tbuckley/cabot-search huggingface dataset:
Abstract 471: HER2 regulates PARP-1 expression by suppressing the let-7a microRNA in HER2+ breast cancer
Authors: Eddy Shih-Hsin Yang, Monicka Wielgos, Rajani Rajbhandari, Shi Wei, Susan Nozell
Journal: Cancer Research (2017)

Abstract Background: HER2+ breast cancers are sensitive to PARP inhibition and express elevated levels of the PARP-1 protein. However, the mode of regulation of PARP-1 expression by HER2 is not well understood. MicroRNAs are small non-coding RNAs that function in RNA silencing and post-transcriptional regulation of gene expression. In this study, we investigate whether PARP1 expression in human breast cancer cells is regulated by HER2 regulation of microRNAs. Methods: Human HER2+ breast cancer cell lines BT-474 and SKBR3 were used in this study. MDA-MB-231 (non-HER2 expressing breast cancer cells) stably transfected with a HER2 wild-type plasmid (231 HER2) or the vector control (231 NEO) were also utilized. To identify candidate microRNAs regulated by HER2 overexpression, we performed the nCounter miRNA Expression Assay. MicroRNA and mRNA expression were validated via qRT-PCR analysis in breast cancer cell lines or patient primary tumors. Cells were also transfected with a HER2 siRNA, a let-7a mimic, and an inhibitor of let-7a as well as their respective controls. Western blot analysis and firefly luciferase assays were used to determine whether the 3’UTR of PARP1 was being directly targeted by the let-7a microRNA. Results: HER2 did not regulate PARP-1 at the mRNA level but increased PARP-1 protein in HER2+ breast cancer cells. Specifically, ectopic HER2 overexpression correlated with increased PARP-1 protein levels in the 231 HER2 cell line. Conversely, silencing HER2 reduced PARP-1 protein levels in the BT-474 and SKBR3 cell lines. NanoString nCounter analysis revealed that the HER2+ breast cancer cell lines expressed low levels of the let-7a microRNA. Further, let-7a expression was upregulated after HER2 knockdown in the two native HER2+ breast cancer cell lines. The let-7a mimic also reduced both PARP1 protein expression and luciferase activity in the 231 HER2 and BT-474 cell lines, whereas the let-7a inhibitor reversed these effects in the 231 NEO cell line. Importantly, human HER2+ breast tumors expressed higher levels of PARP-1 and lower levels of let-7a; whereas, the HER2- breast tumors expressed lower levels of PARP-1 and higher levels of let-7a. Further, overexpression of the let-7a mimic reduced cell proliferation in HER2+ breast cancer cells. Conclusions: These results suggest that let-7a regulates PARP-1 expression in HER2+ breast tumors. Let-7a may also be a potential therapeutic target and predictive biomarker of PARPi sensitivity in HER2+ breast cancer patients. Citation Format: Eddy Shih-Hsin Yang, Monicka Wielgos, Rajani Rajbhandari, Shi Wei, Susan Nozell. HER2 regulates PARP-1 expression by suppressing the let-7a microRNA in HER2+ 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 471. doi:10.1158/1538-7445.AM2017-471
Abstract 4375: Complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas
Authors: Dunfa Peng, Yan Guo, Heidi Chen, Shilin Zhao, Kay Washington, Tianling Hu, Yu Shyr, Wael El-Rafai
Journal: Cancer Research (2017)

Abstract Background: The incidence of Barrett’s-related esophageal adenocarcinoma (EAC) is rapidly rising in the USA and the Western countries. However, the interaction between genomic and epigenomic alterations in regulating gene expression networks in EAC is poorly understood. Results and Discussion: We carried out an integrative analytical approach to identify DNA copy number, promoter DNA methylation and gene expression in a panel of esophageal adenocarcinomas, using chip-based technologies. Our analysis displayed significant differences between EAC and normal samples in DNA copy numbers, gene expression, and DNA methylation profiles. Our results identified remarkable incidence of DNA copy number (CN) alterations showing that 90% of probes had a copy number aberration (gain or loss) in at least one tumor, suggesting a vast chromosomal instability in EAC. Integrative analysis indicated that altered expression of 1755 genes was associated with changes in CN or methylation. We found that expression alterations in 84 genes (56 overexpressed and 28 down regulated) were associated with changes in both CN and methylation. These data suggest a strong interaction between genetic and epigenetic events to modulate gene expression in EAC. Of note, we detected a prominent K-RAS signature in EAC. Network analysis predicted activation of several important transcription factor networks in EAC, including β-catenin, MYB, TWIST1, SOX7, GATA3 and GATA6. 56 genes were overexpressed in EAC with simultaneous promoter hypomethylation and gene amplification, including CDH17 and GATA6. Notably, several genes associated with inflammation such as COX2, IL8 and IL23R were overexpressed and hypomethylated in EAC, a reaffirmation of the underlying inflammatory process in Barrett’s tumorigenesis and a suggestion of an epigenetic regulation of these genes. Conclusions: In summary, our integrative analysis of genetic and epigenetic alterations in EAC demonstrates a complex interaction between molecular mechanisms in EAC and provides several novel insights for future studies. Citation Format: Dunfa Peng, Yan Guo, Heidi Chen, Shilin Zhao, Kay Washington, Tianling Hu, Yu Shyr, Wael El-Rafai. Complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas [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 4375. doi:10.1158/1538-7445.AM2017-4375
Abstract 4661: Omentin as an adjunct to CA-125 in detecting recurrent ovarian cancer
Authors: Kelsey Lewis, Chi Lam Au Yeung, Samuel Mok, Karen Lu
Journal: Cancer Research (2017)

Abstract Omentin (Intestinal Lactoferrin Receptor ITLN1) is an adipokine that is mainly secreted by the mesothelial cells lining visceral adipose tissues. It has been shown in previous studies that ovarian cancer cells down-regulate omentin which allows increased proclivity to spread to the omentum. Levels of serum omentin are decreased in patients with high-grade serous ovarian cancer (HGSOC) compared with patients with benign gynecologic diseases. Moreover, survival correlation studies showed that patients with lower serum omentin level at the time of first treatment experienced significantly shorter survival times than those with higher levels of omentin. CA-125 is currently the only biomarker used to monitor progression and re-occurrence of ovarian cancer. To our best knowledge, the relationship between omentin and CA-125 has not been investigated previously. We hypothesize that omentin may be a clinically useful adjunct to CA-125 in detecting recurrent ovarian cancer. 92 serum samples were collected prospectively from 27 HGSOC patients during the postoperative period until recurrence was detected. Patients had an average of 3.37 follow up visits and CA-125 levels were concurrently established. Recurrence was determined by imaging or an increase from baseline in CA-125 level. Samples were stored frozen at -80 degrees Celsius until use for this study. Circulating omentin levels were quantified using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The results showed that 24 patients experienced a rise in CA-125 level during the postoperative period and 12 of these patients had an associated decrease in serum omentin level (average = 127.8 ng/mL). A significant negative correlation between omentin and CA-125 levels was observed (p = 0.02). This study provides the first evidence that omentin may be a clinically useful adjunct to CA-125 in detecting recurrent ovarian cancer and warrants further investigation. Citation Format: Kelsey Lewis, Chi Lam Au Yeung, Samuel Mok, Karen Lu. Omentin as an adjunct to CA-125 in detecting recurrent ovarian 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 4661. doi:10.1158/1538-7445.AM2017-4661
Abstract 85: Establishment of cabazitaxel-resistant prostate cancer cell lines
Authors: Atsushi Mizokami, Kazuaki Machioka, Kouji Izumi, Maolake Aerken, Ariunbold Natsagdorji, Yoshifumi Kadono, Yuta Takezawa, Hiroaki Iwamoto, Evan T. Keller
Journal: Cancer Research (2017)

Abstract Background: The final treatment for castration-resistant prostate cancer (CRPC) is generally cabazitaxel treatment. However, once CRPC becomes resistant to cabazitaxel, the patients are obliged to best supportive care. Therefore, the elucidation of the mechanism of the cabazitaxel-resistance and the conquest are important themes to improve the prognosis of the patients. We already established paclitaxel/docetaxel-resistant prostate cancer, PC-3-TxR and DU145-TxR cells, and characterized those cell lines previously. Then we further tried to establish cabazitaxel-resistant prostate cancer cell lines, and characterized those cell lines. Materials and Methods: We established two cabazitaxel-resistant cell lines, PC-3-TxR/CxR and DU145-TxR/CxR by increasing concentration of cabazitaxel from 1 nM to 30 nM gradually when PC-3-TxR and DU145-TxR cells were passaged. We confirmed the IC50 of docetaxel and cabazitaxel of these cells. Next we purified total RNA and performed cDNA microarray (Agilent and compared gene expression profiles among these cells. Results and Conclusion: IC50 of PC-3-TxR and PC-3-TxR/CxR for cabazitaxel was 1.3 nM and 15.4 nM, respectively. IC50 of DU145-TxR and DU145-TxR/CxR was 7.0 nM and 30. 8 nM, respectively. Comparison of cDNA microarray between PC-3-TxR and PC-3-TxR/CxR cells or between DU145-TxR and DU145-TxR/CxR cells revealed that 4,470 genes in PC-3-TxR/CxR, and 1,345 genes in DU145-TxR/CxR cells were upregulated more than 3-fold and 4,683 genes PC-3-TxR/CxR and 1,537 genes were downregulated less than 0.3-fold, respectively. Especially, although expression of ABCB1 (MDR) gene was upregulated in DU145-TxR by 500-fold compared with DU145 cells, it was not upregulated in not upregulated in DU145-TxR/CxR cells any more. In contrast, expression of ABCB1 gene was upregulated in PC-3-TxR by 20-fold compared with PC-3 cells and it was further upregulated in PC-3-TxR/CxR by 40-fold compared with PC-3-TxR. In conclusion, various genes were regulated in cabazitaxel-resistant PCa cells and different mechanisms might be involved in this resistance in different cell lines. Citation Format: Atsushi Mizokami, Kazuaki Machioka, Kouji Izumi, Maolake Aerken, Ariunbold Natsagdorji, Yoshifumi Kadono, Yuta Takezawa, Hiroaki Iwamoto, Evan T. Keller. Establishment of cabazitaxel-resistant prostate cancer cell lines [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 85. doi:10.1158/1538-7445.AM2017-85
Abstract 3386: Brazilian melanoma genome project: mutational landscape based on whole-genome sequencing
Authors: Vinicius L. Vazquez, Adriane Evangelista, Henrique C. Silveira, Camila Crovador, Andre L. Carvalho, Cristovam Scapulatempo-Neto, Jin Lee, Gilles Landman, Joao P. Kitagima, Rui M. Reis
Journal: Cancer Research (2017)

Abstract Melanoma is the most aggressive form of skin cancer with increasing prevalence in Brazil. The comprehensive molecular profiling of these tumors and the recent genomic classification has improved the knowledge of melanoma biology and foster the identification of potential clinical biomarkers. The aim of this project, as part of the International Cancer Genome Consortium (ICGC) is to perform a genomic profile by whole genome sequencing (WGS) of Brazilian melanomas patients. We reported the WGS using Illumina paired-end sequencing strategy (&amp;gt;30 X-fold coverage) of 66 cases (45% primary and 55% metastatic) and respective matched normal. Overall we observed an average of 46K mutations/genome. The most frequent type of substitutions identified were: C&amp;gt;T (22.5%), T&amp;gt;C (6.4%), T&amp;gt;G (4.4%), T&amp;gt;A (2.9%), C&amp;gt;A (2.8%) and C&amp;gt;G (1.7%). A significative difference between frequency of C&amp;gt;T substitutions was observed among histological subtypes, i.e., acral lentiginous (11.3%), nodular (31.2%) and superficial spreading (25.9%). Among the classic genes involved in melanoma biology, we found that 31.8% of patients had BRAF mutations, being the V600E the most frequent (82.6%). A total of 6.1% of patients had NRAS, 3.0% showed KRAS, one case (1.5%) showed HRAS, and 12.1% showed NF1 mutations. TERT promoter mutation (C250T) was found in 28.8% of patients. TP53 mutations found 4.5% and RB1 in 1.5% of cases. Oncogenic KIT and PDGFRA mutations were observed in 6.1%and 1.5%, respectively. BRAF, NRAS, HRAS, KRAS and NF1 mutation were mutually exclusive. BRAF and TERT mutations were significantly more frequent in superficial than acral lentiginous melanomas. We showed that Brazilian melanoma patients exhibit a high number of single mutations and a similar mutation profile to the one reported in other populations. Acral/lentiginous melanoma subtype, which is a common subtype in our setting, showed a distinct mutation frequency. Further analysis will extend to other relevant genes and will also include the study of additional genomes to reach the goal of genomic landscape of 100 Brazilian melanomas cases. Citation Format: Vinicius L. Vazquez, Adriane Evangelista, Henrique C. Silveira, Camila Crovador, Andre L. Carvalho, Cristovam Scapulatempo-Neto, Jin Lee, Gilles Landman, Joao P. Kitagima, Rui M. Reis. Brazilian melanoma genome project: mutational landscape based on whole-genome sequencing [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 3386. doi:10.1158/1538-7445.AM2017-3386
Abstract 4319: Analysis of Bcl-2 family members and protein-protein interactions using novel multiplex immunoassays
Authors: Reeti Maheshwari, Melissa Schluter, Danielle Pepin, Joseph Hwang
Journal: Cancer Research (2017)

Abstract Bcl-2 family members play a very important role in intrinsic apoptotic pathways. The family consists of more than 17 members that can be functionally separated into pro-apoptotic and anti-apoptotic subfamilies. Interactions between these family members determine cell fate, and dysregulation can lead to tumor growth and tumor cell survival. There are several investigational drugs for cancer treatment targeting Bcl-2 family members in clinical trials, driving the need for robust assays to measure Bcl-2 family members and their interactions. Though existing assays measure Bcl-2 family members, there is a lack of reliable assays to evaluate total proteins and protein-protein interactions simultaneously. To address this issue, we have developed two Luminex®-based multiplex immunoassay panels that allow for the simultaneous detection of multiple components of the Bcl-2 family in a single well, including Total Bcl-2, Bcl-xL, Mcl-1, BAD, BIM, and BAX as well as protein interactions like NOXA/Mcl-1, Mcl-1/BIM, and Bcl-xL/BAD. Using these panels, we analyzed changes in the expression and interactions of Bcl-2 family members in response to known apoptotic drugs, including Camptothecin (topoisomerase inhibitor), Anisomycin (protein translation inhibitor), and AT101 (BH3 mimetic drug). Camptothecin and Anisomycin each elicited a significant decrease in the levels of Mcl-1. Additionally, the Mcl-1/BIM interaction was disrupted by both Camptothecin and Anisomycin, perhaps a consequence of the reduced Mcl-1 levels. However, expression of the other anti-apoptotic proteins was unaffected by any of the three drugs. Interestingly, all three treatments had different effects on the Mcl-1/NOXA interaction. Mcl-1/NOXA signal was increased by AT101, decreased by Anisomycin, and showed a dose dependent effect with Camptothecin. In contrast to their disparate effects on the Mcl-1/NOXA interaction, all three drugs acted in a similar manner in blocking the Bcl-xL/BAD interaction without affecting the total levels of either protein. Overall, these results illustrate the dynamic responses of the Bcl-2 family to apoptosis-inducing drugs. The novel multiplex immunoassays described here provide a powerful tool for studying the underlying mechanisms regulating the Bcl-2 family of proteins. Citation Format: Reeti Maheshwari, Melissa Schluter, Danielle Pepin, Joseph Hwang. Analysis of Bcl-2 family members and protein-protein interactions using novel multiplex immunoassays [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 4319. doi:10.1158/1538-7445.AM2017-4319
Abstract 2423: Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents
Authors: Donghai Xiong, Jing Pan, Qi Zhang, Eva Szabo, Mark S. Miller, Ronald A. Lubet, Ming You, Yian Wang
Journal: Cancer Research (2017)

Abstract Due to exposure to environmental toxicants, a “field cancerization” effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3k and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis. Citation Format: Donghai Xiong, Jing Pan, Qi Zhang, Eva Szabo, Mark S. Miller, Ronald A. Lubet, Ming You, Yian Wang. Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents [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 2423. doi:10.1158/1538-7445.AM2017-2423
Refining Targeted Therapy Opportunities for <i>BRAF</i>-Mutant Melanoma
Authors: Russell W. Jenkins, David A. Barbie
Journal: Cancer Discovery (2017)

<b/> Identifying molecular and cellular features associated with resistance to targeted BRAF/MAPK pathway inhibition may guide development of novel therapeutic approaches. Integrated, comparative analysis of genomic and functional data in sensitive and resistant cell lines unveils novel targetable regulators of resistance to MAPK pathway inhibition in melanoma. Cancer Discov; 7(8); 799-801. ©2017 AACR.See related article by Eskiocak et al., p. 832.
Abstract 3630: Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin
Authors: Alexander Sternjak, Fei Lee, Joachim Wahl, Dan Rock, Oliver Thomas, Sabine Stienen, Ralf Lutterbuese, Patrick Hoffmann, Tobias Raum, Peter Kufer, Benno Rattel, Angela Coxon, Matthias Friedrich, Julie Bailis
Journal: Cancer Research (2017)

Abstract Bispecific T cell engager (BiTE®) antibody constructs redirect T cells to induce lysis of tumor cells. The anti-CD19/CD3 BiTE® Blincyto® can deplete target cells in both the blood and tissue compartment in B cell malignancies, suggesting that the BiTE® mechanism of action will also be effective against solid tumors. The tumor differentiation antigen mesothelin (MSLN) is an attractive target for the BiTE® approach. MSLN is highly expressed in &amp;gt;80% of ovarian and pancreatic tumors and mesothelioma. Expression of MSLN in normal tissues appears restricted to mesothelial cell surfaces such as the pleural, pericardial, and peritoneal layer. Here, we report the preclinical characterization of an anti-MSLN/CD3 BiTE® antibody construct with extended half-life. The BiTE® antibody construct binds MSLN and CD3 with low nM affinity and has low pM cytotoxic activity against MSLN-positive ovarian, pancreatic and lung cancer cell lines in vitro. Activity of the anti-MSLN/CD3 BiTE® antibody construct is observed at low effector to target cell ratios, and in cancer cells that express low levels of MSLN. This BiTE® antibody construct is also cytotoxic to cell lines that are resistant to chemotherapy. In mice, significant tumor growth inhibition of an established ovarian tumor xenograft model was achieved by IV dosing of the anti-MSLN/CD3 BiTE® antibody construct every 5 days. Pharmacokinetic evaluation of the anti-MSLN/CD3 BiTE® antibody construct in non-human primates demonstrated a half-life of 4-10 days. The potency and specificity of the anti-MSLN/CD3 BiTE® antibody construct, together with projected ability to dose once a week IV in humans, supports development of this BiTE® for treatment of MSLN-positive tumors. Citation Format: Alexander Sternjak, Fei Lee, Joachim Wahl, Dan Rock, Oliver Thomas, Sabine Stienen, Ralf Lutterbuese, Patrick Hoffmann, Tobias Raum, Peter Kufer, Benno Rattel, Angela Coxon, Matthias Friedrich, Julie Bailis. Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin [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 3630. doi:10.1158/1538-7445.AM2017-3630