tbuckley/cabot-search huggingface dataset:
Abstract LB-328: Mir-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44
Authors: Ann-Joy Cheng, Ya-Ching Lu, Joseph T. Chang
Journal: Cancer Research (2017)

Abstract Cancer stem cells preferentially acquire the specific characteristics of stress tolerance and high mobility, allowing them to progress to a therapy-refractive state. To identify a critical molecule to regulate cancer stemness is indispensable to erratically cure cancer. In this study, we identified miR-520b as a novel molecular target to suppress head-neck cancer (HNC) with stemness phenotype. MiR-520b inhibited cellular migration and invasion via the mechanism of epithelial-mesenchymal transition. It also sensitized cells to therapeutic drug and irradiation. Significantly, miR-520b suppressed spheroid cell formation, as well as reduced expressions of multiple stemness regulators (Nestin, Twist, Nanog, Oct4). The CD44 molecule was identified as a direct target of miR-520b, as shown by the reverse correlative expressions, the response to miR-520 modulation, the luciferase reporter assay, and the functional rescue analyses. These cellular results were confirmed by a tumor xenograft mice study. Administration of miR-520b dramatically restrained tumorigenesis and liver colonization. Conversely, miR-520b silencing led to an acceleration of tumor growth. Taken together, our study demonstrated that miR-520b inhibits the malignancy of HNC through regulation of cancer stemness conversion by targeting CD44. MiR-520b may serve as an emerging therapeutic target that may be further developed for the intervention of refractory HNC. Note: This abstract was not presented at the meeting. Citation Format: Ann-Joy Cheng, Ya-Ching Lu, Joseph T. Chang. Mir-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44 [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-328. doi:10.1158/1538-7445.AM2017-LB-328
Weekly Personal Ozone Exposure and Respiratory Health in a Panel of Greek Schoolchildren
Authors: Anna Karakatsani, Evangelia Samoli, Sophia Rodopoulou, Konstantina Dimakopoulou, Despina Papakosta, Dionisios Spyratos, Georgios Grivas, Sofia Tasi, Nikolaos Angelis, Athanasios Thirios, Anastasios Tsiotsios, Klea Katsouyanni
Journal: Environmental Health Perspectives (2017)

The association of ozone exposure with respiratory outcomes has been investigated in epidemiologic studies mainly including asthmatic children. The findings reported had methodological gaps and inconsistencies.We aimed to investigate effects of personal ozone exposure on various respiratory outcomes in school-age children generally representative of the population during their normal activities.We conducted a panel study in a representative sample of school-age children in the two major cities of Greece, Athens and Thessaloniki. We followed 188, 10- to 11-y-old, elementary school students for 5 wk spread throughout the 2013–2014 academic year, during which ozone was measured using personal samplers. At the end of each study week, spirometry was performed by trained physicians, and the fractional concentration of nitric oxide in exhaled air (FeNO) was measured. Students kept a daily time–activity–symptom diary and measured PEF (peak expiratory flow) using peak flow meters. Mixed models accounting for repeated measurements were applied.An increase of 10 μg/m3 in weekly ozone concentration was associated with a decrease in FVC (forced vital capacity) and FEV1 (forced expiratory volume in 1 s) of 0.03 L [95% confidence interval (CI): −0.05, −0.01] and 0.01 L (95% CI: −0.03, 0.003) respectively. The same increase in exposure was associated with a 11.10% (95% CI: 4.23, 18.43) increase in FeNO and 19% (95% CI: −0.53, 42.75) increase in days with any symptom. The effect estimates were robust to PM10 adjustment. No inverse association was found between ozone exposure and PEF.The study provides evidence that airway inflammation and the frequency of respiratory symptoms increase, whereas lung function decreases with increased ozone exposure in schoolchildren. https://doi.org/10.1289/EHP635.
Abstract 5073: Determination of sensitivity to BET and HDAC inhibitors in lung cancer cell lines
Authors: Sara Verdura, Manuel Torres-Diz, Montserrat Sanchez-Cespedes
Journal: Cancer Research (2017)

Abstract Purpose: To determine the sensitivity of lung cancer cell lines to different combinations of BET and HDAC inhibitors and to inquire possible associations with the genetic and molecular profiles. Methods: A panel of lung cancer cell lines were treated in vitro with BET and HDAC inhibitors. The capability of each compound, administered individually or in combination (IC50), to inhibit cell proliferation was assessed by MTT assays. Drug interaction analysis was performed using Compusyn software. The protein and gene expression levels were determined using western blot and real time PCR, respectively. Results: We found that about 70% of the cell lines tested were sensitive to BET inhibitors and about 60% responded to HDAC inhibitors. In both cases, increased sensitivity was accompanied by changes in cell morphology, a reduction of the MYC protein levels and an increase in the levels of apoptotic-related markers. We also determined the effects of the combination of these epigenetic treatments in cell growth. Our results showed a synergic effect in about 75% of the cell lines which was also correlated with dramatic changes in cell morphology, in apoptosis and in decreasing the levels of the MYC protein. Finally, we determined the possible correlation of the sensitivity to these epigenetic drugs and the expression levels of some genes implicated in lung carcinogenesis. Conclusions: Our data showed that lung cancer cells responded to BET and HDAC inhibitors and that the combination of both drugs has a synergistic effect in cell growth inhibition, suggesting that this could be an effective treatment in lung cancer. Our data also point out to certain genes as potential biomarkers to determine sensitivity to these compounds. Citation Format: Sara Verdura, Manuel Torres-Diz, Montserrat Sanchez-Cespedes. Determination of sensitivity to BET and HDAC inhibitors in lung 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 5073. doi:10.1158/1538-7445.AM2017-5073
Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors
Authors: Weicai Chen, Ye Kuang, Hai-Bo Qiu, Zhifa Cao, Yuqing Tu, Qing Sheng, Grant Eilers, Quan He, Hai-Long Li, Meijun Zhu, Yuexiang Wang, Rongqing Zhang, Yeqing Wu, Fanguo Meng, Jonathan A. Fletcher, Wen-Bin Ou
Journal: Cancer Research (2017)

Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GISTs eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state. Using phospho-RTK and immunoblot assays, we demonstrate activation of KIT and insulin receptor (IR) in imatinib-resistant GIST cell lines (GIST430 and GIST48) and biopsies with acquisition of KIT secondary mutations, but not in imatinib-sensitive GIST cells (GIST882 and GIST-T1). Treatment with linsitinib, a specific IR inhibitor, inhibited IR and downstream intermediates AKT, MAPK, and S6 in GIST430 and GIST48, but not in GIST882, exerting minimal effect on KIT phosphorylation in these cell lines. Additive effects showing increased apoptosis, antiproliferative effects, cell-cycle arrest, and decreased pAKT and pS6 expression, tumor growth, migration, and invasiveness were observed in imatinib-resistant GIST cells with IR activation after coordinated inhibition of IR and KIT by linsitinib (or IR shRNA) and imatinib, respectively, compared with either intervention alone. IGF2 overexpression was responsible for IR activation in imatinib-resistant GIST cells, whereas IR activation did not result from IR amplification, IR mutation, or KIT phosphorylation. Our findings suggest that combinatorial inhibition of IR and KIT warrants clinical evaluation as a novel therapeutic strategy in imatinib-resistant GISTs. Cancer Res; 77(18); 5107-17. ©2017 AACR.
Abstract 5320: Folate and other nutrients related to one-carbon metabolism and risk of melanoma
Authors: Ashar Dhana, Hsi Yen, Tricia Li, Michelle Holmes, Abrar Qureshi, Eunyoung Cho
Journal: Cancer Research (2017)

Abstract Background: Nutrients involved in one-carbon metabolism - folate, vitamins B6 and B12, methionine, choline, and betaine - have been associated with multiple cancer sites. However, no study has assessed the association between these nutrients and risk of melanoma. Thus, the aim of this study was to evaluate the association between intake of these nutrients and melanoma risk within two prospective cohorts: the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Methods: The cohorts included a total of 81,685 women in the NHS (1984 to 2010) and 49,617 men in the HPFS (1986 to 2010). We assessed nutrient intakes using a semi-quantitative food frequency questionnaire every 2 to 4 years. Total nutrient intake included both dietary and supplemental intake. Dietary intake included intake from food only. Study physicians reviewed medical and pathological records to confirm self-reported cases of invasive melanoma. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and then pooled the HRs for both cohorts using a random effects model. Results: Over 24 to 26 years of follow-up, we documented 1,321 cases (641 men and 680 women) of invasive melanoma. Higher intake of folate from food only, but not total folate, was associated with increased risk of melanoma. The pooled multivariable HRs for the top versus bottom quintiles were 1.17 (95 % CI: 0.98-1.41; P for trend = 0.17) for total folate and 1.37 (95 % CI: 1.13-1.65; P for trend = 0.001) for folate from food only. The association was statistically significant in men, but not in women. Higher intake of vitamins B6 and B12, choline, betaine, and methionine was not associated with risk of melanoma. Conclusion: We found some evidence that folate from food only, but not total folate, was associated with a modest increased risk of melanoma - a finding that warrants further investigation. Conversely, our findings suggest that other nutrients involved in one-carbon metabolism do not play an important role in the etiology of melanoma. Citation Format: Ashar Dhana, Hsi Yen, Tricia Li, Michelle Holmes, Abrar Qureshi, Eunyoung Cho. Folate and other nutrients related to one-carbon metabolism and risk of melanoma [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 5320. doi:10.1158/1538-7445.AM2017-5320
Abstract 310: Enhanced stability of D-type cyclins correlates with glioblastoma resistance to ionizing radiation
Authors: Fadila Guessous, Mouadh Benamar, Hui Zhong, Tarek Abbas
Journal: Cancer Research (2017)

Abstract Transition from G1 to S phase of the cell cycle is promoted by D-type cyclins (D1, D2 and D3), regulatory subunits critical for the activation of cyclin dependent kinases 4 and 6 (CDK4/6), which phosphorylate and inactivate the retinoblastoma protein (pRb) and activate the transcription factor E2F1 to promote the expression of genes essential for DNA synthesis. Deregulated expression of D-type cyclins is frequently observed in human malignancies and correlates with increased proliferation. Cyclin Ds overexpression is also associated with radioresistance, leading to radiotherapy failure and disease recurrence. Cyclin D1 undergoes ubiquitin-dependent degradation following the exposure of cancer cells to ionizing radiation (IR), and this has been shown to be critical for IR-induced G1 growth arrest and sensitivity of cancer cells to IR. While the role of cyclin D1 overexpression in drug resistance is already well documented, less is known about the role of cyclins D2 and D3 in radio-resistance in human cancer cells, particularly in brain neoplasms. In the present study, we investigated the effect of IR on different D-type cyclins (D1, D2, D3) in human glioblastoma cell lines as well as in tumor-derived mouse oligodendrocytes progenitor cells (OPCs). Here, we show that exposure of human astrocytes to increasing levels of IR led to a rapid proteasomal degradation of all three D-type cyclins. On the other hand, IR failed to induce significant cyclin Ds degradation in a number of human glioblastoma cells (U87, A172, U251, Snb19). Analysis of cell cycle profile of all glioblastoma cells tested and exposed to IR showed prominent cell cycle arrest in G1 starting at 24 hours following exposure. Furthermore, we show that the steady-state levels of D-type cyclin is higher in OPCs compared to mouse NIH3T3 cells and fail to undergo proteasomal degradation following IR exposure. Collectively, these results suggest that the degradation of D-type cyclins is not critical for IR-induced G1 cell cycle arrest in GMB and may underlie their resistance to IR. Understanding the role of cyclin Ds in promoting radioresistance may lead to a useful pharmacological strategy to enhance radiotherapy outcome and help implement a more effective treatment modality. Citation Format: Fadila Guessous, Mouadh Benamar, Hui Zhong, Tarek Abbas. Enhanced stability of D-type cyclins correlates with glioblastoma resistance to ionizing radiation [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 310. doi:10.1158/1538-7445.AM2017-310
Abstract 933: Bcl-xL overexpression promotes tumor aggressiveness
Authors: Maria Grazia Tupone, Daniela Trisciuoglio, Marianna Desideri, Marta Di Martile, Chiara Gabellini, Simonetta Buglioni, Laura De Salvo, Gabriele Alessandrini, Simona D'Aguanno, Donatella Del Bufalo
Journal: Cancer Research (2017)

Abstract Bcl-xL is an antiapoptotic protein highly expressed in cancer and contributes to tumor initiation and progression by promoting cell survival. It also promotes tumor angiogenesis and metastasis. By using M14 melanoma and ADF glioblastoma cell lines and their derivative bcl-xL overexpressing clones, in the current study, we investigated the role of bcl-xL in aggressive features of melanoma and glioblastoma models. We found that in both models, bcl-xL overexpression increased in vitro cell migration and invasion and facilitated tumor cells to form de novo vasculogenic structures. Furthermore, bcl-xL overexpressing cells exhibited significantly higher tumorsphere formation capacity, reflecting the self-renewal activity, and expressed high levels of some stem cell markers, supporting the concept that bcl-xL plays essential roles in the maintenance of cancer stem cells phenotype. Forced expression of bcl-xL in melanoma cells also increased vascular endothelial growth factor (VEGF) and matrix metalloprotease-2 (MMP-2) expression, and the activation of hypoxia-inducible factor 1 (HIF-1), a key pathway involved in melanoma vascularization and aggressiveness. On the contrary, no differences were observed after bcl-xL overexpression in glioblastoma model, in terms of HIF-1 expression and activity, and VEGF protein secretion. Immunohistochemical analysis revealed that the expression of the vascular markers, and the vasculogenic mimicry were upregulated in the bcl-xL overexpressing xenografts derived from both tumor histotypes. The work presented here brings further support to the understanding of the malignant actions of bcl-xL both in melanoma and glioblastoma, and in particular to the concept that bcl-xL contributes to the aggressiveness of these two tumor histotypes by promoting invasion, migration, vasculogenic mimicry and cancer stem cells phenotype. It also indicates a cell type-specific effect of bcl-xL on HIF-1/VEGF axis. Citation Format: Maria Grazia Tupone, Daniela Trisciuoglio, Marianna Desideri, Marta Di Martile, Chiara Gabellini, Simonetta Buglioni, Laura De Salvo, Gabriele Alessandrini, Simona D'Aguanno, Donatella Del Bufalo. Bcl-xL overexpression promotes tumor aggressiveness [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 933. doi:10.1158/1538-7445.AM2017-933
Abstract 2878: Anti-cancer effects of retinoic acid in CRC occurs via decreased growth of ALDH+ cancer stem cells and increased differentiation of stem cells to neuroendocrine cells
Authors: Shirin R. Modarai, Lynn M. Opdenaker, Anindita Gupta, Jeremy Z. Fields, Bruce M. Boman
Journal: Cancer Research (2017)

Abstract Our studies on tissues from colon cancer patients show that in the development of colorectal cancer (CRC), stem cell (SC) overpopulation underlies tumor initiation and progression. Because aldehyde dehydrogenase (ALDH) is a marker for SCs in several tissues and is a key enzyme in retinoid acid (RA) signaling, we investigated the role of RA signaling in normal and malignant colonic SCs. Our overall hypothesis is that RA signaling regulates growth and differentiation of ALDH+ colonic SCs and dysregulation of RA signaling contributes to SC overpopulation in CRC development. To begin to investigate underlying mechanisms, we analyzed CRC cell lines/tissues to see if retinoid receptors RXR and RAR are exclusively expressed in ALDH+ SCs and if the RA pathway components change during CRC development. We determined whether RA signaling influences SC proliferation, differentiation, self-renewal, and SC population size. RXR &amp; RAR were selectively expressed in ALDH+ colonic SCs, but not in MCM2+ proliferative cells, suggesting that RA signaling mainly occurs in SCs. Western blotting/immunostaining of CRCs revealed that RA signaling components, including RAR and RXR, become overexpressed in parallel with ALDH overexpression, which coincides with the known overpopulation of ALDH+ SCs that occurs during CRC development. Treatment of cells with RA ligands (ATRA, 9-cis RA) inhibited proliferation, reduced sphere formation, decreased ALDH+ SC population size, and induced differentiation along the neuroendocrine cell (NEC) lineage. Taken together, our findings indicate that: (1) retinoid signaling, by regulating ALDH+ colonic SCs, reduces SC proliferation, self-renewal and SC population size, and promotes SC differentiation to NECs, and (2) dysregulation of RA signaling in colonic SCs likely contributes to overpopulation of ALDH+ SCs and CRC growth. Thus, RA signaling, by inducing increased differentiation of the SC population, suggests a novel therapeutic target. Citation Format: Shirin R. Modarai, Lynn M. Opdenaker, Anindita Gupta, Jeremy Z. Fields, Bruce M. Boman. Anti-cancer effects of retinoic acid in CRC occurs via decreased growth of ALDH+ cancer stem cells and increased differentiation of stem cells to neuroendocrine 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 2878. doi:10.1158/1538-7445.AM2017-2878
Abstract 1182: A novel curcumin derivative inhibits active ras and its downstream pathway in pancreatic cancer
Authors: Naveen Mallangada, Gerardo G. Mackenzie
Journal: Cancer Research (2017)

Abstract Pancreatic Cancer’s (PC’s) 5-year survival rate of only 6.7% indicate the need to improve treatment modalities. Despite decades of research, current chemotherapy and radiation therapy regimens offer minimal or no help. It is critical to develop new agents for the effective management of PC. Given that Kras mutations initiate and maintain PC, inhibition of this pathway is widely considered a therapeutic target of exceptional importance. Our laboratory is currently exploring the chemotherapeutic efficacy of a novel Chemically-Modified Curcumin (CMC2.24) as a potential chemotherapeutic agent for PC. Preliminary studies have shown that CMC2.24 has higher bioavailability than curcumin, as shown in pharmacokinetic studies in rats, and inhibits PC growth in vitro and in vivo. However, the exact mechanism on how CMC2.24 reduces cell growth remains unidentified. The objective of this work was to determine the mechanism of CMC2.24 in PC. Using human PC MIA PaCa-2 and Panc-1 cell lines and pancreatic acinar explants from Kras mutant mice, we explored the effects of CMC2.24 on Ras activation, ERK phosphorylation, mitochondrial reactive oxygen species, mitochondrial ATP production, and intrinsic apoptosis. In human PC MIA PaCa-2 cells CMC2.24 inhibited Ras activation by 90% (p&amp;lt;0.05). This was confirmed in primary acinar explants isolated from Kras mutant mice in which CMC treatment reduced Ras activation by 70%, compared to control. Furthermore, CMC 2.24 treatment reduced the phosphorylation MEK, ERK and c-Raf, down-stream pathway of Ras, both in vitro and in vivo. The effect of CMC2.24 on ERK phosphorylation was confirmed by Immunofluorescence, showing a significant decrease in ERK phosphorylation (47.8%; p&amp;lt;0.05). Moreover, CMC2.24 treatment enhanced the levels of superoxide anion in mitochondria by 200% (p&amp;lt;0.02), decreased ATP levels in a concentration-dependent manner (p&amp;lt;0.05), and induced intrinsic apoptosis, as shown by the increase in caspase 9 and Parp cleavage downstream of cytochrome C cytosolic release. In conclusion, our results indicate that the Ras pathway is a key molecular target for CMC2.24 and that CMC induces apoptosis in PC cells through the intrinsic pathway. This research was supported by the Stony Brook Cancer Center and a URECA Summer Grant. Citation Format: Naveen Mallangada, Gerardo G. Mackenzie. A novel curcumin derivative inhibits active ras and its downstream pathway in pancreatic 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 1182. doi:10.1158/1538-7445.AM2017-1182