bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 452: Monocytic Gr-1+/CD11b+ myeloid cells are necessary for natural killer cells to eradicate glioma and are inhibited by tumor-derived galectin-1
Authors: Baker Gregory J. , Chockley Peter , Zamler Daniel , Yadav Viveka Nand , Castro Maria G. , Lowenstein Pedro R.
Published: August 2015

We have recently demonstrated that natural killer (NK) cells eradicate galectin-1 (gal-1)-deficient glioma (Baker et al, Cancer Research. 2014. Sep 15;74(18):5079-90). Here we present our progress towards understanding the cellular mechanism(s) by which NK cells eradicate such tumors. We demonstrate that monocytic Gr-1+/CD11b+ myeloid cells are required to stimulate NK-mediated lysis of gal-1-deficient glioma. Immunodepletion of Gr-1+ cells in RAG1-/- mice permits lethal gal-1-deficient glioma formation despite the presence of NK cells, demonstrating that Gr-1+ cells (i.e. myeloid cells) are necessary for NK-mediated tumor rejection in vivo. We also demonstrate that the effect of glioma-derived gal-1 is to conceal glioma cells from recognition by NK cells by inhibiting myeloid-NK cell crosstalk. In vitro experiments reveal that gal-1-deficient glioma cells stimulate cross-activation between NK cells and monocytic Gr-1+/CD11b+ myeloid cells, causing the myeloid cells to morph into a phenotypically distinct cell population reminiscent of macrophages or dendritic cells. Cell-killing assays show that monocytic Gr-1+/CD11b+ myeloid cells significantly enhance NK-mediated glioma cell lysis in vitro. Recombinant mouse gal-1 protein inhibits the myeloid cell enhancement of NK-mediated tumor lysis, but fails to suppress intrinsic NK-mediated tumor lysis. This result strongly suggests that the role of glioma-derived gal-1 is to suppress the ability of monocytic myeloid cells to stimulate cytotoxic potential in NK cells. Further in vivo experiments also reveal that RAG1-/- mice bearing gal-1-deficient glioma have 7-fold more Gr-1+/CD11b+ myeloid cells present within the tumor microenvironment 48hrs after tumor implantation compared to gal-1-expressing tumors. Together our data show that glioma-derived gal-1 acts to potently suppress anti-glioma NK immune surveillance through a tripartite mechanism involving: (1) the inhibition of myeloid cell recruitment into the brain tumor microenvironment, (2) the suppression of enhanced NK-mediated glioma lysis stimulated by monocytic myeloid cells, and (3) an increased resistance to NK-mediated glioma cell lysis. We now aim to identify the molecular factors used by gal-1-deficient glioma cells to stimulate monocytic myeloid cell activation and the factors that myeloid cells use to in turn amplify NK cell cytotoxicity.

Citation Format: Gregory J. Baker, Peter Chockley, Daniel Zamler, Viveka Nand Yadav, Maria G. Castro, Pedro R. Lowenstein. Monocytic Gr-1+/CD11b+ myeloid cells are necessary for natural killer cells to eradicate glioma and are inhibited by tumor-derived galectin-1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 452. doi:10.1158/1538-7445.AM2015-452
Abstract 4534: Cyclooxygenase inhibitors as delivery vehicles for histone deacetylase inhibitors
Authors: Raji Idris Olawale , Janeira Emily , Yadudu Fatima , Shaghayegh Fathi , Kornacki James , Mrksich Milan , Oyelere Adegboyega
Published: August 2015

Reversible acetylation state of histones determines the existence of the chromatin in either the euchromatin state or the heterochromatin state, which in turn control the accessibility of transcription factors to promoter regions of genes on the chromatin. This reversible acetylation state is regulated by two enzymes: histone deacetylases (HDAC) and histone acetyl transferases (HAT). Imbalance in the expression of these enzymes is associated with many diseases, with equilibrium tilted towards HDAC in tumors. Reversal of the HDAC enzymes to their basal expression level, by small molecule inhibition, has been shown to significantly reduce the growth of tumors and/or completely eliminate them. Currently, there are three (3) FDA approved HDAC inhibitors in the market: vorinostat, FK228 and belinostat (all approved by the FDA for treatment of cutaneous T-cell lymphoma). Although highly effective, these compounds suffer drawbacks such as lack of activity against solid tumors, off-target toxicities, short half-life, and lack of HDAC isoform selectivity. To address some of these challenges, we chose to incorporate a targeting moiety to the head group in the classical vorinostat pharmacophoric model (comprising head group, linker and zinc binding group (ZBG)). We envisaged that selective toxicity towards tumors (hence, reduction in off-target toxicities), may be achieved if the HDAC inhibitor is selectively delivered to tumor cells expressing cyclooxygenase 2 (COX-2) enzyme. COX-2, which catalyzes the conversion of arachidonic acid to prostaglandins, is ubiquitously expressed in a wide range of cancer types and has been exploited to selectively image cancer cells in the past. To achieve this, we designed and synthesized series of hydroxamic acid-based compounds having either celecoxib or indomethacin (COX-2 inhibitors) as the targeting moiety. In addition to these compounds, we made compounds having “biaryl group” as ZBG. Compounds based on this ZBG have been reported to selectively inhibit HDAC isoforms 1&2, both culprits in a wide range of cancer types.

Consistent with the reported HDAC isoform selectivity, our “biaryl” ZBG compounds potently and selectively inhibited HDACs 1& 2. Also, our hydroxamic acid-based compounds were better than vorinostat in cell-free assay and showed potent activity in MCF-7, A549 and HCT-116 cancer cell lines. Effort is underway to evaluate the in vivo activity of our lead compounds in animal models.

Citation Format: Idris Olawale Raji, Emily Janeira, Fatima Yadudu, Fathi Shaghayegh, James Kornacki, Milan Mrksich, Adegboyega Oyelere. Cyclooxygenase inhibitors as delivery vehicles for histone deacetylase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4534. doi:10.1158/1538-7445.AM2015-4534
Abstract 4550: Antiproliferative activity of 8-methoxypsoralen without UV light irradiation: A new perspective for cancer therapy
Authors: de Oliveira Diêgo M. , Lima Rute M F , Velozo Eudes S. , Amorim Ilza A. , Mota Tales H A , Costa Silvia L. , Silva Fabio P. , El-Bachá Ramon S.
Published: August 2015

The furanocoumarin-derivative 8-methoxypsoralen (8-MOP) is commonly used combined with UV light irradiation for treatment of skin diseases. We have recently demonstrated that 8-MOP inhibits GST-P1 in tumor cells and acts as chemosensitizer. These new data show direct antitumor activity of this compound without photoactivation in an in vitro model of glioma, the most common and lethal primary malignant brain tumor. Rat glioma C6 cells and human glioblastoma GL-15 cells were submitted to treatment with 8-MOP, as well as primary rat astrocytes cultures for comparison. Cell viability was measured by MTT assay; phase contrast microscopy and quantification of total protein content were also performed. The trypan blue dye exclusion assay and colony formation test were used to analyze cell proliferation. Flow cytometry was used for cell cycle analyses. Morphological changes were accessed by electron microscopy and proteins expression was studied by using immunolabeling techniques. As main results, 8-MOP reduced cell viability and cellularity, time- and dose-dependently, more efficiently in tumor than in normal cells. The compound also showed considerable antiproliferative effect against tumor cells and induced cell death by apoptosis when used at high concentration. However, 8-MOP did not promote cell cycle arrest and also did not increase labeling of markers associated to bad prognostic. Additional tests with cell lines from other tumors (breast cancer, colorectal cancer and lymphoma) showed that they respond differently to 8-MOP treatment, pointing to a pathway-specificity of its action. A qualitative structure-activity relationship study was also performed using coumarin derivatives structurally related to 8-MOP, from these experiments it was possible to suggest the relevance of each part of 8-MOP molecular structure for antiproliferative action. These results point furanocoumarin derivatives as a possible new class of anticancer agents.

Note: This abstract was not presented at the meeting.

Citation Format: Diêgo M. de Oliveira, Rute M F Lima, Eudes S. Velozo, Ilza A. Amorim, Tales H A Mota, Silvia L. Costa, Fabio P. Silva, Ramon S. El-Bachá. Antiproliferative activity of 8-methoxypsoralen without UV light irradiation: A new perspective for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4550. doi:10.1158/1538-7445.AM2015-4550
Abstract 4551: Impairment of c-kit expression in human cancer cell lines by a novel pharmacophoric unit selected for the recognition of the proto-oncogene KIT promotorial region
Authors: Sissi Claudia , Da Ros Silvia , Zorzan Eleonora , Musetti Caterina , Shahidian Lara Zorro , Palumbo Manlio , Giantin Mery , Dacasto Mauro
Published: August 2015

G-quadruplex structures at telomeric region and in oncogene promotorial sequences represent promising chemotherapeutic targets. Among these latter ones, an interesting site of intervention is represented by the promotorial sequence of KIT, a proto-oncogene whose overexpression or mutations characterize several human cancers. This region contains two G-rich sequences, kit1 and kit2, whose G-quadruplex structures have been extensively studied by using X-ray crystallography and NMR. The stabilization of these secondary structures by small molecules has been shown to result in a suppression of gene transcription. The peculiarity of these G-quadruplex structures rest in the presence of unprecedented structural domains which foresees the possibility to design small molecules able to recognize them, with a higher selectivity in comparison to other nucleic acid tetra-helixes.

In order to identify novel ligands for these sequences, we started a screening program by using an available “in house” library of compounds. Each member was previously confirmed to provide a basal level of nucleic acid recognition. Ligand selection was performed by applying two validated different screening assays (FRET and FID); they were properly designed to identify the best binders and to preliminary exclude compounds with low selectivity among different G-quadruplexes.

For selected compounds, the DNA binding properties were fully characterized in terms of binding affinity, binding mode and ability to convert unfolded sequences into a G-quadruplex structure. On parallel, the ligands cellular effects were explored in two human cancer cell lines (MCF7 and HCG27). At first, we evaluated their cytotoxic potential; then, we examined the extent of potential c-kit down-regulation following the exposure to candidates at both mRNA and protein level.

By merging these results we were able to highlight the relevance of one pharmacophore as potential selective KIT targeting agent.

Citation Format: Claudia Sissi, Silvia Da Ros, Eleonora Zorzan, Caterina Musetti, Lara Zorro Shahidian, Manlio Palumbo, Mery Giantin, Mauro Dacasto. Impairment of c-kit expression in human cancer cell lines by a novel pharmacophoric unit selected for the recognition of the proto-oncogene KIT promotorial region. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4551. doi:10.1158/1538-7445.AM2015-4551
Abstract 4553: Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance
Authors: Mohan Rishabh , Gangjee Aleem , Bai Ruoli , Hamel Ernest
Published: August 2015

Tubulin is involved in several critical cellular functions, including cell division, cell motility and development and maintenance of cell shape. Although microtubule disrupting agents like paclitaxel are highly successful chemotherapeutic agents, these compounds are easily recognized by P-glycoprotein (Pgp) and are pumped out of cancer cells, resulting in resistance to the agent. Thus, these compounds have major limitations against multidrug resistant tumors. Recently, we reported simple, monocyclic pyrimidines with the N-methyl-4′-methoxyaniline moiety at the 4-position. These compounds circumvent some of the important limitations of paclitaxel while preserving its antimitotic activity. To further evaluate the SAR at the 4-position of the pyrimidine scaffold, a series of compounds were designed and synthesized that involved replacing the chloro moiety of the 5-amino-4,6-dichloro-2-methylpyrimidine with various anilines. The replacement of the N-methyl-4′-methoxyaniline moiety of the lead molecule with a conformationally restricted 6′-methoxy-tetrahydroquinoline moiety resulted in potent tubulin assembly inhibition (IC50 = 3.0 ± 0.03 μM) comparable to that observed with combretastatin A-4 (CSA4, IC50 = 1.1 ± 0.1 μM), of which the phosphorylated derivative is currently in clinical trials. It is a potent inhibitor of [3H]colchicine binding (65% at 5 μM concentration) indicating that it binds at the colchicine binding site on tubulin similar to CSA4. Similarly, the monocyclic pyrimidine with a conformationally restricted 4-N-methyl 2′,3′-dihydrobenzofuran moiety was also a potent inhibitor of bovine tubulin assembly. Replacement of the 4′-methoxy of the lead with a 4′-thiomethyl retained potency against tubulin assembly (IC50 = 2.6 ± 0.1 μM). In Pgp overexpressing NCI/ADR-RES cell line, three of the newly synthesized compounds were found to be 1.5-5-fold more potent (IC50 = 170-630 nM) than in the wild type OVCAR-8 cell line, thus, overcoming an important mechanism associated with clinical resistance to paclitaxel. These attributes of the 4-N-substituted monocyclic pyrimidines provide the impetus for further preclinical development of these compounds.

Citation Format: Rishabh Mohan, Aleem Gangjee, Ruoli Bai, Ernest Hamel. Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4553. doi:10.1158/1538-7445.AM2015-4553
Abstract 4575: Açaí intake reduces the aberrant crypt foci development in a colitis-associated carcinogenesis model in male Wistar rats
Authors: FRAGOSO MARIANA F. , ROMUALDO GUILHERME R. , PELLIZZON CLAUDIA H. , BARBISAN LUIS F.
Published: August 2015

Colorectal cancer is a main cause of cancer death in the western world. In Brazil, it is the third more common neoplasia in both men and women (INCA, 2014). In our previous study (Fragoso et al., Food Chem Toxicol., 2013), we showed that spray-dried açaí (Euterpe oleraceae Mart.) pulp intake retarded the development of colon cancer in male Wistar rats. Therefore, the objective of this research was to evaluate the potential protection of dietary freeze-dried açaí pulp using a chemically-induced colon carcinogenesis and colitis-associated model in male Wistar rats. The animals were randomly distributed into four groups: G1, DMH [dimethylhydrazine] + TNBS [2,4,6-trinitrobenzene sulfonic acid] + basal diet; G2, DMH + TNBS + basal diet with 5% açai pulp; G3, DMH + TNBS + basal diet with 7.5% açai pulp; G4, DMH + TNBS + basal diet with 0.2% of NAC [N-acetylcysteine]. The acute colitis was induced with the administration of 10 mg of TNBS dissolved in 0.25 ml 50% ethanol (v/v) by means of a Teflon cannula inserted 8 cm into the anus. At the end of the 25th week, animals were sacrificed for evaluation of Aberrant Crypt Foci (ACF) in the colon. Unsenctioned and fixed colons were analyzed for total aberrant crypt (AC) and total ACF and ACF multiplicity under methylene blue staining. The results were analyzed by ANOVA followed by post hoc Tukey test. A significant reduction in total ACF and AC for G2 when compared to G1 (p ≤0.001) was seen. Regarding the ACF multiplicity, it was observed a significant reduction in ACF with 4-10 aberrant crypts for G2 and G4 and for ACF with >10 aberrant crypts for G2-G4 groups in relation to the G1 group (p = ≤0.001, respectively). Also, it was observed a significant reduction in the number of total AC in the distal colon from the G2 and G4 groups compared to G1 group (p = 0.003) and in the medial colon from the G2 group compared to G1 group (p = 0.016). These results suggest that açaí intake may reduce the number of AC and ACF and the number of ACF with more than four aberrant crypts in this chemically-induced colon carcinogenesis and colitis-associated model in rats.

Citation Format: MARIANA F. FRAGOSO, GUILHERME R. ROMUALDO, CLAUDIA H. PELLIZZON, LUIS F. BARBISAN. Açaí intake reduces the aberrant crypt foci development in a colitis-associated carcinogenesis model in male Wistar rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4575. doi:10.1158/1538-7445.AM2015-4575
Abstract 4579: The role of carnosol in reducing skin cancer development and progression
Authors: Tong Lingying , Wu Shiyong
Published: August 2015

Carnosol is a natural compound extracted from rosemary and sage, which are commonly used in traditional Mediterranean cuisine. Among all the compounds extracted from Mediterranean herbs, carnosol, first isolated from sage in 1941, has been demonstrated to be beneficial to health for its anti-inflammation, anti-oxidation and anti-cancer properties. Because of its structure similarity to sex hormones, research has been done on the effect of carnosol mainly on breast and prostate cancers. However, very little is known on the effect of carnosol on UV-induced skin cancer. In this report, we studied the effect of carnosol on UV-induced skin cancer formation and progression. Our data showed that carnosol could partially reduce UVB-induced reactive oxygen species (ROS) elevation and thus protect UV-induced DNA damage in normal skin cells. We also showed that carnosol could inhibit the UVB-induced NF-κB activation. As a result, the normal cell apoptosis induced by UV radiation was partially protected. Moreover, it could also prohibit skin cancer cell progression with or without UV radiation. Therefore, we propose that carnosol could be a potential therapeutic for chemoprevention and treatment of UVB-induced skin cancers.

Citation Format: Lingying Tong, Shiyong Wu. The role of carnosol in reducing skin cancer development and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4579. doi:10.1158/1538-7445.AM2015-4579
Abstract 4581: Genetic variations in CDKN1A and RHPN2 associated with prognosis for patients with colorectal cancer
Authors: Kang Byung Woog , Kim Jong Gwang , Chae Yee Soo , Lee Shin Yup , Lee Soo Jung , Yoon Shinkyo
Published: August 2015

Genome-wide association studies (GWASs) have already identified at least 22 common susceptibility loci associated with an increased risk of colorectal cancer (CRC). This study examined the relationship between these single nucleotide polymorphisms (SNPs) and the clinical outcomes of patients with colorectal cancer. Seven hundred seventy-six patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Twenty-two of the GWAS-identified SNPs were genotyped using a Sequenom MassARRAY. Among the 22 SNPs, two (rs1321311G>T in CDKN1A and rs10411210C>T in RHPN2) were significantly associated with the survival outcomes of CRC in a multivariate survival analysis. In a recessive model, the rs1321311 TT genotype (vs. GG + GT) and rs10411210 TT genotype (vs. CC + CT) were associated with a worse prognosis for disease-free survival (adjusted HR = 1.90; 95% confidence interval = 1.00-3.60; P = 0.050, adjusted HR = 1.94; 95% confidence interval = 1.05-3.57; P = 0.034, respectively) and overall survival (adjusted HR = 2.05; 95% confidence interval = 1.00-4.20; P = 0.049, adjusted HR = 2.06; 95% confidence interval = 1.05-4.05; P = 0.036, respectively). None of the other SNPs was significantly associated with any clinicopathologic features or survival. The present results suggest that the genetic variants of the CDKN1A (rs1321311) and RHPN2 (rs10411210) genes can be used as prognostic biomarkers for patients with surgically resected colorectal cancer.

Citation Format: Byung Woog Kang, Jong Gwang Kim, Yee Soo Chae, Shin Yup Lee, Soo Jung Lee, Shinkyo Yoon. Genetic variations in CDKN1A and RHPN2 associated with prognosis for patients with colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4581. doi:10.1158/1538-7445.AM2015-4581
Abstract 4591: Differential expression of tight junction polarity genes in human colon cancer
Authors: Royse Kathryn E. , Chen Liang , Uriostegui Jocelyn , Ittmann Michael , Graham David Y. , El-Serag Hashem , Jiao Li
Published: August 2015

Tight junctions perform significant and multifactorial functions in cellular polarity maintenance and paracellular transport. A number of studies have found structural disruption of epithelial colon cells can significantly impact early tumorigenesis and progression. However, little is known about the direct contribution of polarity gene expression in human colon cancer development. We compared the expression of tight junction genes in colon cancer with normal control mucosa. Total RNA was extracted from fresh frozen tissue biopsies of six white male patients (N = 3 for early stage tumore, N = 3 for late stage tumor, and N = 2 for normal adjacent controls) and four unrelated normal colon mucosa from polyp-free individuals. We used the Qiagen RT2 Profiler PCR array to determine the expression of 84 genes in the tight junction pathway. Student's t test was used to compare the expression levels between different groups (control vs. early-stage tumor and late-stage tumor) using normalized gene expression data. Functional annotation clustering of statistically significant genes by group was conducted using DAVID. Significant (P<0.05) down regulation of claudin (CLDN5, CLDN6, CLDN7) expression was seen in both early and late-stage tumor compared with controls, all with fold change (FC)> 2; while CLDN1 (FC = 15) was only significantly upregulated (P = 0.0007) in early-stage tumor. Down regulation (FC>2) of polarity complex gene PARD6A (P<.001) and associated genes (JAM2, P<.001 and JAM3, P <.001) were present in both early and late-stage tumors along with associated down-regulation of tumor suppressor PTEN (P<.0001). We found differential expression of tight junction genes in normal versus colon tumor. Down regulation of polarity genes is likely to affect apico-basal polarity and promote random non-coordinated migration which can lead to disruption of epithelial structure and to carcinogenic tissue infiltration. Further larger studies are warranted to investigate the role of tight junction proteins in the progression of human colon tumor.

Citation Format: Kathryn E. Royse, Liang Chen, Jocelyn Uriostegui, Michael Ittmann, David Y. Graham, Hashem El-Serag, Li Jiao. Differential expression of tight junction polarity genes in human colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4591. doi:10.1158/1538-7445.AM2015-4591
Abstract 4598: Low-frequency coding variants in BAT2, HIST1H1E and BPIFB1 are associated with lung cancer risk in Chinese populations
Authors: Jin Guangfu , Zhu Meng , Yin Rong , Shen Wei , Xu Lin , Hu Zhibin , Lin Dongxin , Shen Hongbing
Published: August 2015

Objective: Genome-wide association studies have successfully identified a subset of common variants associated with lung cancer risk. However, these variants explain only a fraction of lung cancer heritability. Alternatively, it is proposed that uncommon variants may have strong effects and contribute to the missing heritability. The aim of the study was to evaluate the role of low-frequency or rare variants in lung cancer development.

Methods: We analyzed exome chips with a total of 247,870 variants in 1,348 lung cancer cases and 1,998 controls in discovery stage and subsequently validated promising associations in additional 3,581 cases and 3,669 controls in replication stages. Single-variant and gene-based analyses were carried out in coding variants with minor allele frequency less than 0.05.

Results: We identified three low-frequency missense variants in BAT2 (OR = 0.54, P = 1.02×10-9), HIST1H1E (OR = 0.49, P = 5.66×10-7) and BPIFB1 genes (OR = 1.79, P = 3.99×10-7) significantly associated with lung cancer risk. The risk allele of variant in BPIFB1 was also associated with early onset of lung cancer. BAT2 and HIST1H1E located at MHC III region across 6p22.2-6p21.31 and BPIFB1 at 20q11.21 were frequently associated with inflammation/immune-related diseases, and were found to be differentially expressed between lung tumors and paired normal tissues. In addition, down-regulation of BPIFB1 was significantly associated with poor prognosis of lung cancer patients.

Conclusions: Our results highlight importance of uncommon variants in lung cancer susceptibility, and indicate potential biology of candidate genes at 6p22.2-6p21.31 and 20q11.21 in the process of lung carcinogenesis.

Citation Format: Guangfu Jin, Meng Zhu, Rong Yin, Wei Shen, Lin Xu, Zhibin Hu, Dongxin Lin, Hongbing Shen. Low-frequency coding variants in BAT2, HIST1H1E and BPIFB1 are associated with lung cancer risk in Chinese populations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4598. doi:10.1158/1538-7445.AM2015-4598
Abstract 4601: Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival
Authors: Kong Jinyu , Xu Fangxiu , Qu Jinli , Wang Yu , Gao Ming , Yu Herbert , Qian Biyun
Published: August 2015

Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival.

Note: This abstract was not presented at the meeting.

Citation Format: Jinyu Kong, Fangxiu Xu, Jinli Qu, Yu Wang, Ming Gao, Herbert Yu, Biyun Qian. Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4601. doi:10.1158/1538-7445.AM2015-4601
Abstract 4603: Male pattern baldness in relation to prostate cancer-specific mortality: A prospective analysis in the NHANES I Epidemiologic Followup Study (NHEFS)
Authors: Zhou Cindy Ke , Levine Paul H. , Cleary Sean D. , Hoffman Heather J. , Graubard Barry I. , Cook Michael B.
Published: August 2015

Background: Androgenic action underlies prostate gland development and prostate cancer progression. However, the role of such in prostate carcinogenesis remains unclear. Results from studies that have quantitated pre-diagnostic, circulating androgens at a single time-point in relation to prostate cancer are inconsistent, possibly due to the failure to capture cumulative or relevant age-specific hormone exposure. Therefore, we used male pattern baldness as a proxy of long-term androgen exposure, and investigated the association between dermatologist-assessed male pattern baldness and prostate cancer-specific mortality in the NHANES-I Epidemiologic Followup Study (NHEFS).

Methods: We included 4,316 men from NHEFS, who were 25-74 years, received dermatologic exams, and had no prior cancer diagnosis at baseline. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated using Cox proportional hazards regression with age as the time-metric and baseline hazard stratified by age at baseline. A hybrid model was used to account for stratification and clustering of the survey design, while adjusting for variables used to calculate sample weights.

Results: During follow-up (median = 21 years), 3,284 deaths occurred, 107 of which had the underlying cause of prostate cancer. Any degree of baldness was associated with a 56% increased risk of prostate cancer-specific mortality (HR = 1.56; 95%CI = 1.02, 2.37) and, specifically, moderate balding was associated with an 83% increased risk of the outcome (HR = 1.83; 95%CI = 1.15, 2.92), each compared with no balding. Conversely, male pattern baldness was not statistically significantly associated with all-cause mortality.

Conclusion: Our analysis suggests that male pattern baldness is associated with an increased risk of fatal prostate cancer, and supports the hypothesis of overlapping pathophysiological mechanisms.

Impact: If the association between male pattern baldness and fatal prostate cancer is substantiated in future studies, male pattern baldness may contribute to predictive algorithms of prostate cancer risk, helping guide individuals as to whether they should opt to undergo cancer screening.

Citation Format: Cindy Ke Zhou, Paul H. Levine, Sean D. Cleary, Heather J. Hoffman, Barry I. Graubard, Michael B. Cook. Male pattern baldness in relation to prostate cancer-specific mortality: A prospective analysis in the NHANES I Epidemiologic Followup Study (NHEFS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4603. doi:10.1158/1538-7445.AM2015-4603
Abstract 4608: Racial differences in the distribution of prostate tumor biomarkers and treatment failure: The SCORE study
Authors: Lal* Priti , Yamoah* Kosj , Ziober Amy , Walker Amy , Zhou Wenting , Spangler Elaine , Zeigler-Johnson Charnita , Feldman Michael , Rebbeck Timothy R.
Published: August 2015

Prostate cancer exhibits the greatest disparity in mortality between African American (AA) and European American (EA) men of any cancer in the US. The reasons for this disparity include access to care, screening patterns, and behavior. Biological differences may lead some AA men to have biologically aggressive tumors. Using the Study of Clinical Outcomes, Risk, and Ethnicity (SCORE) study, we identified prostate tumor tissues from men undergoing prostatectomy at the Hospital of the University of Pennsylvania between 1991-2008. Immunohistochemistry was undertaken on the FFPE tumors of 45 EA and 55 AA men (mean age: 59.1 years, range: 41-71). No statistically significant difference in marker phenotypes was observed for prevalence of TMPRSS2/ERG fusion proteins, or in staining intensity for PSMA or Rb. We observed statistically significant differences in marker phenotype for RACEMASE (EA Mean: 188.1 vs. AA Mean: 144.7, p = 0.004), c-myc (EA Mean: 54.7 vs. AA Mean: 21.6, p = 0.005), and AR (EA Mean: 192.1 vs. AA Mean: 136.5, p = 0.002). These data suggest that markers that have been reported to be associated with tumor aggressiveness differ between EA and AA men.

We further evaluated whether these markers were associated with clinical outcome as measured by biochemical (PSA) failure (BF) after radical prostatectomy (RP). We observed 41 BF with a mean follow up of 32.6 months post-RP, compared with 68 non-BF with a mean follow up of 53.7 months post-RP. After adjusting for pathology tumor grade, only the presence of a TMPRSS2-ERG fusion protein was significantly associated with BF. We observed a significant interaction (p = 0.031) by race suggesting TMPRSS2-ERG fusions were less likely to be associated with BF in AA than in EA. These data suggest that TMPRSS2-ERG fusions may not be important predictors of prostate cancer outcomes in AA men as has been suggested in EA men.

*These authors contributed equally to the work.

Citation Format: Priti Lal*, Kosj Yamoah*, Amy Ziober, Amy Walker, Wenting Zhou, Elaine Spangler, Charnita Zeigler-Johnson, Michael Feldman, Timothy R. Rebbeck. Racial differences in the distribution of prostate tumor biomarkers and treatment failure: The SCORE study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4608. doi:10.1158/1538-7445.AM2015-4608
Abstract 4639: Metformin decreases cellular ceramides in MCF-7 and MDA-MB 231 breast cancer cell lines by inhibition of ceramide synthetic enzymes
Authors: Wann Daniel , Palau Victoria , Lightner Janet , Brannon Marianne , Stone William , Krishnan Koyamangalath
Published: August 2015

Metformin, an anti-diabetic biguanide, has been shown to have cytotoxic and chemopreventive properties in in vitro and epidemiological studies, respectively.  Metformin's predominant cytotoxic functions may be through activation of 5′ adenosine monophosphate-activated protein kinase (AMPK) with subsequent cell apoptosis.  Ceramides, a group of waxy lipids found in the cellular membrane, are key players in many elements of cell signaling, including the regulation of cell differentiation, proliferation, and apoptosis. While traditionally thought of as being pro-apoptotic, this notion has been questioned with the discovery of pro-survival ceramides, as well as the demonstration that certain species of ceramides are increased in breast cancer cells. Metformin reduces ceramides in insulin-resistant mouse myoblasts and may reduce the vascular complications of diabetes mellitus.

MCF-7 and MDA-MB-231 breast cancer cell lines were treated with increasing concentrations of metformin and cytotoxicity was determined by MTT cell culture experiments after 72 hours of drug exposure. Metformin induces cytotoxicity in these breast cancer cells at a lowest concentration of 1.25 mM, and percentage cytotoxicity increases in a dose-dependent manner. We then determined the effect of metformin on cell ceramide synthesis by analyzing key ceramide synthetic enzymes.  Using western immunoblot and polymerase chain reaction (PCR) analysis, we determined that metformin induces a reduction in serine palmitoyl transferase, ceramide synthase, dihydroceramide desaturase, and neutral sphingomyelinase in MCF-7 and MDA-MB-231 breast cancer cells.  We also analyzed the distribution of ceramides in treated breast cancer cells using polyclonal antibodies against ceramides. By confocal microscopy, ceramides are globally decreased in MCF-7 and MDA-MB-231 cells treated with metformin.

This data suggests that the pro-apoptotic effect of metformin may be partly mediated through its disruption of the balance of ceramides and/or through the reduction of pro-survival ceramides within breast cancer cells. It is also possible that the predominant ceramides in MCF-7 and MDA-MB-231 breast cancer cells are pro-survival and metformin suppresses these ceramides.  Further work is necessary to characterize the ceramide content of MCF-7 and MDA-MB-231 cancer cells before and after metformin treatment.

Citation Format: Daniel Wann, Victoria Palau, Janet Lightner, Marianne Brannon, William Stone, Koyamangalath Krishnan. Metformin decreases cellular ceramides in MCF-7 and MDA-MB 231 breast cancer cell lines by inhibition of ceramide synthetic enzymes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4639. doi:10.1158/1538-7445.AM2015-4639
Abstract 4641: Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the Cheliensisin A (Chel A) inhibition of cell transformation
Authors: Huang Chuanshu , Zhu Junlan , Li Jingxia
Published: August 2015

Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the present study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP down-regulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A.

Citation Format: Chuanshu Huang, Junlan Zhu, Jingxia Li. Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the Cheliensisin A (Chel A) inhibition of cell transformation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4641. doi:10.1158/1538-7445.AM2015-4641
Abstract 4647: Bioactive tanshinones and tea polyphenols inhibit prostate cancer stem cells by targeting bmi1
Authors: Zhou Jin-Rong , Gong Yi , Abdolmaleky Hamid
Published: August 2015

Prostate cancer (CaP) is the most common invasive malignancy and the second leading cause of cancer-related death in U.S. men. Androgen-independent/hormone-refractory CaP remains the primary cause of CaP death. The search for effective therapeutic and preventive strategies, particularly the ways to intervene in the progression of androgen-independent tumors remains the top priority of CaP research. Prostate cancer stem cells (CSCs) are suggested to be responsible for initiation, progression, drug resistance, recurrence and metastasis of CaP. Strategies that target prostate CSCs may significantly prevent and/or delay cancer progression and metastasis. The objective of this study was to identify the potent natural bioactive compounds for targeting prostate CSCs. The sphere-forming efficiencies in LNCaP, DUCaP, PC3 and DU145 prostate cancer cell lines were 2.8%, 15.7%, 1%, and 5.6%, respectively. The expression of several CSC related biomarkers, such as c-met, c-kit, bmi1 and CD44 were increased, whereas the expression of androgen receptor was decreased in prostate spheres. Natural compounds, especially tanshinones (tanshinone I (T1), tanshinone IIA (T2A), cryptotanshinone) and tea compounds (epigallocatechin gallate (EGCG) and theaflavines), inhibited the sphere-forming efficiency of CaP cells with T1 and T2A the most potent. Furthermore, T1 and EGCG significantly downregulated Bmi1 gene expression and protein level. Since Bmi1 has been reported to be a crucial regulator of stem cell self-renewal and malignant transformation, we further studied the functional role of bmi1 in self-renewal of prostate CSCs. Silencing of bmi1 dramatically inhibited the growth and decreased the sphere-forming ability of CaP cells. Animal studies showed that T1 and EGCG inhibited the growth and metastasis of prostate tumors associated with downregulation of bmi1 expression. The results derived from our preliminary studies suggest that bmi1 may play an important role in self-renewal ability of prostate CSCs, and that some natural bioactive agents, such as T1 and EGCG, may inhibit self-renewal of prostate CSCs in part via downregulation of bmi1 gene expression and function. Supported in part by NCI/NIH R21 CA153355.

Note: This abstract was not presented at the meeting.

Citation Format: Jin-Rong Zhou, Yi Gong, Hamid Abdolmaleky. Bioactive tanshinones and tea polyphenols inhibit prostate cancer stem cells by targeting bmi1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4647. doi:10.1158/1538-7445.AM2015-4647
Abstract 4662: Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment
Authors: Walsh Naomi , Alberts David S. , Brown Powel , Limburg Paul , Sherman Mark , Szabo Eva
Published: August 2015

Background Although a number of cancer chemopreventive agents have now been evaluated in phase II and phase III clinical trials that assess their efficacy and tolerability in both high risk and general populations, few have shown clear efficacy and uptake of approved agents has been disappointingly low. Therefore, chemopreventive agents should undergo rigorous screening prior to clinical trial evaluation in order to improve the selection of suitable agents for testing in large, expensive multi-center phase III trials. The aim of this study is to develop a descriptive method for prioritizing candidate agents for further development.

Methods This framework was developed through a systematic literature review of Pubmed/Medline, Embase and The Cochrane Library. A semi-quantitative assessment focusing on efficacy and toxicity/tolerability was established based on expert input. Data from clinical trials, cancer epidemiological, observational and preclinical studies, including in vivo and in vitro basic research, was used to retrospectively evaluate the clinical application and effectiveness of cancer chemopreventive agents. Two chemopreventive agents with either a positive (aromatase inhibitors (AIs) for breast cancer) or negative (selenium for lung cancer) phase III clinical trial outcome were subsequently evaluated to determine the usefulness of the framework.

Results Chemopreventive agents must reduce or reverse the process of carcinogenesis in normal or pre-malignant tissue with minimal toxicity. Evaluation of efficacy included data from preclinical and animal models, epidemiological studies, and clinical trials (both early phase trials in the organ of interest as well as secondary endpoints from other relevant studies). Agent suitability evaluation included assessment of toxicities, tolerability, and agent specific attributes (PK/PD, bioavailability, dosing, etc.). Examination of selenium and AI historical data in these categories revealed strong concordance with phase III outcomes. The detailed descriptive evaluation of the agents will be presented.

Conclusion This framework provides a descriptive paradigm for cancer chemopreventive agent evaluation through systematic and rigorous interrogation. Thorough, standardized evaluation of all available preclinical, epidemiological, and clinical data should be strongly encouraged to better inform the investments required for clinical trials.

Citation Format: Naomi Walsh, David S. Alberts, Powel Brown, Paul Limburg, Mark Sherman, Eva Szabo. Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2015-4662
Abstract 4714: Targeting p53 mutant cancers through inhibition of the phosphatidylinositol-5-phosphate 4-kinases
Authors: Emerling Brooke M. , Yang Zhiwei , Loughran Ryan , Yang T.Jonathan , Johnson Jared , Pragani Rajan , Davis Mindy , Shen Min , Boxer Matthew , Simeonov Anton , Cantley Lewis C.
Published: August 2015

The bulk of cellular phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) is generated by the canonical pathway in which a 5-kinase converts phosphatidylinositol-4-phosphate (PI-4-P) to PI-4,5-P2. However, several years ago we discovered that PI-4, 5-P2 can also be generated at intracellular sites by a family of kinases that phosphorylate the 4 position of phosphatidylinositol-5-phosphate (PI-5-P), a lipid that was not previously known to exist in nature. These enzymes are called the type 2 phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks). To date, we have shown that a subset of breast cancers express high levels of PI5P4Kα and/or β, and have provided evidence that these kinases are essential for growth in the absence of p53 (Emerling et al., 2013). Furthermore, we showed that PI5P4Kα and β play critical roles in mediating changes in metabolism in response to cellular stress, in particular, stress that occurs in the absence of p53. Here, we disclose the discovery of potent and selective inhibitors of PI5P4K (Kis in the range of 10 to 200 nM). These novel PI5P4K inhibitors have provided us with powerful tools to further investigate the role of the PI5P4K enzymes in cancer metabolism. Through pharmacological inhibition of PI5P4K, we now have support that PI5P4K provides an alternative pathway to p53 in regard to mediating responses to metabolic and oxidative stress, thereby suggesting that the PI5P4K enzymes are essential for survival mechanisms when p53 function is lost. Above all, these inhibitors may be effective therapies not only for breast cancers with genetic aberrations in TP53, but in all cancer types with loss of p53 function.

Supported by DOD Breast Research Program Breakthrough Award to B.M.E.

References

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Citation Format: Brooke M. Emerling, Zhiwei Yang, Ryan Loughran, T.Jonathan Yang, Jared Johnson, Rajan Pragani, Mindy Davis, Min Shen, Matthew Boxer, Anton Simeonov, Lewis C. Cantley. Targeting p53 mutant cancers through inhibition of the phosphatidylinositol-5-phosphate 4-kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2015-4714