurred in 40%, 55%, 12%, and 13%, respectively. There was no significant nausea/vomiting, nephrotoxicity. Febrile neutropenia was encountered in 6 pts. Dose modifications were required in 4 pts due to myelotoxicity. CNS toxicity was observed in one pts. Conclusions: IMA regimen has moderate anti-tumor activity (48.6%) with acceptable toxicity in pts with recurrent or metastatic uterine sarcomas. No significant financial relationships to disclose.
Abstract 4964: Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor
Authors: John T. Hunt, Aaron Balog, Christine Huang, Tai-An Lin, Tai-An Lin, Derrick Maley, Johnni Gullo-Brown, Jesse Swanson, Jennifer Brown
Journal: Cancer Research (2017)

Abstract The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the degradation of tryptophan along the kynurenine pathway, and is frequently expressed in human malignancies. The activity of IDO1 induces an immunosuppressive microenvironment in tissues by inhibiting T-cell function through local depletion of tryptophan and through generation of kynurenine pathway metabolites. Inhibition of IDO1 is expected to diminish the immunosuppressive tumor microenvironment and improve cancer patient outcomes, particularly when used in combination with cancer immunotherapy agents such as nivolumab and ipilimumab. In this presentation, we will disclose the chemical structure, enzyme inhibitory mechanism, in vitro potency and in vivo pharmacodynamic (PD) activity of BMS’ IDO1 inhibitor currently in Phase I clinical trials. The compound is a potent and selective IDO1 inhibitor with no activity against another tryptophan degrading enzyme, tryptophan 2,3-dioxygenase (TDO). It exhibited potent cellular activity, suppressing kynurenine production in HEK293 cells overexpressing human IDO1 (IC50 = 1.1 nM) and in HeLa cells stimulated with IFNγ (IC50 = 1.7 nM). The compound also potently restored T-cell proliferation in a co-culture of T cells and human cancer cells and in a mixed lymphocyte reaction where T cells were co-cultured with allogeneic IDO1-expressing dendritic cells (EC50 = 1.2 nM). In vivo, when given once a day orally, the compound exhibited significant PD activity in mouse tumors grown subcutaneously in syngeneic hosts and in human tumors grown as xenografts in nude mice. Citation Format: John T. Hunt, Aaron Balog, Christine Huang, Tai-An Lin, Tai-An Lin, Derrick Maley, Johnni Gullo-Brown, Jesse Swanson, Jennifer Brown. Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor [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 4964. doi:10.1158/1538-7445.AM2017-4964
Abstract 5367: Ngago: no evidence of targeted endonuclease activity
Authors: Sabine Topka, Sara Kazzaz, Kenneth Offit, Vijai Joseph
Journal: Cancer Research (2017)

Abstract The development of a versatile and easy to use genome editing tool based on the bacterial CRISPR/Cas9 system has led to a vast increase in applications of genome editing in laboratories around the world. As an extremely powerful and versatile tool it has facilitated important discoveries in both basic and translational research as well as in a potentially wide range of therapeutic applications. Natronobacterium gregoryi Argonaute (NgAgo) protein was described as a favorable alternative to Cas9 due to its simplicity and higher endonuclease specificity. Thus far, there are no formal reports documenting the success of NgAgo in other laboratory settings and cellular systems. Utilizing the identical cellular background and protocol that was made publicly available by the authors of the initial study, we were unable to reproduce the endonuclease function of NgAgo. These results do not support the role of NgAgo in gene editing experiments. Note: This abstract was not presented at the meeting. Citation Format: Sabine Topka, Sara Kazzaz, Kenneth Offit, Vijai Joseph. Ngago: no evidence of targeted endonuclease activity [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 5367. doi:10.1158/1538-7445.AM2017-5367
Abstract 4512: The landscape of hypoxia-driven alternative splicing in breast cancer
Authors: Hani Choudhry, Spyridon Oikonomopoulos, Peng Yu, Cristina Ivan, Mircea Ivan, Adrian L. Harris, Jiannis Ragoussis
Journal: Cancer Research (2017)

Abstract Tumor hypoxia is generally associated with poor patient outcome and resistance to therapy. Hypoxia has an impact on multiple pathways inside the cell and a widespread effect on phenotype. Here we determined the changes in transcript architecture that arise as result of alternative splicing in hypoxic cells. A panel of breast cancer cell lines that include the Luminal A and B, HER2+, Triple-Negative subcategories grown in hypoxic and normoxic conditions were subjected for deep RNA-sequencing. Depending on the cell lines we found between 23- 927 splicing events with 3-45% of them also present in the differentially expressed fraction of genes. This points to an extensive isoform switching control independently of the transcriptional control of the genes themselves. The splicing events appear on genes responsible for mRNA processing (splicing, nuclear export and catabolism) as well as initiation of translation. Members of the SR family of proteins involved in RNA splicing, appear to be potential regulators of the biogenesis of the hypoxia specific splicing events. The differentially spliced exons are frequently part of both the coding and noncoding isoforms of a given gene potentially indicating a switch between these two types under hypoxia. Ten of the hypoxia specific splicing events were also found to be associated with the hypoxia status of primary breast cancer samples taken from The Cancer Genome Atlas (TCGA) database. Altogether, these data demonstrate the important role of hypoxia in driving alternative splicing events in breast cancer. Citation Format: Hani Choudhry, Spyridon Oikonomopoulos, Peng Yu, Cristina Ivan, Mircea Ivan, Adrian L. Harris, Jiannis Ragoussis. The landscape of hypoxia-driven alternative splicing in breast 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 4512. doi:10.1158/1538-7445.AM2017-4512
Abstract 5615: Genomic differential expression analysis of fusion proteins incorporating the pro-apoptotic molecule Granzyme B reveals new potential targets for treatment of breast cancer
Authors: Khalid A. Mohamedali, Lawrence H. Cheung, Ana Alvarez-Cienfuegos, Michael G. Rosenblum
Journal: Cancer Research (2017)

Abstract Granzyme B (GrB) is a member of the serine protease family of enzymes that play a critical role in the body’s defense against viral infection and tumor development. Cytotoxic T lymphocyctes (CTL) and natural killer (NK) cells directly deliver granzymes to target cells, which induces apoptosis through both caspase-dependent and caspase-independent multiple-cascade mechanisms. Anti-tumor efficacy studies have suggested that the targeted delivery of human Granzyme B to tumor cells has a significant potential for cancer treatment. We had previously developed a novel fusion construct composed of the VEGF121 growth factor and human GrB. The GrB/VEGF121 construct was found to be highly cytotoxic to vascular endothelial cells expressing the R2 (KDR) receptor for VEGF. In this study, we examined the mechanism of GrB/VEGF121-induced cytotoxicity against cells in culture at the genomic level. The TNBC cell line MDA-MB-231 was treated with an IC50 dose of GrB/VEGF121 for 24 hours; the cells were then harvested and the effect of GrB/VEGF121 on intracellular events was examined by extraction of mRNA followed by microarray analysis. Gene-level differential expression analysis revealed that a total of twenty genes were upregulated by over 3-fold, while 25 were downregulated 3-fold or more. These included genes involved in signal transduction, stress response, cell cycle control, hypoxia and metastasis. Particularly impacted were the Nuclear Receptors Meta pathway, NRF2 pathway, nuclear receptors in lipid metabolism and toxicity, matrix metalloproteinases, and the notch signaling pathway. Validated data will be reported following complete analysis of gene level differential expression and alternative splicing. Our data suggests that GrB/VEGF121 induces expression of genes known to be induced by VEGF alone, as well as molecules previously not associated with either Granzyme B or VEGF.This data suggests a previously unsuspected impact of the serine protease GrB on various molecular pathways within the cell and may lead to a new understanding of how these agents operate at the molecular level. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Ana Alvarez-Cienfuegos, Michael G. Rosenblum. Genomic differential expression analysis of fusion proteins incorporating the pro-apoptotic molecule Granzyme B reveals new potential targets for treatment of breast 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 5615. doi:10.1158/1538-7445.AM2017-5615
Abstract 1910: NF-kappaB classical versus alternative pathways support distinct populations of ovarian cancer tumor-initiating cells
Authors: Carrie D. House, Christina M. Annunziata
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the most lethal gynecological malignancy in the United States with high morbidity and mortality due to recurrence and chemoresistance. Our data suggest tumor-initiating cells (TICs) play an important role in disease biology. We previously showed that a subset of ovarian cancer cells depends on NF-kappaB signaling, and that expression of NF-kappaB proteins is associated with poor survival. Given that NF-kappaB expression correlates with a poor outcome in ovarian cancer, and NF-kappaB activity supports drug resistance and tumorigenicity, we hypothesize that NF-kappaB supports a TIC program responsible for ovarian cancer relapse. To investigate this pathway in TICs, we designed a novel method to enrich for TICs from cell lines and patient samples by culturing non-adherent, floating cells in stem cell conditions defined by low attachment flasks and serum free media. Preliminary data confirm that these cells have higher stem cell marker expression, are chemoresistant, and are more tumorigenic in nude mice compared to their adherent counterparts. These TIC-enriched culture conditions enhance NF-kappaB expression and activity. More specifically, alternative NF-kappaB signaling through the RelB transcription factor supports TIC populations by regulating aldehyde dehydrogenase (ALDH), an enzyme with high activity in TICs. Using an inducible shRNA targeting RelB we show that spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in both subcutaneous and intrabursal xenograft models, significantly decreased in the absence of RelB. Interestingly, loss of classical NF-kappaB signaling, through an shRNA targeting the RelA transcription factor, was less effective in targeting TICs, but more effective at targeting a proliferative subpopulation with high Ki67 staining. We conclude that classical and alternative NF-kappaB signaling support ovarian tumor cells with distinct phenotypes and the collaboration of these pathways may be critical for supporting tumor repopulation following chemotherapy. Current studies will measure system level changes induced by these shRNAs, and identify a gene signature specific to each NF-kappaB pathway in ovarian TICs. Clarifying the nuances of NF-kappaB signaling in TICs will increase our understanding of ovarian cancer recurrence and further focus therapeutic strategies to prevent relapse. Citation Format: Carrie D. House, Christina M. Annunziata. NF-kappaB classical versus alternative pathways support distinct populations of ovarian cancer tumor-initiating 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 1910. doi:10.1158/1538-7445.AM2017-1910