tbuckley/cabot-search huggingface dataset:
Abstract 2573: TP73's regulation and expression in human cancer cell lines
Authors: Zhixing Yao, David R. Yao, William Yu, Hassan Brim, Hassan Ashktorab, Zaki A. Sherif
Journal: Cancer Research (2017)

Abstract TP73 is the homologue of the master tumor suppressor TP53. It is involved in cellular responses to stress and development. The TP73 gene encodes two different proteins, TAp73 and ΔNp73 and maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and thought to contain multiple tumor suppressor genes. However, the analysis of p73-knockout mice yielded conflicting results with respect to tumor suppression. World-wide efforts in sequencing the TP73 gene in patient tumor samples have not provided evidence for genetic alterations as a common cause of p73 inactivation in human cancer. The role of TP73 in tumorigenesis has remained elusive to date. In this study, we isolated two stem cell lines from normal young and old human liver tissues and determined TP73 expression in human breast cancer cell lines (MCF7 &amp; MDA321), human hepatocellular carcinoma (HCC) cell lines (HepG2, SNU398, SNU449 &amp; SNU475), neuroblastoma cell lines (IMR32 &amp; SK-N-SH), normal liver stem cell, non-cancerous Li-Fraumeni Syndrome (LFS) skin fibroblasts cells and normal skin fibroblasts. Results show that TAp73 only expresses in cancer cell lines. Moreover, when HepG2 and MDA231 were treated with paclitaxel, a cytoskeletal drug that targets tubulin, TAp73 expression was drastically down-regulated in HepG2 cells and abrogated in MDA231 cells at 1 to 5 µmol/L concentrations. Furthermore, ChIP assay results demonstrated that TP53 and CTCF (a chromosomal networking protein CCCTC binding factor) bind to TP73 promoter and regulate TP73 expression. Our observation may prove significant for the development of future therapeutic and diagnostic applications. *These authors contributed equally to this work. Citation Format: Zhixing Yao, David R. Yao, William Yu, Hassan Brim, Hassan Ashktorab, Zaki A. Sherif. TP73's regulation and expression in human 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 2573. doi:10.1158/1538-7445.AM2017-2573
Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation
Authors: Chai-Wan Kim, Carol Addy, Jun Kusunoki, Norma N. Anderson, Stanislaw Deja, Xiaorong Fu, Shawn C. Burgess, Cai Li, Marcie Ruddy, Manu Chakravarthy, Steve Previs, Stuart Milstein, Kevin Fitzgerald, David E. Kelley, Jay D. Horton
Journal: Cell Metabolism (2017)
Abstract 5882: FAK is required for the survival of tumor cells in MMTV-Wnt1 driven basal-like mammary tumors
Authors: Ritama Paul, Syn K. Yeo, Ming Luo, Susan Waltz, Jun-Lin Guan
Journal: Cancer Research (2017)

Abstract Breast cancer is a heterogeneous disease. Stratification of patients based on the subtype of breast cancer is a key to successful treatment of breast cancer. Focal Adhesion Kinase (FAK), a cytoplasmic tyrosine kinase is over expressed and activated in several cancers including breast cancer. Our earlier studies have shown inhibition of FAK in MMTV-PyMT mouse mammary tumors that are classified as Luminal B subtype, delays tumor onset and reduces tumor growth. To address whether inhibition of FAK would be beneficial in basal-like mammary tumors, we generated a conditional deletion of FAK and a knock in mutation of FAK lacking its kinase activity, in MMTV-WNT1 mouse model, which classifies as basal-like. Similar to PyMT mammary tumors we found that loss of FAK or its kinase function delays tumor onset and tumor growth of basal like WNT1 mammary tumors. However unlike the PyMT tumors, the reduced tumor growth in WNT1 model is not due to decreased proliferation. Interestingly loss of FAK activity in WNT1 tumors results in accumulation of cleaved caspase 3, suggesting that loss of FAK activity results in compromised tumor cell survival. When we investigated the pathways through which FAK could affect survival, we found that loss of FAK activity reduces activation of AKT. Reduced AKT activation induces the expression of pro-apoptotic genes. In summary our studies show that in a basal-like tumor model, FAK is required for survival of the tumor cells. Hence inhibition of FAK could be beneficial for elimination of basal-like tumor cells. Citation Format: Ritama Paul, Syn K. Yeo, Ming Luo, Susan Waltz, Jun-Lin Guan. FAK is required for the survival of tumor cells in MMTV-Wnt1 driven basal-like mammary tumors [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 5882. doi:10.1158/1538-7445.AM2017-5882
Abstract 2137: JAK2 as a novel therapeutic target in anaplastic thyroid cancer
Authors: Nicole C. Pinto, Kara Ruicci, Stephenie Prokopec, Karlee Searle, Matthew Lowerison, John Yoo, Kevin Fung, Danielle MacNeil, Hon S. Leong, Alessandro Datti, Paul C. Boutros, John W. Barrett, Anthony C. Nichols
Journal: Cancer Research (2017)

Abstract Introduction: Thyroid carcinoma is the most common endocrine malignancy. Anaplastic thyroid cancer (ATC) is rare (1.3%) and represents arguably the most lethal human malignancy with 1-year survival rates of only 10%. There are currently no effective treatments for the majority of patients, highlighting an urgent need for novel therapeutics to manage this disease. Objective: To validate the functional importance of JAK2 as a therapeutic target in ATC. Methods: In this study, we have used siRNA knockdown to interrogate the JAK2 signaling pathway as a therapeutic target in ATC. We investigated the mechanism of action and cell death, and assayed for migration and invasion, in vitro. The chick chorioallantoic membrane (CAM) model was also utilized for drug testing, whereby 1x106 Cal62 ATC cells were on-planted to the chick embryo membrane. Two days post on-plant, CAM models were treated with the vehicle (DMSO) or lestaurtinib to measure outcomes including tumor volume and vascularity. Results: We identified the JAK2 inhibitor lestaurtinib as an inhibitory agent controlling cell line proliferation at submicromolar mean inhibitory concentrations. Immunoblotting revealed the inhibition of phosphorylation of the downstream signaling molecule STAT5 in a dose-dependent manner. Treatment of Cal62 cells resulted in a decrease in cell migration using the scratch-wound assay. The anti-proliferative effective of lestaurtinib did not cause apoptosis, autophagy or cell senescence. CAM models treated with a 4 uM dose of lestaurtinib showed a significant decrease in both tumor volume and vascularity. Conclusions: Lestaurtinib was found to provide potent control of ATC cell proliferation and migration, and was also found to decrease tumor growth and vascularity in a CAM model. Knockout studies are underway to confirm that the anticancer effect of this drug is indeed mediated through JAK2 signaling. If validated, JAK2 represents a novel therapeutic target for the treatment of aggressive thyroid cancers. Citation Format: Nicole C. Pinto, Kara Ruicci, Stephenie Prokopec, Karlee Searle, Matthew Lowerison, John Yoo, Kevin Fung, Danielle MacNeil, Hon S. Leong, Alessandro Datti, Paul C. Boutros, John W. Barrett, Anthony C. Nichols. JAK2 as a novel therapeutic target in anaplastic thyroid 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 2137. doi:10.1158/1538-7445.AM2017-2137
Abstract 1924: Caveolin-1 inhibits mammary carcinogenesis <i>via</i> suppressing c-myc-induced metabolism reprogramming in breast cancer stem cells
Authors: Zhiyu Wang, Neng Wang, Shengqi Wang, Yifeng Zheng
Journal: Cancer Research (2017)

Abstract Purpose: Caveolin-1(CAV1), a membrane constituent protein, exhibits tumor suppressor activities in multiple malignancies, whereas the underlying mechanisms remain unclear. The current study aimed to determine the significance of CAV-1 in regulating cancer metabolism and its relation to breast cancer stem cells (CSCs). Experimental Design: The anti-carcinogenic function of CAV1 was evaluated by in vitro cell model, CAV1 knockout mice and MMTV-PyMT spontaneous breast cancer xenografts. Glycolysis activity and mitochondrial metabolism were assessed by immunoblotting, oxygen consumption and mitotacker staining analysis. Mammosphere formation, tumorigenic ability, reattachment differentiation and signaling pathway analysis were applied to study the regulation effects of CAV1 on breast CSCs. The clinical significance of CAV1 was also analyzed by human tissue microarray. Results: In both mammary transformed cells and spontaneous breast cancer xenografts, CAV1 is found significantly downregulated and positively correlated to increased glycolysis activity and impaired mitochondrial metabolism. Cav1 knockout results in increased ductal hyperplasia, associating with increased stem cell population and glycolysis metabolism. Breast CSCs exhibits glycolytic phenotype and decreased CAV1 expression compared to normal mammary stem cells, and CAV1 overexpression significantly limits CSCs’ self-renewal via inhibiting c-myc induced glycolysis. Clinical investigation suggests that high CAV1 expression is revealed with better overall survival and decreased CSCs population. Conclusions: CAV1 loss facilitates mammary carcinogenesis via enhancing glycolytic activity in breast CSCs, and CAV1 based therapy might become a novel strategy for breast cancer prevention. Note: This abstract was not presented at the meeting. Citation Format: Zhiyu Wang, Neng Wang, Shengqi Wang, Yifeng Zheng. Caveolin-1 inhibits mammary carcinogenesis via suppressing c-myc-induced metabolism reprogramming in breast cancer stem 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 1924. doi:10.1158/1538-7445.AM2017-1924
Abstract 3761: Specific and dynamic tumor antigen-specific immune responses were elicited in patients with hepatocellular carcinoma after cell-based immunotherapy
Authors: Yanyan Han, Ye Wu, Chou Yang, Jing Huang, Yabing Guo, Li Liu, Ping Chen, Dongyun Wu, Junyun Liu, Jin Li, Xiangjun Zhou, Jinlin Hou
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers in China and frequently occurs with chronic hepatitis B virus (HBV) infection. To investigate whether cell-based cancer immunotherapy induces tumor specific immune responses in patients with HCC and provides clinical benefits, as well as to elucidate the most immunogenic tumor associated antigens (TAAs), multiple antigen stimulating cellular therapy (MASCT) was applied in addition to standard of care. Mature dendritic cells (DCs) and activated T cells prepared for MASCT were generated from autologous peripheral blood mononuclear cells (PBMCs). DCs were loaded with a peptide pool of multiple HCC-related tumor antigens, and T cells were stimulated by these DCs. Thirteen patients with HCC received repeated MASCT after tumor resection during which their immune responses were examined. After three courses of MASCT, the frequency of regulatory T cells in the patients’ PBMCs significantly decreased (p &amp;lt; 0.001), while the antigen peptide pool-triggered T cell proliferation (p &amp;lt; 0.001) and IFNγ production (p = 0.001) were significantly enhanced. The specific T cell responses against each antigen in the pool were detected in eleven patients, but with individualized distinct patterns. The most immunogenic TAAs for HCC are survivin, CCND1, and RGS5. Moreover, the antigen-specific immune responses observed in tumor-free patients’ PBMCs were significantly stronger than that in the patients with recurrence (p = 0.037). Conclusion: Our study demonstrates that MASCT is well-tolerated by patients with HCC and elicits strong and dynamic immune responses specifically against multiple tumor associated antigens, which may correlate with clinical outcomes. Citation Format: Yanyan Han, Ye Wu, Chou Yang, Jing Huang, Yabing Guo, Li Liu, Ping Chen, Dongyun Wu, Junyun Liu, Jin Li, Xiangjun Zhou, Jinlin Hou. Specific and dynamic tumor antigen-specific immune responses were elicited in patients with hepatocellular carcinoma after cell-based immunotherapy [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 3761. doi:10.1158/1538-7445.AM2017-3761
Abstract 4271: Population-wide vs. carrier-probability-based BRCA1/2 mutation testing in the Washington Ashkenazi Study
Authors: Ana F. Best, Margaret A. Tucker, Hormuzd A. Katki
Journal: Cancer Research (2017)

Abstract Background: Currently, women are referred for BRCA1/2 mutation testing if their family history of breast and ovarian cancer indicates they have sufficient probability of carrying mutations. In contrast, calls have intensified for population-wide testing for BRCA1/2 founder mutations among Ashkenazi Jews, due to relatively high mutation prevalence (2.5%) and decreasing genotyping costs. However, population-wide testing would strain genetic counseling resources and incur costs from testing mostly mutation-negative women. We compared the performance of population-wide vs. carrier-probability-based BRCA1/2 testing in the community-based Washington Ashkenazi Study (WAS). Methods: BRCA1/2 carrier-probabilities based on reported family histories were calculated using BRCAPRO for 4589 probands (102 BRCA1/2 mutation-carriers) in WAS. For each carrier-probability threshold, we compared the percent of mutations found (sensitivity) vs. the percent of women requiring mutation testing, overall and by proband age. At example carrier-probability thresholds, undetected and detected carriers’ attributes were compared using nonparametric tests. Results: A 1.2% carrier-probability threshold identified 80% of BRCA1/2 mutations in the 35% of women with highest carrier-probability. For women under age 40, 94% of BRCA1/2 mutations were identified in the 50% of women with highest carrier-probability. Compared to identified mutation-carriers, missed mutation-carriers had no personal cancer history, no affected first- and second-degree relatives (p&amp;lt;0.0001), more unaffected first-degree relatives (p=0.0002), and were older (p=0.012; median age=53). Conclusion: Carrier-probability-based BRCA1/2 mutation testing identified large majorities of mutation-carriers and would have avoided testing for many mutation-negative women. Missed mutation-carriers were older and cancer-free and would gain minimal benefit from risk-reducing interventions. A cost-effective carrier-probability threshold could acceptably tradeoff identifying BRCA1/2 mutation carriers before they get cancer while testing as few women as possible. Citation Format: Ana F. Best, Margaret A. Tucker, Hormuzd A. Katki. Population-wide vs. carrier-probability-based BRCA1/2 mutation testing in the Washington Ashkenazi Study [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 4271. doi:10.1158/1538-7445.AM2017-4271
Abstract 3198: Using a genome-wide CRISPR-Cas9 knockout library to identify therapeutic combinations in oral cancer
Authors: Megan Ludwig, Andrew Birkeland, Sai Nimmagadda, Sue Foltin, Aditi Kulkarni, Hui Jiang, Thomas Carey, Chad Brenner
Journal: Cancer Research (2017)

Abstract Oral squamous cell carcinoma (OSCC) has remained a disease with poor survival for decades with few novel treatment options. We anticipate great potential for personalized targeted therapies, facilitated by recent characterizations of the mutational landscape of OSCCs. Combinations of targeted therapies may have greater efficacy through inhibiting compensatory pathways. For example, targeting EGFR has had limited success. To identify synergistic combinations with EGFR-targeted therapy, we introduced Genome-scale CRISPR-Cas9 Knock-Out (GeCKO) libraries into OSCC cell lines. CRISPR-Cas9 generates individual genetic knockouts through targeted gene editing. We used a pool of CRISPRs targeting over 18,000 genes to perform genome-scale screening for drivers of sensitivity to EGFR-targeted therapy. Upon selection of the OSCC GeCKO pool, we identified gene knockouts in the FGFR pathway that increased sensitivity to the EGFR inhibitor gefitinib. Using resazurin viability assays we tested combinations of EGFR and FGFR inhibitors in 14 OSCC cell lines. Six/14 (43%) of the cell lines were responsive to the combination, indicating that the FGFR pathway is an alternate mechanism of resistance to EGFR-targeted therapy in some tumors. In complement, we again used CRISPR-Cas9 to generate a syngeneic EGFR knockout (KO) OSCC cell line. The parent OSCC cell line is responsive to the EGFR and FGFR dual inhibition, and the EGFR KO derivative retains sensitivity to FGFR-targeted monotherapies. We expect that this EGFR KO cell line will be a useful tool in further evaluating the compensatory mechanism of the FGFR pathway. OSCC remains a common and frequently lethal cancer with great potential for the development of personalized targeted therapies. Here, we describe the use of genome-wide CRISPR-Cas9 library to discover the synergistic combination of EGFR and FGFR inhibition. Further investigation suggests the FGFR pathway is a common compensatory mechanism to EGFR inhibition. We hope to use this approach to identify additional compensatory mechanisms of resistance to targeted therapies with the eventual goal of translating these findings to clinic. Citation Format: Megan Ludwig, Andrew Birkeland, Sai Nimmagadda, Sue Foltin, Aditi Kulkarni, Hui Jiang, Thomas Carey, Chad Brenner. Using a genome-wide CRISPR-Cas9 knockout library to identify therapeutic combinations in oral 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 3198. doi:10.1158/1538-7445.AM2017-3198
Abstract 4409: Cholesterol pathway determines ovarian cancer drug resistance through transcription factor SREBP2
Authors: Galina Karashchuk, Nataliya Karashchuk, Signe Caksa, Tyler S. Smith, Alexander S. Brodsky
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the most common cause of gynecological cancer death in women in United States. Up to 70% of all ovarian cancer cases are high-grade serous carcinomas with 5-year survival rates less than 30%. Recent studies have suggested the importance of the cholesterol pathway in multiple cancers including gynecological malignancies. Here we demonstrate that genetic or pharmacological disturbance of cholesterol pathway in high-grade serous ovarian carcinoma cell lines results in significant changes in survival rate after drug treatment, and in protein and RNA expression patterns. SREBP2 is a transcription factor encoded by SREBF2 gene that regulates expression of sterol-regulated genes and thus maintains cholesterol homeostasis. To assess the role of SREBP2 in ovarian cancer we have created a stable OVCAR8 cell line with SREBF2 disrupted using CRISPR technology. This SREBF2-KD line has reduced SREBF2 mRNA and protein expression level that indicates an effective gene knockdown. Activation of SREBF2 is dependent on the cholesterol status of the cell. We observed that expression of the SREBP2 precursor form is significantly reduced in SREBF2-KD line when cells are maintained under low serum conditions. Mutant cells treated with paclitaxel in low, but not high serum or in presence of statin, revealed significantly lower cell viability. SREBF2-KD cells do not survive long-term, high concentrations of paclitaxel, nor do they grow back as efficiently as control cells. RNA expression and proteomic analysis revealed the critical regulators mediating SREBP2 activity in stressed cells. Together, these observations suggest that the cholesterol pathway is critical for ovarian cancer cells not only to resist stresses, such as chemotherapy, but also to return to a high proliferation state upon recurrence. Further studies will provide important targets for developing new drugs for treatment of ovarian cancer. Citation Format: Galina Karashchuk, Nataliya Karashchuk, Signe Caksa, Tyler S. Smith, Alexander S. Brodsky. Cholesterol pathway determines ovarian cancer drug resistance through transcription factor SREBP2 [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 4409. doi:10.1158/1538-7445.AM2017-4409
Isoform Evolution in Primates through Independent Combination of Alternative RNA Processing Events
Authors: Shi-Jian Zhang, Chenqu Wang, Shouyu Yan, Aisi Fu, Xuke Luan, Yumei Li, Qing Sunny Shen, Xiaoming Zhong, Jia-Yu Chen, Xiangfeng Wang, Bertrand Chin-Ming Tan, Aibin He, Chuan-Yun Li
Journal: Molecular Biology and Evolution (2017)

Recent RNA-seq technology revealed thousands of splicing events that are under rapid evolution in primates, whereas the reliability of these events, as well as their combination on the isoform level, have not been adequately addressed due to its limited sequencing length. Here, we performed comparative transcriptome analyses in human and rhesus macaque cerebellum using single molecule long-read sequencing (Iso-seq) and matched RNA-seq. Besides 359 million RNA-seq reads, 4,165,527 Iso-seq reads were generated with a mean length of 14,875 bp, covering 11,466 human genes, and 10,159 macaque genes. With Iso-seq data, we substantially expanded the repertoire of alternative RNA processing events in primates, and found that intron retention and alternative polyadenylation are surprisingly more prevalent in primates than previously estimated. We then investigated the combinatorial mode of these alternative events at the whole-transcript level, and found that the combination of these events is largely independent along the transcript, leading to thousands of novel isoforms missed by current annotations. Notably, these novel isoforms are selectively constrained in general, and 1,119 isoforms have even higher expression than the previously annotated major isoforms in human, indicating that the complexity of the human transcriptome is still significantly underestimated. Comparative transcriptome analysis further revealed 502 genes encoding selectively constrained, lineage-specific isoforms in human but not in rhesus macaque, linking them to some lineage-specific functions. Overall, we propose that the independent combination of alternative RNA processing events has contributed to complex isoform evolution in primates, which provides a new foundation for the study of phenotypic difference among primates.