bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-233: Unique physicochemical properties of the potent FGFR 1, 2, 3 and 4 inhibitor JNJ-42756493 contribute to prolonged target shutdown
Authors: Jovcheva Eleonora , Paulussen Caroline , Bergen Patrick Van , Chong Yolanda , Vialard Jorge , Mevellec Laurence , Angibaud Patrick , Perera Timothy 
Published: May 2015

Abstract
The ability of drugs to penetrate into cells and tissues is a fundamentally important property that is essential for the efficacy of drugs targeting intracellular processes. Many weakly basic small molecule drugs are known to accumulate extensively in acidic sub-cellular compartments such as lysosomes, through a process called ion trapping that is dependent on the physico-chemical properties of a compound. ‘Lysosomal uptake’ has been shown to significantly influence the activity of many agents, including anticancer drugs, both positively and negatively.
Here we describe the unique physico-chemical properties of JNJ-42756493, a potent inhibitor of fibroblast growth factor receptors (FGFRs) 1, 2, 3 and 4, currently undergoing clinical testing for the treatment of malignancies with FGFR pathway activating alterations. JNJ-42756493 has weakly basic and lipophilic characteristics, is highly permeable, and is fluorescent when exposed to UV light. The fluorescent property of JNJ-42756493 enabled rapid and convenient visualization of the drug (spatial and temporal localization) within the lysosomes of cultured cells exposed to JNJ-42756493. In order to evaluate the influence of this lysosomotropic property on the activity of JNJ-42756493, FGFR phosphorylation was monitored in a series of wash-out experiments performed in various cellular models with FGFR1 or FGFR2 amplifications. This comparative washout analysis demonstrated prolonged FGFR kinase inhibition by JNJ-42756493 in comparison to other FGFR inhibitors lacking lysosomotropic properties. This qualitative fluorescence-based data was complemented by accurate quantification of the amount of compound taken up by the cells through the use of radiolabelled JNJ-42756493.
Our results unequivocally demonstrate that JNJ-42756493 accumulates at high concentrations within the lysosomal compartment of cells without undergoing metabolism. The continued, long lasting effects on the target FGF receptor kinase inhibition following drug washout, suggest a novel intrinsic slow release of the unmodified drug from these intracellular stores. The lysosomotropic property of JNJ-42756493 is proposed to be a major contributor to the efficient and persistent inhibition of FGFR phosphorylation leading to potent cellular and in vivo activity.
Citation Format: Eleonora Jovcheva, Caroline Paulussen, Patrick Van Bergen, Yolanda Chong, Jorge Vialard, Laurence Mevellec, Patrick Angibaud, Timothy Perera. Unique physicochemical properties of the potent FGFR 1, 2, 3 and 4 inhibitor JNJ-42756493 contribute to prolonged target shutdown. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-233. doi:10.1158/1538-7445.AM2014-LB-233
Abstract LB-236: Preclinical efficacy of targeting FGF autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230
Authors: Young M. Phillip De , Sherk Christian , Bleam Maureen , Barnette Mary , Ganji Gopi , Hoang Bao , Tunstead James , Bellovin David , Los Gerrit , Minthorn Elisabeth , Kumar Rakesh 
Published: May 2015

Abstract
Fibroblast growth factor (FGF) ligand-dependent signaling plays an important role in cancer development and tumor maintenance through autocrine production of FGFs directly from cancer cells and/or through paracrine production of FGFs from the local stroma. FGF-FGFR autocrine feedback loops have been characterized in several tumor types and may also play a role in drug resistance upon exposure to chemotherapy or targeted agents. FP-1039/GSK3052230 is a ligand trap that sequesters multiple FGFs and inhibits FGF receptor signaling. We previously demonstrated that increased FGF2 mRNA levels correlated with response to GSK3052230. To further extend this hypothesis, we investigated the preclinical efficacy of this drug in models of mesothelioma, a tumor type shown to express high levels of FGF2 mRNA in cell lines and in primary tumor specimens. GSK3052230 inhibited MAPK signaling as evidenced by decreased phospho-ERK levels in both NCI-H226 and MSTO-211H cells. When both cell lines were grown as tumor xenografts in mice, GSK3052230 inhibited tumor growth in a dose-dependent manner (NCI-H226: 16 - 78% TGI; MSTO-211H: 20 - 50% TGI). However, in contrast to what was observed in cultured cells, GSK3052230 had minimal effects on phospho-ERK levels in NCI-H226 tumors. Similarly, two genes downstream of ERK known to be regulated by FGF signaling, DUSP6 and ETV4, displayed modestly reduced mRNA levels upon GSK3052230 treatment. These data demonstrate the limitation of FGF pathway downstream signaling as a pharmacodynamic (PD) readout for this drug in this study despite observing significant tumor growth inhibition. Because FGFs also play a key role in angiogenesis, we explored the effects of GSK3052230 on tumor vessel formation in NCI-H226 xenografts as a potential approach to measure PD. Dose-dependent and statistically-significant reductions in tumor vessel density were observed in GSK3052230-treated tumors compared to vehicle-treated tumors using MECA-32 endothelial cell immunohistochemical staining. These data support the clinical evaluation of this drug in mesothelioma patients.
Citation Format: M. Phillip De Young, Christian Sherk, Maureen Bleam, Mary Barnette, Gopi Ganji, Bao Hoang, James Tunstead, David Bellovin, Gerrit Los, Elisabeth Minthorn, Rakesh Kumar. Preclinical efficacy of targeting FGF autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-236. doi:10.1158/1538-7445.AM2014-LB-236
Abstract LB-237: Targeting HER3 and IGF1R in NRG1 high lung squamous cell carcinoma
Authors: Sheng Qing , Pinzon-Ortiz Maria , Das Rita , Huang Alan , Rong Xianhui , Cao Z. Alexander 
Published: May 2015

Abstract
HER3 is a member of the ErbB family of receptor tyrosine kinases. Aberrant activation of HER3 as a result of HER2 amplification or neuregulin 1 (NRG1) over-expression has been demonstrated to mediate constitutive activation of downstream oncogenic signals. LJM716 is a fully human IgG1 anti-HER3 monoclonal antibody. It locks HER3 in an inactive conformation and prevents HER3 dimerization with other ErbB family members. This unique mode of action enables LJM716 to block both ligand dependent and ligand independent HER3 activation. In search of new indications that may benefit from anti-HER3 therapies, we noted that squamous cell carcinomas (SCC) tend to have relatively higher NRG1 expression as compared to their adenocarcinoma counterparts. Highest NRG1 expression was observed in the lung SCC cell lines in cell line encyclopedia (CLE). A subset of the lung SCC cell lines with high NRG1 expression are moderately sensitive to LJM716, with HER3 activation detected in all of the sensitive lines. Surprisingly, phosphorylation of IGF1R rather than other HER family members tracked closely to HER3 phosphorylation in the lung SCC lines. Consistent with this finding, co-treatment with either IGF1R inhibitor, OSI-906, or anti-IGF1R antibody, Figitumumab, with LJM716 further enhanced LJM716 activity in the three NRG1-high lung SCC lines in vitro. The enhanced anti-tumor activity of LJM716 and Figitumumab is also observed in mouse xenografts generated from these lung SCC lines. Furthermore, pharmacodynamic analysis revealed increased inhibition of PI3K/mTOR signaling with the combined treatment of LJM716 and Figitumumab. These data suggest that NRG1- driven HER3 activation is a common feature in a subset of lung squamous cell carcinoma. Combination of anti-HER3 and anti-IGF1R is effective at suppressing PI3K/mTOR signaling and inhibit growth in these tumors.
Citation Format: Qing Sheng, Maria Pinzon-Ortiz, Rita Das, Alan Huang, Xianhui Rong, Z. Alexander Cao. Targeting HER3 and IGF1R in NRG1 high lung squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-237. doi:10.1158/1538-7445.AM2014-LB-237
Abstract LB-249: Coffee drinking decreases background DNA strand breaks in humans: A randomized controlled trial
Authors: Eisenbrand Gerhard , Bakuradze Tamara , Lang Roman , Hofmann Thomas , Schipp Dorothea , Galan Jens , Richling Elke 
Published: May 2015

Abstract
Effects of coffee consumption on the level of spontaneous DNA strand breaks in peripheral white blood cells have not been reported yet. In this human intervention study the impact of consuming a dark roast coffee blend on the level of spontaneous DNA strand breaks was investigated.
Healthy men (n=84) were randomized to consume daily for 4 weeks either 750 ml of fresh coffee brew or 750 ml of water, subsequent to a run in washout phase of 4 weeks. The study coffee was a blend providing substantial amounts of both, caffeoylquinic acids and the roast product N-methylpyridinium. Before and after the coffee/water phases, spontaneous strand breaks were determined by Comet assay.
Both groups exhibited a similar level of spontaneous DNA strand breaks at baseline.In the intervention phase spontaneous ( background) DNA strand breaks slightly increased in the water only group, whereas they significantly decreased in the coffee group,leading to a 27 percent difference between both arms (p=0.0002).
Food frequency questionnaires indicated no differences in the overall diet between groups, mean body weight during the intervention phases remaining stable. Consumption of the study coffee was found associated with a markedly lower level of pontaneous DNA strand breaks in white blood cells.
Conclusion: Regular coffee consumption contributes to DNA integrity.
Citation Format: Gerhard Eisenbrand, Tamara Bakuradze, Roman Lang, Thomas Hofmann, Dorothea Schipp, Jens Galan, Elke Richling. Coffee drinking decreases background DNA strand breaks in humans: A randomized controlled trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-249. doi:10.1158/1538-7445.AM2014-LB-249
Abstract LB-251: p27Kip1 suppression of colitis-associated colon cancer mediated through cell intrinsic function in both mucosal epithelia and mucosal T cells
Authors: Choi Sung Hee , Kim Byung-Gyu , John Letterio J. 
Published: May 2015

Abstract
The cyclin-dependent kinase inhibitor p27Kip1 is a negative regulator of the cell cycle. Reduced expression of p27Kip1 has prognostic significance in several human epithelial cancers. Loss of p27Kip1 expression in cancer cells correlates with tumor aggressiveness, depth of tumor cell invasion and with lack of tumor cell differentiation. However, p27Kip1 also promotes apoptosis and contraction of effector CD4+ T cells, suggesting the potential that suppression of epithelial tumorigenesis may be linked to an intrinsic function of p27Kip1 in T cells. Here we show both mRNA and protein expression of p27Kip1 are significantly decreased in a murine model wherein a T cell-restricted deletion of the gene encoding the TGF-β intermediate, Smad4 (Smad4TKO), results in spontaneous colitis that invariably progresses to colon cancer by the age of 8 months. This phenotype is associated with a consistent decline in the mucosal expression of p27Kip1. To further investigate the role of p27Kip1 in the maintenance of intestinal mucosal homeostasis, we generated a ‘double knockout’ (Smad4TKO / p27Kip1-/- or ‘DKO’) mouse model in which a germ line p27Kip1 gene deletion (p27Kip1-/-) is combined with the T cell-restricted deletion of the Smad4 gene (Smad4TKO). All DKO mice develop spontaneous gastrointestinal inflammation and colon carcinoma by 1-2 months and 3 months of age, respectively. The p27Kip1 gene deletion, when combined with the T cell-restricted deletion of the Smad4 gene, leads to progressive inflammatory cytokine production (TNF-α, IFN-γ, iNOS, IL-6, IL-1β), activation of Stat1 and Stat3 and suppression of the expression of the tumor suppressor, 15-PGDH. Collectively our data suggest that p27Kip1 deficiency promotes gastrointestinal epithelial malignancy through both enhancement of proliferation of mucosal epithelial cells and through expansion of mucosal effector memory T cells.
Citation Format: Sung Hee Choi, Byung-Gyu Kim, Letterio J. John. p27Kip1 suppression of colitis-associated colon cancer mediated through cell intrinsic function in both mucosal epithelia and mucosal T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-251. doi:10.1158/1538-7445.AM2014-LB-251
Abstract LB-262: Phosphatidylserine-targeting antibody synergizes with anti-PD-1 antibody to inhibit tumor growth in K1735 mouse melanoma model
Authors: Huang Xianming , Ye dan , Brekken Rolf , Yin Yi 
Published: May 2015

Abstract
A large body of evidence indicates that PS is a major player in tumor-associated immunosuppression, including the induction and expansion of immune suppressor cells, such as MDSCs and M2 macrophages, and the production of immunosuppressive cytokines, such as TGF-beta and IL-10. Furthermore, PS also inhibits DCs maturation and antigen presentation. Thus, PS is a critical target for cancer immunotherapy. We have previously shown that anti-PS antibody can override PS-driven immunosuppression and re-program the tumor microenvironment from immunosuppressive to immunosupportive, breaks tumor immune tolerance and elicits potent de novo antitumor T-cell immunity. In the present study, we examined the combination of anti-PD-1 with anti-PS antibody in K1735 mouse melanoma model. Tumor-bearing mice were treated with each antibody alone or the combination at 2.5 mg/kg, twice a week. The combination treatment showed significantly superior tumor growth inhibition than with either antibody alone, animals treated with the combination survived significantly longer than with either antibody alone. Flow cytometry analysis showed the combination has the highest ratio of tumor-infiltrating immune effector to suppressor cells. Finally, no toxicity was observed in all treatment groups following multiple treatment doses. These data suggest that combination of PS blockade with immune checkpoint blockade represents a promising combinatorial strategy for cancer immunotherapy.
Citation Format: Xianming Huang, dan Ye, Rolf Brekken, Yi Yin. Phosphatidylserine-targeting antibody synergizes with anti-PD-1 antibody to inhibit tumor growth in K1735 mouse melanoma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-262. doi:10.1158/1538-7445.AM2014-LB-262
Abstract LB-265: ONO-AE3-208 inhibits myeloid derived suppressor cells and glioma growth
Authors: Gary Kohanbash , Straw Erin , Averick Amram , Ahn Brian , Smith-Cohn Matthew , Ohkuri Takayuki , Kosaka Akemi , Okada Hideho 
Published: May 2015

Abstract
Myeloid Derived Suppressor Cells (MDSCs) are up-regulated in all known solid tumors and suppress anti-tumor T-cell activity. Our recent studies have demonstrated the ability of monocytic, Ly6C+ MDSCs to promote glioma growth through the activation of cyclooxygenase (COX)-2 pathway, which is responsible for plostaglandin-synthesis. ONO-AE3-208 is an antagonist of the prostaglandin E (EP)-4 receptor, which is an important positive feedback regulator of the COX-2 pathway. We thus examined the ability of ONO-AE3-208 to suppress MDSC activity in gliomas. ONO-AE3-208 treatment in mice bearing established GL261-quad glioma in the brain resulted in complete and persistent rejection of the tumors (n=4). Flow cytometric analysis revealed that gliomas in the ONO-AE3-208-treated mice were infiltrated by fewer numbers of Ly6C+ MDSCs compared with non-treated animals. We subsequently isolated glioma-infiltrating Ly6C+ MDSCs by flow-sorting to address their functions. RT-PCR analysis revealed that the Ly6C+ MDSCs derived from ONO-AE3-208 treated mice expressed lower levels of the Arg1 and Cox2 expression compared to control animals. Consistently, brain infiltrating leukocytes in ONO-AE3-208 treated tumor-bearing mice demonstrated enhanced Ifng expression compared with control mice, suggestive of enhanced T-cell activity. Our data demonstrate that ONO-AE3-208 may be useful in the treatment of glioma patients to suppress Ly6C+ MDSCs and promote anti-tumor immunity.
Citation Format: Kohanbash Gary, Erin Straw, Amram Averick, Brian Ahn, Matthew Smith-Cohn, Takayuki Ohkuri, Akemi Kosaka, Hideho Okada. ONO-AE3-208 inhibits myeloid derived suppressor cells and glioma growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-265. doi:10.1158/1538-7445.AM2014-LB-265
Abstract LB-274: Mode of breast cancer detection: Do markers of tumor aggressiveness predict which tumors are “missed” at screening
Authors: Mahmoud Abeer Mostafa , Macias Virgilia , Kresovich Jacob K. , Kajdacsy-Balla Andre , Wiley Elizabeth L. , Rauscher Garth H. 
Published: May 2015

Abstract
Screening mammography reduces breast cancer stage at diagnosis by detecting it early before symptoms develop. Nonetheless, a breast cancer can arise as a lump despite a recent prior negative screen (“missed detection”). In the Breast Cancer Care in Chicago study, Non-Hispanic (nH) Black and Hispanic women were more likely than their nH White counterparts to report a missed detection despite a recent prior screening mammogram. We examined whether breast cancer subtype and immunohistochemical (IHC) markers of tumor aggressiveness predicted missed detection and whether they could explain racial/ethnic disparities in missed detection, in a subsample of 198 patients with a recent prior screening mammogram (63 Non-Hispanic White, 78 Hispanic and 57 African American).
Missed detection was defined as symptomatic awareness despite a negative screen in the prior 24 months. IHC analyses were conducted for estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR and CK5/6, Ki67 and p53 expression. Breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-).
Missed detection was highest for more aggressive TN and HER2 enriched subtypes (61% and 60%) and lowest for luminal A and B tumors (37% and 38%). Greater Ki67, EGFR and p53 expression were each associated with missed detection (p&lt;0.02 for all), while PR and CK5/6 were marginally associated with missed detection. Before accounting for tumor characteristics, missed detection was twice as likely for minority than for nH white patients (47% vs. 24%, p=0.002); and the disparity in missed detected remained nearly the same after adjustment for tumor aggressiveness markers (47% vs. 27%, p=0.013)
In this multi-ethnic sample of breast cancer patients, markers of tumor aggressiveness were strongly associated with missed detection at screening but they did not explain racial/ethnic disparities in missed detection.
Citation Format: Abeer Mostafa Mahmoud, Virgilia Macias, Jacob K. Kresovich, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Mode of breast cancer detection: Do markers of tumor aggressiveness predict which tumors are “missed” at screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2014-LB-274
Abstract LB-283: A prospective study of breast cancer risk associated with occupational exposure to potentially endocrine disrupting compounds
Authors: Ekenga Christine C. 
Published: May 2015

Abstract
Background: Endocrine disrupting compounds, exogenous substances that interfere with normal endocrine functions, have been suspected to play a role in the etiology of breast cancer. The purpose of this study was to investigate the relationship between occupational exposure to potential endocrine disrupting compounds and breast cancer risk among women enrolled in the Sister Study, a prospective cohort study of US and Puerto Rican women designed to examine the genetic and environmental risk factors for breast cancer.
Methods: Over 50,000 women aged 33-74 enrolled in the Sister Study between 2004 and 2009. A comprehensive baseline questionnaire included questions about occupational exposures, including ever use and duration and frequency of use of nine agents containing potential endocrine disrupting compounds: Dyes or Inks, Gasoline or other Petroleum Products, Glues or Adhesives, Lubricating Oils, Metals, Paints, Pesticides, Organic Solvents, and Stains. Cumulative lifetime exposure to each potential endocrine disruptor was estimated and classified into quartiles. Study participants were prospectively followed from baseline until breast cancer diagnosis, death, or end of follow-up. Multivariable Cox proportional hazards regression was used to assess the impact of level of exposure (comparing each quartile of exposure with never exposure) to each of these compounds on breast cancer risk, adjusting for established breast cancer risk factors.
Results: Among the 47,755 women in the Sister Study with an occupational history, a total of 1798 cases of invasive breast cancer were diagnosed. Compared to their respective never exposure groups, an elevated risk of estrogen-receptor positive breast cancer was observed for women in the top quartile of occupational exposure to Dyes or Inks (HR: 1.7, 95%CI: 1.1-2.8). Non-significantly elevated risks were observed for women in the top quartile of occupational exposure to Gasoline or other Petroleum Products (HR: 1.7, 95%CI: 1.0-2.9) and Metals (HR: 1.5, 95%CI: 0.9-2.8).
Conclusions: Results suggest that exposure to occupational dyes or inks may influence breast cancer risk. Dyes and inks contain compounds with endocrine disrupting properties, including organic compounds and heavy metals. Further studies are necessary to elucidate the role of these potential endocrine disrupting compounds in breast cancer.
Citation Format: Christine C. Ekenga. A prospective study of breast cancer risk associated with occupational exposure to potentially endocrine disrupting compounds. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-283. doi:10.1158/1538-7445.AM2014-LB-283