tbuckley/cabot-search huggingface dataset:
Abstract 5209: Ionizing radiation abrogates pro-tumorigenic effects from cancer-associated fibroblasts in xenografts
Authors: Turid Hellevik, Maria T. Grinde, Jørg Vik, Ketil A. Camilio, Inigo Martinez-Zubiaurre
Journal: Cancer Research (2017)

Abstract Non-malignant elements of tumors play fundamental roles in both cancer sustainability and responses to therapies. In the context of clinical radiotherapy (RT), all cells that reside in the tumor mass receive radiation, but the impact of cancer-associated fibroblasts (CAFs) to treatment outcomes remains largely unexplored. In this study, we have investigated the effects of radiation on the natural pro-tumorigenic actions of CAFs in animals. Ionizing radiation (IR) was delivered to CAFs either as a single-high dose or fractionated medium doses. Tumor development was compared in xenografts after co-implantation of A549 lung tumor cells with irradiated or non-irradiated human lung CAFs. Quantitative histology and immunohistochemistry was applied to investigate potential biological mechanisms behind tumor growth regulations. As expected, CAFs showed resistance to radiation-induced cell death, however, the enhanced tumorigenic effects observed with admixed non-irradiated CAFs was nullified. Quantitative determinations of parameters such as desmoplasia, angiogenesis, inflammation, innate immunity or tumor cell proliferation revealed enhanced blood vessel density in tumors established with irradiated CAFs. Experiments to ascertain fate of implanted CAFs showed that both irradiated and non-irradiated CAFs only reside at the implantation site during early stages, suggesting that the regulatory functions of admixed CAFs may take place during the initial phases of tumor formation. In this study, we show that CAFs receiving ionizing radiation lose their pro-tumorigenic potential in vivo, affecting angiogenesis and possibly other mechanisms related to tumor engraftment. This finding represent a previously unknown advantageous effect induced by radiotherapy, which adds to the well-known direct cytotoxic effects on transformed epithelial cells. Note: This abstract was not presented at the meeting. Citation Format: Turid Hellevik, Maria T. Grinde, Jørg Vik, Ketil A. Camilio, Inigo Martinez-Zubiaurre. Ionizing radiation abrogates pro-tumorigenic effects from cancer-associated fibroblasts in xenografts [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 5209. doi:10.1158/1538-7445.AM2017-5209
Abstract 4264: Smoking exposure and quantitative levels of estrogen-receptor expression in ER+ breast tumors
Authors: Eboneé N. Butler, John A. Baron, Jeannette T. Bensen, Mengjie Chen, Kathleen Conway, Andrew F. Olshan, Melissa Troester
Journal: Cancer Research (2017)

Abstract Introduction: Smoking is a suspected risk factor for breast cancer and has been linked to increased risk of estrogen-receptor positive (ER+) disease in some epidemiologic studies. Cigarette smoke has also been shown to have antiestrogenic effects, leading to a potentially contradictory hypothesis that smoking would lead to decreased risk of breast tumors driven by estrogen-signaling. Binary classification of breast tumors with respect to ER may mask quantitative associations between smoking and ER expression. Methods: Using data from the Carolina Breast Cancer Study (CBCS), we examined relationships between smoking and quantitative levels of ER expression from tumors of 1,297 women with ER+ disease (i.e., ≥ 10% of tumor cells ER+ by immunohistochemical analysis). We used multinomial logistic regression to estimate associations between categorical measures of smoking and quartiles of ER protein or ESR1 mRNA expression, represented by odds ratios (OR) and 95% confidence intervals (95% CI). We also examined associations between smoking and quantitative ER levels among women with ER+ breast tumors, stratified by menopausal status. Multivariate regression models include adjustment for age, race, stage, grade, and tumor size. Results: Quantitative ESR1 was positively associated with any history of smoking (i.e., current at time of diagnosis or former smoking) (OR: 1.96 and 95% CI: 1.24 to 3.10). In addition, smoking more than 1 pack of cigarettes per day was associated with high ESR1 expression (OR: 3.19 and 95% CI: 1.29 to 7.91) as was smoking duration of &amp;gt; 20 years (OR: 2.08 and 95% CI: 1.16 to 3.74). Among former smokers, we observed higher ESR1 expression among those who quit 5-10 years prior to diagnosis. The magnitudes of association between smoking and quantitative levels of ESR1 expression were similar for both pre- and post-menopausal women, but were not reflected in similar association on the protein level. Conclusions: Among women with ER+ breast cancer, smoking dose and duration was positively associated with elevated ESR1 mRNA levels, regardless of menopausal status. Absence of this association for protein suggests that ESR1 RNA merits further consideration, but may suggest that ESR1 RNA more sensitively captures biological differences than ER protein expression. Citation Format: Eboneé N. Butler, John A. Baron, Jeannette T. Bensen, Mengjie Chen, Kathleen Conway, Andrew F. Olshan, Melissa Troester. Smoking exposure and quantitative levels of estrogen-receptor expression in ER+ breast 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 4264. doi:10.1158/1538-7445.AM2017-4264
Abstract 404: A bi-clustering based computational approach to identify molecular markers for Neoadjuvant chemotherapy outcome prediction in complement to cancer subtype classifications
Authors: Chi Zhang, Sen Liang
Journal: Cancer Research (2017)

Abstract Molecular stratification models have been well established for most cancer types to classify tumors into sub-types by using genome level molecular characteristics. Tumors of certain sub-type have distinct response to specific therapies. Hence a reliable molecular classification model can be applied to determine treatment strategy. Recent neoadjuvant chemotherapy, immunotherapies and gene targeted drugs and their possible combinations raise a demand for small subsets of novel molecular markers for outcome prediction in addition to the complete molecular profile based classification. However, it is unknown what genes have predictive power for a certain therapeutic strategy while the highly crossed clinical features increase the difficult to determine sample groups for marker identification that form a bi-clustering problem. In addition, predictive maker may be varied among different cancer sub-types. In this work, we developed a bi-clustering based computational framework to identify transcriptomic markers for predicting the outcome of neoadjuvant chemotherapy and adjuvant chemotherapy. Our computational approach identifies functional related gene expression modules show significant expression patterns in a subset of samples that are highly associated with one or several disease sub-types and with high predictive power for the outcome of certain. By applying the analysis to 8 breast carcinoma, 10 colorectal carcinoma and 3 acute myeloid leukemia data sets in public domain, we have identified sets of gene markers with high predictive power for chemotherapy outcome complementary to the existing molecular classifications, suggesting the bi-clustering based approach can improve the whole genome level molecular classification based outcome prediction. Citation Format: Chi Zhang, Sen Liang. A bi-clustering based computational approach to identify molecular markers for Neoadjuvant chemotherapy outcome prediction in complement to cancer subtype classifications [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 404. doi:10.1158/1538-7445.AM2017-404
Demonstrating Noninferiority of Accelerated Radiotherapy With Panitumumab vs Standard Radiotherapy With Cisplatin in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma—Reply
Authors: Bingshu E. Chen, Lillian L. Siu, Wendy R. Parulekar
Journal: JAMA Oncology (2017)

In Reply Regarding the 2-stage test design, we applied in the CCTG HN.6 study1 the following stepwise test procedure (Figure 1 by Wang et al2), which controls the overall type I error rate at 5% used to analyze progression-free survival (PFS):
Abstract 864: Alternated activation of TGFβ pathway and differential expression of epithelial to mesenchymal transition transcription factors in relation to lymph node metastasis in two subtypes of breast cancer tumors
Authors: Victoria Ortega-Hernandez, Patricia Gajardo-Meneses, Wanda Fernandez, Pilar Carvallo
Journal: Cancer Research (2017)

Abstract Breast cancer is the leading cause of cancer death among women worldwide, being distant metastases the main cause of death. Epithelial to mesenchymal transition (EMT) has been implicated in promoting cancer invasion and metastasis. This process can be induced by TGFβ through the expression of transcription factors: TWIST, SNAIL, SLUG and ZEB1, which expression may be promoted by different signaling pathways such as SMAD2/SMAD3, PI3K/AKT and ERK/MAPK. The expression of EMT transcription factors has been previously studied in several cancer cell lines, although no studies have been performed in breast cancer tumors. In this study, we analyzed by immunohistochemistry the expression of the four transcription factors, and the signal transduction key proteins p-SMAD2 (ser465/467), p-SMAD2L (ser245/250/,255) and p-AKT (ser473), in 107 breast cancer tumors. We found expression of at least one transcription factor in all triple negative tumors (n=24), while only 70% luminal tumors showed expression of at least one of these proteins. Expression of ZEB1, SNAIL and SLUG was observed in tumors with metastases to lymph node, whereas the majority of tumors expressing TWIST were negative for lymph node status. All triple negative tumors with an active state of the signal transduction pathway TGFβ/SMAD showed expression of at least one transcription factor, whereas 65% of luminal tumors with an active state of the same pathway showed no expression of these transcription factors. Active state of PI3K/AKT pathway was observed only for luminal tumors as it has been described. Sixty-three percent of tumors having this pathway active showed expression of at least one transcription factor. In conclusion we found differential expression of EMT transcription factors in relation to lymph node status and a differential active state of signaling pathways in relation to tumoral subtype of breast cancer tumors. Our results suggest a different mechanism of EMT induction by TGFβ in relation to two tumor’s subtypes and lymph node metastasis. Citation Format: Victoria Ortega-Hernandez, Patricia Gajardo-Meneses, Wanda Fernandez, Pilar Carvallo. Alternated activation of TGFβ pathway and differential expression of epithelial to mesenchymal transition transcription factors in relation to lymph node metastasis in two subtypes of breast cancer 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 864. doi:10.1158/1538-7445.AM2017-864
Abstract 5125: Muscadine grape extract inhibits breast cancer brain metastatic cells by multiple mechanisms
Authors: Wenhong Chen, Patricia Gallagher, Ann Tallant, Linda J. Metheny-Barlow
Journal: Cancer Research (2017)

Abstract Tumor metastasis to the brain is a common complication of cancer, affecting 500,000 patients each year. Due to poor penetration of most chemotherapeutics into the brain, brain metastasis may occur even while systemic disease in under control. Despite aggressive treatments including radiation therapy, survival at 12 months following diagnosis is only 20%, underscoring the need for better means to prevent and/or treat brain metastases. Natural products have historically been a very successful source of new drugs. We are investigating the anti-cancer potential of a proprietary muscadine grape extract (MGE; from Piedmont Research &amp; Development Corp.) on breast cancer cell lines that are metastatic to the brain. In a colony formation assay, MGE (10 μg/mL) decreased clonogenic survival of 4T1.luc2.Br5 cells by 50% (n=3, p&amp;lt;0.0001). The Eo771.luc.Br5 cells were more sensitive to MGE, showing 33% inhibition at 5 μg/mL (n=3, p&amp;lt;0.001) and 91% inhibition at 7.5 μg/mL (n=3, p&amp;lt;0.0001). We also assessed response to the combined treatment of MGE and ionizing radiation (IR). While MGE did not sensitize cells to IR, combined administration of MGE and IR resulted in decreased clonogenic survival compared to either modality alone for both cell lines (n=3-4 experiments, p&amp;lt;0.01), suggesting an additive effect. Mechanistically, acute exposure (24 h) to 10 μg/mL MGE induced apoptosis in 4T1.luc2.Br5 cells as evidenced by PARP cleavage and detection of activated cleaved caspase 3. Further, ERK1/2 activation was decreased 68% at this time point (n=3, p&amp;lt;0.05). In contrast, although Eo771.luc.Br5 cells are more sensitive to clonogenic inhibition, no PARP cleavage, caspase 3 cleavage, or ERK1/2 inhibition was observed. Analysis of cyclin D1, a major regulator of cell cycle progression, identified &amp;gt;80% decrease following MGE treatment (24 h, 10 μg/mL) in both cell lines. Together these data suggest that MGE inhibits breast cancer brain metastatic cell proliferation by multiple mechanisms, including inhibition of clonogenic growth through induction of apoptosis and/or decreased cell cycle progression, suggesting that MGE may have utility in the treatment of breast cancer brain metastasis. Citation Format: Wenhong Chen, Patricia Gallagher, Ann Tallant, Linda J. Metheny-Barlow. Muscadine grape extract inhibits breast cancer brain metastatic cells by multiple mechanisms [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 5125. doi:10.1158/1538-7445.AM2017-5125
Abstract 4532: Adrenal metastases in lung cancer: Clinical implications of a mathematical model
Authors: Jeremy M. Mason, AnneMarie Ciccarella, Lori Marx-Rubiner, Lyudmila Bazhenova, Paul K. Newton, Kelly Bethel, Jorge J. Nieva, Peter Kuhn
Journal: Cancer Research (2017)

Abstract Adrenal gland metastases are common in lung cancer. It is well recognized that aggressive treatment of solitary adrenal metastases leads to improved outcomes but the exact nature of adrenal deposits is not well understood. Controversy exists as to the routing of cancer cells to the adrenal gland with some believing that this transmission is lymphatic, in contrast to the more generally accepted theory of hematogenous spread. Using an autopsy dataset of 3827 untreated cancer patients, we use the metastatic distribution of common primary cancer types to create Markov models of progression. The anatomical sites of spread in the body represent states in the model, while the transition probability between states represents the probability of metastatic spread from one site to another. We then use the Markov models to run Monte Carlo simulations of random walkers representing circulating tumor cells traveling within the body to simulate metastatic spread. We calculate mean first passage times (MFPT) to each site as a representative of time to metastasis formation. Analysis of 6 common cancer types (bladder [n=120 autopsies; 289 metastases], breast [n=432; 2235], colorectal [n=161; 420], lung [n=560; 859], ovarian [n=418; 806], and prostate [n=62; 212]) from the dataset showed distinct metastatic distributions across the populations. MFPT calculations to anatomical sites in the 6 analyzed primary cancer types indicated model progression times to the adrenal gland similar to the regional and distal lymph nodes in only lung cancer. The times associated with adrenal gland in the other primary cancers were similar to other metastatic sites of hematogenous spread. The Markov models created strongly support the lymphatic theory for metastatic spread to the adrenal glands. After performing a literature review to look for the biological plausibility of the simulated results, we believe evidence supports this theory and validates the models. This could explain improved survival for patients in whom solitary adrenal metastases are managed aggressively with surgical or radiation modalities. In order to further validate this theory, we are calling for clinical trials prospectively testing this hypothesis. Citation Format: Jeremy M. Mason, AnneMarie Ciccarella, Lori Marx-Rubiner, Lyudmila Bazhenova, Paul K. Newton, Kelly Bethel, Jorge J. Nieva, Peter Kuhn. Adrenal metastases in lung cancer: Clinical implications of a mathematical model [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 4532. doi:10.1158/1538-7445.AM2017-4532
Abstract LB-099: BET bromodomain proteins are essential for the oncogenic EWS-fusion driven Ewing Sarcoma
Authors: Paradesi N. Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Carl Engelke, Vijaya L. Dommeti, Pranathi M. Krishnamurthy, Archana Nallasivam, Ingrid A. Apel, Tianlei Xu, Zhaohui S. Qin, Felix Y. Feng, Irfan A. Asangani
Journal: Cancer Research (2017)

Abstract Ewing sarcoma (EWS) is a lethal pediatric small, round, blue cell tumor defined by the characteristic fusion between EWSR1 and a member of the ETS family transcription factor, mostly FLI1 and ERG. Bromodomain and extra-terminal domain (BET) proteins play an essential role in transcription as an epigenetic reader of acetylated histones and transcription factors, and recent studies of inhibitors against these proteins have demonstrated therapeutic potential in various cancers. In this study, we investigated the importance of BET proteins BRD2, BRD3, and BRD4 in EWS-fusion driven transcription program required for maintenance and progression of EWS. Similar to EWS-FLI1 and EWS-ERG, knock-down of BET proteins severely impaired the proliferation and invasion of EWS cells. Gene expression profiling by RNA-Seq showed a common set of genes altered in EWS-FLI1 and BRD2/3/4 knockdown cells implicating a direct role of BET proteins in the transcriptional regulation of EWS-fusion targets. Importantly, BET inhibitor, JQ1, induces apoptosis in EWS cells through an MYC-independent mechanism, and without affecting the EWS-fusion levels. Rather, evidence suggested that BRD4 exists in a complex with EWS-ETS fusion proteins and that its inhibition abrogates the fusion transcriptional program. In vivo, JQ1 inhibited the metastases in chicken CAM model of EWS as well as displayed anti-tumor and anti-metastatic activity in mouse xenograft models of EWS. Together, these results indicate that BET proteins, especially BRD4 interacts with EWS-ETS fusion proteins and this interaction is necessary for the EWS-fusion mediated oncogenesis. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating metastatic Ewing sarcoma patients. Citation Format: Paradesi N. Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Carl Engelke, Vijaya L. Dommeti, Pranathi M. Krishnamurthy, Archana Nallasivam, Ingrid A. Apel, Tianlei Xu, Zhaohui S. Qin, Felix Y. Feng, Irfan A. Asangani. BET bromodomain proteins are essential for the oncogenic EWS-fusion driven Ewing Sarcoma [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-099. doi:10.1158/1538-7445.AM2017-LB-099
Abstract 2700: Intestinal Vitamin D receptor deficiency increases susceptibility for the DSS-induced colon disease
Authors: Jung-Hwan Kim, Satoshi Yamaori, Frank J. Gonzalez
Journal: Cancer Research (2017)

Abstract To investigate the function of the intestinal Vdr gene in inflammatory bowel disease (IBD), in conjunction with the discovery of possible metabolic markers for IBD using intestine-specific Vdr knockout mice. VdrΔIEpC mice were generated, phenotyped and treated with a time-course of 3% dextran sulfate sodium (DSS) to induce colitis. Colitis was diagnosed by evaluating clinical symptoms and intestinal histopathology. Gene expression analysis was carried out. In addition, metabolic markers of IBD were explored by metabolomics. VdrΔIEpC mice showed abnormal body size, colon structures and feces color. Calcium, collagen, and intestinal proliferation-related gene expression were all decreased, and serum alkaline phosphatase was highly increased. In the acute model which was treated with 3% DSS for six days, VdrΔIEpC mice showed a high score of IBD symptoms; enlarged mucosal layer and damaged muscularis layer. In the recovery experiment model, where mice were treated with 3% DSS for four days and water for three days, VdrΔIEpC mice showed a high score of IBD symptoms; severe damage of mucosal layer and increased expression of genes encoding proinflammatory cytokines. Feces metabolomics revealed decreased concentrations of taurine, taurocholic acid, taurodeoxycholic acid and cholic acid in Vdr ΔIEpC mice. In conclusion, disruption of the intestinal Vdr gene showed phenotypical changes. These factors combined may exacerbate IBD. Taken together, the results suggest that VDR may play an important role in IBD. Citation Format: Jung-Hwan Kim, Satoshi Yamaori, Frank J. Gonzalez. Intestinal Vitamin D receptor deficiency increases susceptibility for the DSS-induced colon disease [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 2700. doi:10.1158/1538-7445.AM2017-2700