tbuckley/cabot-search huggingface dataset:
Abstract 2224: Increased 15-lipoxygenase-1 activity limits tumor development in the azoxymethane mouse model of colon cancer: impact of omega-3-acid ethyl esters
Authors: Xiangsheng Zuo, Jennifer K. Colby, Fuyao Liu, Shen Gao, Ling Wu, Jonathan C. Jaoude, Micheline J. Moussalli, Lin Tan, Peiying Yang, Imad Shureiqi
Journal: Cancer Research (2017)

Abstract Pro-inflammatory signaling has been shown to promote colorectal tumorigenesis and is a target for the development of effective chemopreventive approaches. The specialized pro-resolving lipid mediators (SPMs, e.g. resolvins), bioactive metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), actively terminate inflammation and have been proposed to possibly contribute to the anti-tumorigenic effects of DHA and EPA. The enzyme 15-lipoxygenase-1 (ALOX15) is a key biosynthetic enzyme in generation of resolvins. However, 15-LOX-1 expression is commonly lost during human CRC tumorigenesis starting in premalignant stages via transcriptional mechanisms independent of substrate availability. The impact of ALOX15 on DHA and EPA’s effects on tumorigenesis remain unknown. Mice with intestinal epithelium-specific expression of human ALOX15 (15-LOX-1-gut mice) and wild-type FVB controls were injected with azoxymethane (AOM, 7.5mg/kg) once weekly for 6w and followed for 20w. Mice were fed diet with 1% omega-3-acid ethyl esters (O3AEE, a pharmaceutical grade fish oil preparation of EPA and DHA ethyl esters) or control diet starting 3w before initiation with AOM. Colonic tumors developed in 10 of the 13 (77%) wild type (WT) mice fed control diet, 5 of the 10 (50%) WT mice fed O3AEE diet, 5 of the 12 (42%) 15-LOX-1-gut mice fed control diet, and 3 of the 10 (30%) 15-LOX-1-gut mice fed control diet. Lipid mediator levels were measured by liquid chromatography/ tandem mass spectrometry (LC-MS/MS). The SPMs resolvin E1 and D2 (RvE1, RvD2) as well as the pathway intermediates 18-HEPE and 17-HDHE were increased in ALOX15-gut mice on O3AEE (see Table; data are shown as ng/mg protein; mean ± SEM). Our results demonstrate that ALOX15 activity is important to DHA and EPA formation of resolvins and inhibition of colonic tumorigenesis. Supported by grants CPRIT RP150195 and NIH RO1 R01CA195686 SPMs in O3AEE or control diet fed miceWTWT15-LOX-1-gut15-LOX-1-gutControl dietO3AEE dietControl dietO3AEE diet18-HEPE00.46 + 0.500.82 + 0.3117-HDHE0.21 + 0.090.2 + 0.74.2 + 0.4113.35 + 3.1RvE10001.98 + 0.77RvD200.024 + 0.0240.17 + 0.0220.3 + 0.077 Citation Format: Xiangsheng Zuo, Jennifer K. Colby, Fuyao Liu, Shen Gao, Ling Wu, Jonathan C. Jaoude, Micheline J. Moussalli, Lin Tan, Peiying Yang, Imad Shureiqi. Increased 15-lipoxygenase-1 activity limits tumor development in the azoxymethane mouse model of colon cancer: impact of omega-3-acid ethyl esters [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 2224. doi:10.1158/1538-7445.AM2017-2224
Abstract 5341: HPV16 E6 oncoprotein modulates the DPPIV/CD26 in primary keratinocytes
Authors: Aline Beckenkamp, Bruna Prati, Silvya Stuchi Maria-Engler, Guido Lenz, Diogo André Pilger, Enrique Mario Pierulivo, Andréia Buffon
Journal: Cancer Research (2017)

Abstract Cervical cancer is related to the persistent infection by high-risk human papillomavirus (HPV) subtypes, such as types 16 and 18. The E6 and E7 oncoproteins significantly contribute to the carcinogenic potential of high-risk HPV, through the degradation of p53 and pRb, respectively. The exoprotease dipeptidyl peptidase IV (DPPIV) also known as CD26, is a multifunctional protein involved in several processes related to cancer. DPPIV/CD26 has an intrinsic peptidase activity, able to degrade some bioactive peptides and chemokines, thereby regulating cell migration, proliferation and survival. It has been reported that the reduction in DPPIV/CD26 expression is associated with tumor progression in different types of cancer. Moreover, studies in cervical cancer samples and cell lines point to a reduction in the expression of this protein. However, there are no studies addressing the relationship between HPV infection and DPPIV/CD26 expression. We analyzed the influence of HPV oncoproteins on DPPIV/CD26 expression in human keratinocyte transduced with E6, E7 and E6E7. We observed that HPV16 E6 expression is associated to a reduction in DPPIV/CD26 expression at mRNA and protein levels, whereas HPV16 E7 does not affect DPPIV/CD26 expression. HPV16 E6E7 co-expression leads to a reduction in DPPIV/CD26 expression similar to that found in E6 transduced cells. In addition, we note a more pronounced reduction in DPPIV/CD26 expression in immortalized cells expressing E6E7. Furthermore, keratinocytes expressing HPV16 E6 mutant sequence and HPV11 E6, that do not bind to E6AP and do not degrade p53, have no effect on DPPIV/CD26 expression. Our results suggest that the HPV16 E6 oncoprotein can downregulates DPPIV/CD26. In addition, preliminary results suggest that modulation of DPPIV/CD6 mediated by E6 can be dependent on degradation of p53, since HPV16 E6 mutant and low-risk HPV E6 were not able to affect CD26 expression. Furthermore, the process of cell immortalization also appears to be related to the reduction of DPPIV/CD26 expression. Therefore, these results indicate that HPV oncoproteins promote imbalance DPPIV/CD26 expression which may be relate to cervical carcinogenesis. Citation Format: Aline Beckenkamp, Bruna Prati, Silvya Stuchi Maria-Engler, Guido Lenz, Diogo André Pilger, Enrique Mario Pierulivo, Andréia Buffon. HPV16 E6 oncoprotein modulates the DPPIV/CD26 in primary keratinocytes [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 5341. doi:10.1158/1538-7445.AM2017-5341
Abstract 4158: Targeting the imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia through a novel BCR-ABL inhibitor
Authors: Pranav Gupta, Rishil Kathawala, Liuya Wei, Fang Wang, XiaoKun Wang, Brian J. Druker, Li-Wu FU, Zhe-Sheng Chen
Journal: Cancer Research (2017)

Abstract Chronic Myeloid Leukemia (CML), a hematological malignancy, is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain. In this study, we evaluated PBA2, a novel BCR-ABL inhibitor, for its anti-cancer activity against BCR-ABL expressing BaF3 cells. PBA2 shows potent activity against wild-type and T315I mutated BaF3 cells as compared with imatinib. PBA2 inhibited the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. PBA2 inhibited the mRNA expression of BCR-ABL in BaF3/WT and BaF3/T315I cells. Mechanistically, PBA2 increased the cell population in sub G1 phase of the cell cycle, induced apoptosis and elevated ROS production in both BaF3/WT and BaF3/T315I cells. Taken together, our results indicate that PBA2 exhibits anti-proliferative effects and inhibits the imatinib-resistant T315I BCR-ABL mutation. PBA2 may be a novel drug candidate for overcoming the resistance to imatinib in CML patients. Note: This abstract was not presented at the meeting. Citation Format: Pranav Gupta, Rishil Kathawala, Liuya Wei, Fang Wang, XiaoKun Wang, Brian J. Druker, Li-Wu FU, Zhe-Sheng Chen. Targeting the imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia through a novel BCR-ABL 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 4158. doi:10.1158/1538-7445.AM2017-4158
Clinicobiological features and prognostic impact of diffuse large B-cell lymphoma component in the outcome of patients with previously untreated follicular lymphoma
Authors: L. Magnano, O. Balagué, I. Dlouhy, J. Rovira, K. Karube, M. Pinyol, A. Rivas-Delgado, D. Costa, A. Martínez-Trillos, B. González-Farre, A. Martínez-Pozo, E. Giné, D. Colomer, J. Delgado, N. Villamor, E. Campo, A. López-Guillermo
Journal: Annals of Oncology (2017)
Abstract 3627: Validation of PPARG and RXRA as drivers of bladder cancer
Authors: Jonathan T. Goldstein, Craig Strathdee, Fujiko Duke, Juliann Shih, Matthew Meyerson
Journal: Cancer Research (2017)

Abstract A subset of muscle-invasive bladder cancer (BLCA) is typified by PPARG pathway activation. PPARG focal gene amplification occurs in 15% of bladder cancer patients, and similarly, 5% of BLCA patients possess hotspot mutations in the requisite heterodimer partner of PPARG, RXRA (S427F, S427Y). We used genetic perturbation to study the role of PPARG in bladder cancer. Our results show that overexpression of RXRA and PPARG mutant alleles activate expression of PPARG and PPARA target genes in a ligand-independent manner, and that bladder cancer cell lines are dependent on PPARG for viability. These findings suggest that PPARG may be a promising therapeutic target for treatment of bladder cancer. Citation Format: Jonathan T. Goldstein, Craig Strathdee, Fujiko Duke, Juliann Shih, Matthew Meyerson. Validation of PPARG and RXRA as drivers of bladder 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 3627. doi:10.1158/1538-7445.AM2017-3627
Abstract 3595: Under-reporting of research biopsies in clinical trials in oncology
Authors: Christine M. Parseghian, Kanwal Raghav, James Yao, Lee M. Ellis, Alda Tam, Michael J. Overman
Journal: Cancer Research (2017)

Abstract Purpose: Research biopsies are frequently incorporated into clinical trials in oncology, and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting. Methods: We identified a cohort of therapeutic clinical trials wherein at least one image-guided non-diagnostic research biopsy was performed between 1/2005 and 10/2010 from a large interventional radiology database at MD Anderson Cancer Center. Study protocols were compared with the highest level of corresponding publication as a manuscript, registry report, or abstract. Results: A total of 866 research biopsies were performed across 46 clinical trials (median 19 biopsies/trial). After a median follow-up time of 5.8yrs from study completion, 35 trials (76%) had published manuscripts (18 reported biopsy results), 8 (17%) had either a registry or abstract report (1 reported biopsy results), and 3 (7%) were not reported. In total, 19 trials (41%) reported biopsy results. Of these 19 trials, 6 (32%) trials under-reported the number of biopsies performed. Only 14 of 32 (42%) trials with mandatory research biopsies reported on these biopsies. Comments regarding biopsy quality/adequacy were reported in only 5 trials. Complications from these biopsies occurred in 39 pts (grade 3 in 6 pts) in 8 trials, but only 1 (13%) trial reported biopsy complications. Factors associated with better reporting of research biopsies are shown in the Table. When limited to only published manuscripts, results were unchanged. Academic sponsorship and a larger number of biopsies, especially serial biopsies, were associated with increased reporting of research biopsies. Conclusion: Despite ethical obligations to report research biopsies, 59% of trials do not report on these biopsies. Although complications occur, they are rarely reported. Clinical trial design efforts to ensure that an adequate number of research biopsies are obtained may lead to improved reporting of research biopsy biomarker results. VariableNTrials reporting biopsies (%)P-valueMandatory or optional biopsy1Mandatory (+/- optional)3314 (42)Optional135 (38)Total number of biopsies per trial0.002&amp;lt;10193 (16)10-302211 (50)&amp;gt;3055 (100)Trials with serial biopsies (No. of pts.)0.00011-5110 (0)&amp;gt;=51813 (72)Study sponsorship0.03Industry246 (25)Academic2213 (59)Clinical trial0.77Multicenter218 (38)Single center2511 (44)Phase of clinical trial0.51I or I/II3315 (45)II or III134 (31) Citation Format: Christine M. Parseghian, Kanwal Raghav, James Yao, Lee M. Ellis, Alda Tam, Michael J. Overman. Under-reporting of research biopsies in clinical trials in oncology [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 3595. doi:10.1158/1538-7445.AM2017-3595
Abstract LB-115: TPRKB dependency in p53-deficient cancers
Authors: Kelly VanDenBerg, Moloy Goswami, Lei Lucy Wang, Bhavneet Singh, Travis Weiss, Sumin Han, Dan Rhodes, Felix Feng, Scott Tomlins
Journal: Cancer Research (2017)

Abstract TP53 (p53) is an extensively studied tumor suppressor mutated in approximately 50% of all cancers. Identification of vulnerabilities imposed by p53 alterations may enable effective targeted therapy development. Thus, this study aimed to identify and characterize novel vulnerabilities in this context. Through analyzing shRNA screening data from the Broad Institute’s Project Achilles, we identified TPRKB, a poorly characterized member of the tRNA-modifying EKC/KEOPS complex, as the most significant vulnerability in p53 mutated cancer cell lines. In vitro, across multiple benign-immortalized and cancer cell lines, we confirmed that TPRKB knockdown in p53-deficient cells significantly inhibited proliferation, while there was little to no effect in p53 wild-type cells. Furthermore, p53 reintroduction into TPRKB-sensitive p53-null cells resulted in loss of TPRKB sensitivity, confirming the importance of p53 status in this context. To determine whether this response was unique to TPRKB or a result of impairment of the EKC/KEOPS complex, we knocked down other members of the complex: PRPK, OSGEP, and LAGE3. PRPK loss showed minor changes between p53 wild type versus deficient cells; while OSGEP and LAGE3 loss resulted in a significant decrease regardless of p53 status. For the first time, we have demonstrated a potential role for TPRKB in cancer, and our results suggest that effects of TPRKB knockdown in p53-deficient cancer cells may be independent of its role in the EKC/KEOPS complex. Citation Format: Kelly VanDenBerg, Moloy Goswami, Lei Lucy Wang, Bhavneet Singh, Travis Weiss, Sumin Han, Dan Rhodes, Felix Feng, Scott Tomlins. TPRKB dependency in p53-deficient cancers [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-115. doi:10.1158/1538-7445.AM2017-LB-115
Abstract 2819: Intestinal estrogen receptor beta attenuates colon cancer signaling pathways <i>in vivo</i>
Authors: Linnea Pettersson, Ashish Saxena, Trang Vu, Jan-Åke Gustafsson, Amena Archer, Cecilia Williams
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause for cancer deaths. Several epidemiological, in vitro and in vivo studies suggest that Estrogen receptor β (ERβ) could be a possible target for CRC prevention and treatment, but the potential mechanism is not demonstrated. ERβ is expressed in intestinal epithelial cells, as well as in some intestinal immune cells and other tissues. Previous studies have seen increased CRC after full ERβ knockout, but it is not clear if this is mediated by intestinal ERβ. The specific aim of our study is to determine the role of intestinal ERβ during colon cancer development in vivo. We deleted ERβ specifically in the intestine epithelia of mice (iERβKO), and induced CRC using Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS) treatment. After 9 weeks treatment, all mice presented colitis and two iERβKO mice but none of the wild-type (WT) mice had developed tumors. qPCR showed that the expression of pro-inflammatory markers was higher in iERβKO treated mice than in untreated or WT mice, Immunohistochemistry (IHC) of proliferative markers showed that iERβKO exhibited higher cell proliferation in the top of the crypts compared to controls. After 16 weeks treatment, all mice developed tumors. qPCR showed that the expression of mesenchymal markers was higher in treated iERβKO mice compared to treated WT mice. Our results demonstrate that intestinal ERβ attenuates colon cancer-related pathways. Citation Format: Linnea Pettersson, Ashish Saxena, Trang Vu, Jan-Åke Gustafsson, Amena Archer, Cecilia Williams. Intestinal estrogen receptor beta attenuates colon cancer signaling pathways in vivo [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 2819. doi:10.1158/1538-7445.AM2017-2819
Abstract 2345: CDK4 inhibition enhances anti-melanoma effects of BRAF/MEK inhibition
Authors: Yanping Zhang, Eddy C. Hsueh
Journal: Cancer Research (2017)

Abstract Introduction: Targeted therapy against BRAF-mutated melanoma has shown clinical efficacy. However, resistance to therapy often occurs. CDK4 (INK4)-retinoblastoma (RB) pathway controls cell cycle progression by regulating the G1-S checkpoint. Defect in the p16INK4A: cycling D-CDK4/6: RB pathway is also detected in melanoma. We study the effect of combining CDK4-RB pathway inhibition with BRAF/MEK inhibition as a possible strategy to overcome resistance to therapy. Methods: Three BRAF wild-type and three BRAF-mutated melanoma cell lines were selected. CDK4/6 inhibitor (PD0332991; PD), BRAF inhibitor (PLX4032; PLX), MEK inhibitor (AZD6244; AZD), and PI3K/AKT inhibitor (XL765; XL) were used alone or in combination. Cell proliferation assay was performed using Cell Titer Blue assay. Cell migration assay was performed by artificial wounding of melanoma cell monolayer and observing migration of cells into the wound up to 48 hours. Western blotting was performed for expression of pERK/ERK, pRB/RB, Cyclin D1, CDK4, and GAPDH. Data were presented as means ± SD for triplicate experiments. For comparison between groups, the student’s t test was used and p&amp;lt;0.05 was considered to be statically significant. Results: Variable inhibition of cell proliferation and migration was observed in a dose- and time-dependent fashion. Enhanced inhibition of melanoma proliferation and migration was observed with PD+AZD and PD+PLX combination compared with single agent AZD or PLX. Differential enhancement was observed in BRAF wild-type cell lines with PD+AZD and in BRAF mutated cell lines with PD+PLX combination. Minimal change in tumor proliferation and migration inhibition was noted with PD+XL combination compared with PD or PLX alone. No correlation was observed between expression of CDK4 and cyclin D1 and sensitivity to singe agent or the combination. Inhibition of phosphorylated RB1 and ERK expression was observed with exposure to single agent PD, PLX, XL, AZD. Enhancement of pRB1 and pERK inhibition was noted with PD+PLX and PD+AZD combination but not PD+XL. Conclusion: CDK4 inhibition can enhance anti-proliferation and migration effects of BRAF/ MEK inhibition in melanoma cells. The mechanism is via augmented down-regulation of pRB expression. Citation Format: Yanping Zhang, Eddy C. Hsueh. CDK4 inhibition enhances anti-melanoma effects of BRAF/MEK inhibition [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 2345. doi:10.1158/1538-7445.AM2017-2345
Abstract 2190: Theranostical nanoscale metal-organic frameworks-mediated rapid multiplexed microRNA detection and highly therapeutic efficacy in living oral cancer cells
Authors: Pei Yu, Zehang Zhuang, Guihua Qiu, Haolin Chen, Yuying Zhao, Jinxiang Chen, Xiqiang Liu
Journal: Cancer Research (2017)

Abstract Oral cancer represents the sixth most frequent cancer in the world, characterized by high poor prognosis and low survival rate due to local relapse and metastasis. MicroRNAs (miRNAs) have been discovered as diagnostic biomarkers and therapeutic targets for oral cancer. However, one of the major challenges of miRNAs-based theranostical approach is to achieve efficient and safe delivery. Thus, a reliable sensing strategy that can detect miRNAs expression levels in living cancer cells is urgently needed. Herein, a novel sensing platform based on nanoscale metal-organic framework (NMOF) conjugated with the fluorophores-labeled single-stranded DNA probe (p-DNA) was fabricated to monitor and inhibit multiplexed miRNAs expression in living oral cancer cells. The flow cytometry and confocal laser scanning microscopy (CLSM) were carried out to evaluate the expression levels of miRNAs in oral cancer cells. The miRNA inhibition efficiency was examined by RT-PCR. The effects of the complexes on tumor cell invasion and migration were assessed by transwell assay and wound healing. The flow cytometry, colony formation assay and CCK8 were used to assess cell apoptosis and proliferation. The results showed that NMOF works as fluorescence quencher of the labeled p-DNA. In presence of the target miRNA (including miR-7, miR-21, and miR-155), p-DNA was able to rapidly hybridize and release from the NMOF leading to the recovery of fluorescence in living cells, which can be detected in real-time. Moreover, RT-PCR results demonstrated that the multiplexed miRNAs could be effectively downregulated after treatment of p-DNA@NMOF, resulting in the simultaneous suppression of oral cancer cell proliferation, anti-apoptosis, migration and invasion in vitro. In summary, our study suggests that p-DNA@NMOF possess great potential for combining early diagnosis and gene therapy of oral cancer. Note: This abstract was not presented at the meeting. Citation Format: Pei Yu, Zehang Zhuang, Guihua Qiu, Haolin Chen, Yuying Zhao, Jinxiang Chen, Xiqiang Liu. Theranostical nanoscale metal-organic frameworks-mediated rapid multiplexed microRNA detection and highly therapeutic efficacy in living oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2190. doi:10.1158/1538-7445.AM2017-2190