bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4714: Vemurafenib reverses immunosuppression by myeloid derived suppressor cells.
Authors: Schilling Bastian , Sucker Antje , Griewank Klaus , Zhao Fang , Weide Benjamin , Görgens Andre , Giebel Bernd , Schadendorf Dirk , Paschen Annette
Published: August 2014

Purpose: To evaluate the impact of Vemurafenib on myeloid derived suppressor cell (MDSC) populations in patients with advanced melanoma.

Experimental Design: Ex vivo MDSCs were obtained from PBMCs of late stage melanoma patients treated with Vemurafenib as well as healthy controls. The frequency and phenotype of MDSCs was determined by flow cytometry. MDSC populations were characterized for their suppressive function on autologous T cells in CFSE proliferation assays. Additionally, conditioned medium of a melanoma cell line treated with Vemurafenib or not was studied for its effect on MDSCs in vitro.

Results: In comparison to healthy donors, patient PBMCs showed an increased frequency of CD14+HLA-DR−/low monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14−CD66b+Arginase1+ granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T-cell proliferation. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. Accordingly, conditioned medium from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro.

Conclusion: Patients with advanced melanoma show increased levels of moMDSCs, as well as a population of CD14−CD66b+Arginase1+ grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T-cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as a part of future immunotherapies.

Citation Format: Bastian Schilling, Antje Sucker, Klaus Griewank, Fang Zhao, Benjamin Weide, Andre Görgens, Bernd Giebel, Dirk Schadendorf, Annette Paschen. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2013-4714
Abstract 4730: The double bromodomain protein Brd2 controls B cell expansion and mitogenesis.
Authors: Belkina Anna C. , Blanton Wanda P. , Lombardi Frank L. , Denis Gerald V.
Published: August 2014

Background: Bromodomain-containing coregulators of transcription have been identified recently as new epigenetic targets to treat a variety of hematologic malignancies, including acute myeloid leukemias. However, the bromodomain mechanisms that couple histone acetylation to transcription in lymphopoiesis, and that govern mature lymphocyte responsiveness to growth signals, are only partly understood. Brd2 is a transcriptional co-regulator that contains dual Bromodomains and an ExtraTerminal domain (defining the BET family) that couples chromatin modification to cell cycle progression. We previously reported the first functional characterization of a BET protein as an effector of mammalian mitogenic signal transduction: Eμ-Brd2 transgenic mice develop an ‘activated B cell’ type of diffuse large B cell lymphoma. There have been no other animal models reported for genetic or lentiviral expression of BET proteins, which hampers testing of novel anticancer drugs such as JQ1 and its derivatives.

Methods: Here we use Brd2 lentivirus transduction of hematopoietic stem cells and reconstitution of lethally irradiated recipient mice to examine the function of Brd2 in hematopoiesis in the bone marrow and mitogenesis in the periphery.

Results: Three-fold over-expression of Brd2 in hematopoietic stem cells selectively leads to a doubling of the B cell compartment and increases mature B cell mitogenic responsiveness ex vivo. Knockdown of Brd2 by shRNA totally ablates hematopoietic lineages, likely by inhibiting the lineage-committed progenitor expansion through down-regulation of cyclin A, which reinforces results from Eμ-Brd2 transgenic mice. The novel small molecule BET inhibitor JQ1 reduces B cell mitogenesis by about 60% in parallel experiments, but this effect likely extends to other related BET family members and lacks Brd2 specificity.

Conclusion/Significance: The Brd2 pathway integrates lymphopoiesis, leukemogenesis and normal mitogenesis. Targeting this pathway with therapeutic drugs may therefore confer multiple, diverse benefits in the treatment of hematologic malignancy, B cell mediated disease and likely inflammation.

Citation Format: Anna C. Belkina, Wanda P. Blanton, Frank L. Lombardi, Gerald V. Denis. The double bromodomain protein Brd2 controls B cell expansion and mitogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4730. doi:10.1158/1538-7445.AM2013-4730
Abstract 4733: Novel therapeutic and diagnostic antibodies against KIR3DL2, a unique tumor antigen overexpressed on subtypes of T Cell Lymphomas .
Authors: Viaud Nicolas , Granier Nathalie , Zerbib Stephanie , Dujardin Arnaud , Bonnafous Cecile , Blery Mathieu , Paturel Carine , Rossi Benjamin , Marie-Cardine Anne , Bensussan Armand , Bagot Martine , Sicard Helene
Published: August 2014

KIR3DL2 belongs to the killer immunoglobulin (Ig)-like receptors (KIRs) family and is composed of three extracellular Ig-like domains. KIR3DL2 is naturally expressed on some NK cells and minor subpopulations of CD8+ and CD4+ T cells. Physiologically, KIRD3L2 is an inhibitory receptor for human leukocyte antigen (HLA) class I molecules regulating NK cell activation. Remarkably, KIR3DL2 is also aberrantly overexpressed on several subtypes of T lymphomas/leukemias, such as Sezary Syndrome, transformed Mycosis Fungoides and HTLV1+ Adult T Cell Leukemia, making it a unique therapeutic target in cancer. We have generated a series of anti-KIR3DL2 monoclonal antibodies (mAbs) binding selectively to KIR3DL2, spanning epitopes on each of the three Ig domains. Their efficacy was evaluated in vitro and in vivo against KIR3DL2-expressing tumors and Sezary cell lines as disease model. Various modes of action, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC) were found involved in their anti-tumor activity. In parallel, anti-KIR3DL2 mAbs were also developed as unique and sensitive tools for the detection by immunohistochemistry of KIR3DL2 on tumor biopsies. Owing to the promising efficacy profile of our anti-KIR3DL2 mAb candidates and to the highly restricted expression pattern of the target on some T leukemia/lymphoma cells, an antibody-based therapy targeting KIR3DL2 stands as a potentially unequalled strategy in several orphan diseases with critical unmet medical need.

Citation Format: Nicolas Viaud, Nathalie Granier, Stephanie Zerbib, Arnaud Dujardin, Cecile Bonnafous, Mathieu Blery, Carine Paturel, Benjamin Rossi, Anne Marie-Cardine, Armand Bensussan, Martine Bagot, Helene Sicard. Novel therapeutic and diagnostic antibodies against KIR3DL2, a unique tumor antigen overexpressed on subtypes of T Cell Lymphomas . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4733. doi:10.1158/1538-7445.AM2013-4733
Abstract 474: Complete regression and long-term specific protective immune responses obtained in rodent tumor models after intratumoral treatment with LTX-315 .
Authors: Rekdal Øystein , Kvalheim Gunnar , Line Pål-Dag , Rolstad Bent , Camilio Ketil , Berge Gerd , Nestvold Janne , Wang Mengyu , Shi Jihua , Areffard Ali , Sveinbjørnsson Baldur
Published: August 2014

LTX-315 is a de novo designed peptide derived from a naturally occurring host defence peptide. LTX-315 has the potential to induce long-term specific protective immune responses by stimulating immune cells, inducing tumor cell lysis with subsequent release of danger signals (e.g. HMGB1) and tumor associated antigens (TAA`s). A complete tumor regression has been obtained in several syngenic rodent tumor models by intratumoral (i.t.) injection with LTX-315. The effect was T- cell- dependent since the intervention was inefficient in immune-deficient animals. Studies on treated tumor tissue confirmed infiltration of immune cells and a switch in the cytokine profile towards a Th1 response. Successfully treated animals were protected against re-challenge with the tumor cell type treated, but not against other types of tumor cells. Moreover, tumor resistance could be adoptively transferred by spleen cells from LTX-315-treated animals. The resistance was abrogated by depletion of T- lymphocytes. Additional studies also indicate that LTX-315`s potential to locally activate the innate immune system by the immunogenic stressing of cells, in addition to the subsequent release of endogenous adjuvants and natural danger signals, provides a strong rationale for using LTX-315 as an adjuvant for vaccines based on tumor-associated antigens (TAA) and for combination with other types of immune–modulatory therapies. LTX-315 is currently being tested in a Phase I dose escalation clinical study and may represents a novel strategy for personalized in situ vaccination against cancer.

Citation Format: Øystein Rekdal, Gunnar Kvalheim, Pål-Dag Line, Bent Rolstad, Ketil Camilio, Gerd Berge, Janne Nestvold, Mengyu Wang, Jihua Shi, Ali Areffard, Baldur Sveinbjørnsson. Complete regression and long-term specific protective immune responses obtained in rodent tumor models after intratumoral treatment with LTX-315 . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 474. doi:10.1158/1538-7445.AM2013-474
Abstract 4754: A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function.
Authors: Chang DeKuan , Han Thomas , Clark Rachael A. , Zhu Quan , Kupper Thomas S. , Marasco Wayne A.
Published: August 2014

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of neoplastic disorders characterized by clonally derived and skin-homing malignant T cells that express high level of chemokine receptor CCR4, which is associated with their skin-homing capacity. CCR4 is also highly expressed on T-regulatory cells (Tregs) that can migrate to several different types of chemotactic ligand CCL17- and CCL22-secreting tumors to facilitate tumor cell evasion from immune surveillance. Thus, its high-level expression on CTCL cells and Tregs makes CCR4 a potential ideal target for antibody-based immunotherapy for CTCL and other types of solid tumors. Here, a humanized and affinity optimized anti-CCR4 monoclonal antibody (mAb), mAb2-3, was evaluated. In vitro mechanism studies demonstrated that the potent in vivo anti-tumor effects of this humanized anti-CCR4 mAb could be attributed to antibody dependent cellular cytotoxicity (ADCC), complement mediated cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP). In a mouse CTCL tumor model, anti-CCR4 mAb exhibited an antitumor effect by mediating cellular cytotoxicity through CDC and ADCC via FcγRIIIa expressed murine neutrophils and human nature killer (NK) cells. Moreover, this anti-CCR4 mAb also effectively inhibits chemotaxis of CD4+CD25high Tregs via CCL22 and abrogates Treg suppression activity in vitro by restoring the proliferation of CD4+CD25− effector T cells (Teffs). Taken together, this high-affinity humanized mAb2-3 with potent antitumor effect and a broad range of mechanisms of action on immunity may provide a novel immunotherapy for CTCL and other solid tumors.

Citation Format: DeKuan Chang, Thomas Han, Rachael A. Clark, Quan Zhu, Thomas S. Kupper, Wayne A. Marasco. A humanized, high affinity anti-CCR4 antibody for immunotherapy of cutaneous T cell lymphoma and characterization on T cell function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2013-4754
Abstract 4781: EBV infection of mammary epithelial cells promotes malignant transformation.
Authors: Hu Hai , Wulf Gerburg , Juvekar Ashish , Dittmer Dirk P , Fingeroth Joyce
Published: August 2014

Whether the human tumor virus, Epstein-Barr virus (EBV) promotes breast cancers remains controversial and a potential mechanism has remained elusive. Herein we show EBV binds mammary epithelial cells (MECs) via CD21 and upon establishing a persistent infection triggers expansion of MEC progenitor cells (CD24low/CD44high), increases mammosphere formation, blocks differentiation and in conjunction with activated Ras accelerates formation of breast cancers in NOD/SCID mice. Similar to nasopharyngeal carcinoma (NPC), breast cancers derived from EBV-infected and Ras-transduced MECs exhibited a latency II pattern infection (LMP1 high, LMP2A positive) with a significant number of lytic transcripts. A human gene expression signature for “EBVness” was derived from these tumors and application to publicly available data sets of breast cancer patients showed “EBVness” was - associated with high grade (40 vs 13.5%) estrogen-receptor (ER)-negative status (31.8 vs. 10.5%), p53 mutation (37.5 vs 14.5%) and poor survival.

Citation Format: Hai Hu, Gerburg Wulf, Ashish Juvekar, Dirk P Dittmer, Joyce Fingeroth. EBV infection of mammary epithelial cells promotes malignant transformation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4781. doi:10.1158/1538-7445.AM2013-4781

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4817: Dietary fiber intake reduces colorectal polyp risk in cigarette smokers.
Authors: Fu Zhenming , Shrubsole Martha J. , Zheng Wei
Published: August 2014

BACKGROUND

Results regarding the association of dietary fiber intake with colorectal tumor risk remain inconsistent. The association may differ between smokers and nonsmokers. We evaluated this hypothesis in a large colonoscopy-based case-control study.

METHODS

Dietary fiber intakes were estimated by a food frequency questionnaire designed to capture dietary intakes in the study population. Unconditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence limits (95% CLs) with adjustment for potential confounders. Analysis also was stratified by cigarette-smoking status and sex.

RESULTS

Overall, colorectal polyps (P-trend < 0.001), including adenoma only (P-trend = 0.006), were associated inversely with high dietary fiber intake. When stratified by smoking status, this inverse association was only observed among tobacco smokers, but not among never smokers, (Pheterogeneity = 0.039) for either males or females and for all participants. The protective effect was observed only among smokers for high-risk adenomas (Pheterogeneity = 0.018) and low-risk adenomas, but not for never smokers. The protective effect was particularly strong for high-risk adenomas in smokers. Consuming more than 19.9 g/day of dietary fiber was associated with a 41-44% decreased risk for high-risk adenomas among smokers (P-trend < 0.001).

CONCLUSIONS

Cigarette smoking may modify the association of dietary fiber intake and the risk of colorectal polyps, especially high-risk adenoma risk.

Citation Format: Zhenming Fu, Martha J. Shrubsole, Wei Zheng. Dietary fiber intake reduces colorectal polyp risk in cigarette smokers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4817. doi:10.1158/1538-7445.AM2013-4817
Abstract 4823: Isoflavones from phytoestrogens and colorectal cancer risk: A nested case-control study within the Korean Multicenter Cancer Cohort.
Authors: Yeo Yohwan , Ko Kwang-Pil , Ma Seung-Hyun , Yang Jae Jeong , Shin Aesun , Park Sue K. , Chang Soung-Hoon , Shin Hai-Rim , Kang Daehee , Yoo Keun-Young
Published: August 2014

Background

The association of soybean products related with colorectal cancer risk is inconsistent. This may be due to information bias from measuring food intake by questionnaires and different degrees of bias according to study design. To assess the association between soybean products and colorectal cancer, we directly measured phytoestrogen biomarkers in a nested case-control study in Korea.

Methods

Study population was composed of 101 cases and 398 matched controls matched for age within 5-year, sex, area and year at recruitment of cases within the Korean Multicenter Cancer Cohort. The concentrations of four biomarkers in the plasma were measured by Liquid Chromatography-Mass Spectrometry. Conditional logistic regression models were used to calculate the odds ratio and 95% confidence intervals (CI).

Results

Median plasma concentrations of genistein, daidzein, glycitein and enterolactone were not statistically significant between cases and controls. However, there was a significant trend of decreasing risk according to an increase of genistein (p=0.03). This protective effect of genistein was more prominent in women. There was no association between other plasma concentrations of isoflavones or lignans and colorectal cancer.

Conclusions

High serum concentrations of isoflavones, i.e, genistein, were associated with a decreased trend of colorectal cancer, especially in women.

Citation Format: Yohwan Yeo, Kwang-Pil Ko, Seung-Hyun Ma, Jae Jeong Yang, Aesun Shin, Sue K. Park, Soung-Hoon Chang, Hai-Rim Shin, Daehee Kang, Keun-Young Yoo. Isoflavones from phytoestrogens and colorectal cancer risk: A nested case-control study within the Korean Multicenter Cancer Cohort. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4823. doi:10.1158/1538-7445.AM2013-4823
Abstract 4843: Genetic variants in Notch signaling pathway and ovarian cancer.
Authors: Xu Enping , Lu Karen H. , Hildebrandt Michelle AT , Huang Maosheng , Wu Xifeng , Liang Dong
Published: August 2014

The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate choices, and has a key role in the regulation of stem cells in a variety of cancers. In this study, we applied a pathway-based approach to evaluate the associations between single nucleotide polymorphisms in Notch signaling pathway and ovarian cancer risk, survival, and response to chemotherapy. Towards this, we systematically genotyped 139 SNPs from 10 genes in the pathway in 339 Caucasian ovarian cancer cases and 349 Caucasian healthy controls. Individually, four SNPs were significantly associated with the ovarian cancer risk. The most significant SNP was NOTCH4: rs397081, with an adjusted odds ratio (OR) of 0.38 (95% CI = 0.22-0.66, P=0.00057). A highly significant gene-dosage effect was observed for these top variants (P for trend < 0.00001) with those carrying ≥ 3 risk genotypes having a nearly 6-fold increase in risk (OR = 5.67, 95% CI = 2.58 - 12.44] . Classification and regression tree (CART) analysis further revealed potential higher order gene-gene interactions between these four SNPs, with the highest risk group having almost 7-fold increased risk. Ten SNPs were significantly associated with overall survival, of which the strongest association was identified for NOTCH4: rs3131290 (OR = 0.48, 95% CI = 0.27-0.84). Cumulative effect analysis showed that multiple adverse genotypes had a significant dose-dependent effect on overall survival. The median survival times for individuals carrying ≤3, 4 to 6, and ≥7 of these adverse genotypes were >186.3, 62.82, and 28.58 months, respectively. Similarly, a significant association was identified between a poor response to platinum-based chemotherapy and the number of unfavorable SNPs (P for trend < 0.0001). Our findings suggest that genetic variants in the Notch signaling pathway are associated with ovarian cancer risk and could serve as potential predictors of clinical outcomes in ovarian cancer patients.

Citation Format: Enping Xu, Karen H. Lu, Michelle AT Hildebrandt, Maosheng Huang, Xifeng Wu, Dong Liang. Genetic variants in Notch signaling pathway and ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4843. doi:10.1158/1538-7445.AM2013-4843
Abstract 4852: Comparison of manual and automated scoring of androgen receptor staining in prostate tissue.
Authors: Ondracek Rochelle P. , Mohler James L. , Pilarz Catherine , McEvoy Sarah , Kasza Karin , Morrison Carl , Marshall James
Published: August 2014

Although manual scoring is generally used to evaluate the presence of androgen receptor (AR) protein as detected by immunohistochemistry in tissue, manual evaluation is tedious, inefficient and subjective. Therefore, manual scoring is not feasible for the evaluation of large numbers of patients. In this study, a technician (CP) rated AR staining in tissue sections of 3 tissue microarrays (TMAs) constructed from 3 cores each of benign and malignant tissue from 134 patients who underwent radical prostatectomy between 1993 and 2006 at Roswell Park Cancer Institute. The manual scorer randomly sampled 50 nuclei from each core and scored each nuclei as not stained (score =0), or lightly (score = 1), moderately (score=2) or darkly (score = 3) stained. The average staining intensity was recorded per patient across the benign cores, and across the tumor cores. Automated staining used the Image Pro image processing program, in which the entire core was scanned, all nuclei segmented and average intensity values per between 0 (completely black) and 255 (completely white) were determined for each nucleus. The mean staining score for each core is calculated by taking the average of all the identified nuclei in the core, and an average intensity is calculated per patient across the benign cores, and across the malignant cores.

The Pearson correlation between manual and automated scoring was 0.76. When stratified by benign or malignant tissue, the Pearson correlation between manual and automated scoring was 0.75 (benign) and 0.78 (malignant).

Automated scoring of AR staining is comparable to manual scoring of AR in prostate tissue. In light of the greater efficiency of automated scoring, future evaluations of immunohistochemical staining may be usefully conducted using automated scoring of nuclei.

Citation Format: Rochelle P. Ondracek, James L. Mohler, Catherine Pilarz, Sarah McEvoy, Karin Kasza, Carl Morrison, James Marshall. Comparison of manual and automated scoring of androgen receptor staining in prostate tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4852. doi:10.1158/1538-7445.AM2013-4852
Abstract 4856: Association between breast cancer and constitutively decreased TGFBR1 signaling.
Authors: Henegan John C. , Moore-Smith Lakisha , Yi Nengjun , Zhang Kui , Ahsan Habibul , Whittemore Alice S. , Pasche Boris ,   BCFR Co-Investigators
Published: August 2014

Background: We previously identified a hypomorphic TGF-β type 1 receptor variant (TGFBR1*6A) that is associated with cancer risk, has impaired TGF-β signaling capability and enhances the migration and invasion of breast cancer cells. Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (ORs 1.16,1.01-1.34; 1.15,1.01-1.31). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression. In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk.

Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and healthy controls recruited by the Breast Cancer Family Registry. The samples in this multinational cohort were primarily from younger patients (average age 49.4 and 48.1 years for cases and controls, respectively, at time of interview).

Results: Using the Cockerham model, rs7034462 was found to be associated with breast cancer risk under the dominance genetic effect but, unexpectedly, there was a significant decreased association with breast cancer for this SNP under the additive genetic effect for this model.

SNP Cases Controls Cockerham Model Genetic Effect Odds Ratio 95% CI P rs7034462 (n = 2,934) 1509 1425 Additive 0.60 0.38-0.93 0.020 Dominance 2.09 1.29-3.38 0.002

Conclusion: rs7034462 heterozygotes have an increased risk of breast cancer but rare homozygotes have a decreased risk. This is the first evidence in humans that constitutively decreased TGFBR1-mediated TGF-β signaling is associated with breast cancer risk.

Citation Format: John C. Henegan, Lakisha Moore-Smith, Nengjun Yi, Kui Zhang, Habibul Ahsan, Alice S. Whittemore, Boris Pasche, BCFR Co-Investigators. Association between breast cancer and constitutively decreased TGFBR1 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4856. doi:10.1158/1538-7445.AM2013-4856
Abstract 4865: Lack of efficacy of aerosolized resveratrol on B[A]P induced pulmonary adenoma formation in A/J mice.
Authors: Seabloom Donna , Gailbraith Art , Antonides Jenny , Wuertz Beverly , Wattenberg Lee , Ondrey Frank G.
Published: August 2014

Natural products constitute an emerging class of compounds for carcinogenesis prevention in a variety of solid tumor malignancies. Resveratrol is a compound that has outstanding efficacy on cancer prevention in in vitro carcinogenesis models but rapid solubility and metabolism limits its efficacy in animal models when delivered in the diet. However, if regional or topical delivery could be achieved effects of first pass metabolism might be avoided. In the present study, we sought to use aerosol resveratrol to examine whether it could inhibit Benzpyrene inducd pulmonary adenoma formation in A/J mice. Eight groups of 24 mice were given Benzpyrene and aerosol resveratrol was started either one week or 8 weeks after the conclusion of the Benzpyrene. Aerosolized resveratrol (1.0, 0.3, and 0.1 mg/kg) was delivered 5x per week Monday through Friday for weeks 2- 15. At the conclusion of the experiment animals were sacrificed and adenomas counted. We found that the animals tolerated the aerosol resveratrol without toxicity and without weight differences between all groups. Animals formed between 9 and 12 adenomas, on average throughout all groups. There were no effects of aerosol resveratrol on either early stage or late stage carcinogenesis, nor were there any trends between the groups. We conclude that the high water solubility of resveratrol likely allowed for its rapid transit and metabolism through the bronchioles and lung parenchyma and that possibly chemical modifications of resveratrol that allow for its deposition in the lung fields in a way to increase its residence time would allow for better efficacy.

Citation Format: Donna Seabloom, Art Gailbraith, Jenny Antonides, Beverly Wuertz, Lee Wattenberg, Frank G. Ondrey. Lack of efficacy of aerosolized resveratrol on B[A]P induced pulmonary adenoma formation in A/J mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4865. doi:10.1158/1538-7445.AM2013-4865
Abstract 4868: Dietary resveratrol promotes breast cancer progression in immunocompromised mice.
Authors: Castillo-Pichardo Linette , Cubano Luis A. , Rodríguez-Orengo José F. , Dharmawardhane Suranganie
Published: August 2014

Resveratrol, a polyphenol from grapes and red wine has been widely studied due to its beneficial effects against cardiovascular diseases and cancer. However, our group and others have provided evidence for a dual cancer promoting or inhibitory role for resveratrol in breast cancer, dependent on the concentration. Moreover, much of the reported inhibitory effects of resveratrol are from studies with high non-physiological concentrations. Herein, we investigated the effects of low (0.5 and 5 mg/kg body weight) and moderate concentrations (50 mg/kg body weight) of resveratrol on mammary tumor growth, using immunocompromised mice. Our findings suggest promotion of mammary tumor growth and metastasis by resveratrol at all concentrations tested in tumors derived from the low metastatic estrogen receptor (ER)α(-), ERβ(+) MDA-MB-231 and the highly metastatic ER(-) MDA-MB-435 cancer cell lines. Additionally, the activity of the migration/invasion regulator Rac, which we have previously shown to be regulated by resveratrol in vitro, was measured in tumors from resveratrol treated mice. Our results show a significant induction of tumoral Rac activity and a trend in increased expression of the Rac downstream effector PAK1, Akt, and jun kinase (JNK) following resveratrol treatment. Taken together, our findings implicate low concentrations of resveratrol in potential promotion of breast cancer. Because of this dual role of resveratrol on cancer progression, measuring circulating plasma levels of resveratrol becomes critical and could be used as a prognostic tool for resveratrol's responsiveness. Since, detection and quantification of low levels of resveratrol is limited by the sensitivity of existing methodologies, we developed a rapid UPLC-tandem MS method to quantify resveratrol from plasma. This method requires minimal sample preparation and allows the quantification of resveratrol in mouse plasma at lower levels and shorter retention times than those previously reported by similar methodologies. This study was supported by DoD/BCRP W81XWH-08-1-0258 to LCP, DoD/BCRP W81XWH-07-1-0330 to SD, the UCC Pilot Project Program, the UCC Postdoctoral Program sponsored by the PR Science, Technology and Research Trust, and the Title V PPOHA grant number PO31M105050 from U.S. Department of Education to UCC.

Citation Format: Linette Castillo-Pichardo, Luis A. Cubano, José F. Rodríguez-Orengo, Suranganie Dharmawardhane. Dietary resveratrol promotes breast cancer progression in immunocompromised mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4868. doi:10.1158/1538-7445.AM2013-4868
Abstract 4872: Gynostemma pentaphyllum saponins alter the gut microflora composition and convert dysbiosis to eubiosis state in xenograft nude mice.
Authors: Chen Lei , Tai William C.S. , Leung Frederick CC , Singh Manreet , Hsiao W.L. Wendy
Published: August 2014

Increasing evidence has shown that the gut microflora may have a crucial role in many diseases, including cancers. In our previous studies, we have demonstrated that treatment with total saponins of Gynostemma pentaphyllum (GpS) exerts anti-cancer effects in cellular and animal models. Our study showed that an unnatural shift in the microflora composition was observed in nude mice with xenografted tumors induced by GFP/Ras cells. To investigate the potential association between the anti-cancer effect of GpS and the gut microflora, we first investigated whether GpS treatment would affect the microflora composition. Enterobacterial Repetitive Intergenic Consensus sequence-based PCR (ERIC-PCR) was used to analyze the bacterial genomic DNA from the fecal samples of the experimental mice. ERIC-PCR analysis revealed that gut microbiota communities were able to restore back to the non-tumor state (day 0)) after treatment with GpS for 10 days. In addition, we found that GpS treatment can increase the levels of certain beneficial bacteria, including Bifidobacterium spp. and Lactobacillus spp. Furthermore, we defined the detailed changes in the gut microbiome by pyrosequencing of the 16S rRNA gene sequences. We found that Bacteroidetes/Firmicutes ratio showed an increased trend upon GpS treatment in xenograft nude mice. Furthermore, GpS altered certain species of bacteria, including the Clostridium cocleatum and Bacteroides acidifaciens, which have well-documented beneficial effects. In conclusion, this study has demonstrated GpS can potentially regulate and balance the gut microbial ecosystem by increasing symbionts. However, further investigation is required on whether this alteration of the gut microflora is the cause or consequence of the drug action. [This study was partially supported by FRG2/11-12/102 to WLWHsiao]

Citation Format: Lei Chen, William C.S. Tai, Frederick CC Leung, Manreet Singh, W.L. Wendy Hsiao. Gynostemma pentaphyllum saponins alter the gut microflora composition and convert dysbiosis to eubiosis state in xenograft nude mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4872. doi:10.1158/1538-7445.AM2013-4872
Abstract 4883: Zinc and prostate cancer: a systematic review.
Authors: Mahmoud Abeer M. , Al-alem Umaima , Shah Ebony , Batai Ken , Dabbous Firas , Ali Mohamed , Kittles Rick
Published: August 2014

Background: Zinc is involved in many essential cellular functions. It has been shown that the prostate contains high concentrations of zinc, but zinc levels decrease in prostate cancer tissues. Although, experimental evidence implicates zinc in the pathogenesis of prostate cancer, epidemiological data are inconsistent. We conducted a systematic review of the literature to summarize the evidence regarding the association between zinc and prostate cancer.

Methods: Relevant studies were identified by searching PubMed and the Cochrane Library databases through November 2012 and reviewing reference lists of retrieved articles. Inclusion criteria were original and peer-reviewed publications reporting the association between zinc intake or status and prostate cancer outcomes (diagnosis, progression). No reviews, editorials, or comments were included. Two investigators abstracted study information and evaluated quality independently using standardized forms.

Results: Sixteen studies met inclusion criteria, including 3 cohorts, 2 nested case-control, 10 case-control, and 1 randomized clinical trial, with a total of 111,288 participants and 11,681 cases of prostate cancer. All studies measured the association between zinc levels and prostate cancer. In most studies, regardless of the study design or source of zinc, the highest dose of zinc was associated with a modest elevation of odds of prostate cancer. Four studies had decreased odds of prostate cancer for the highest dose of zinc but the confidence interval crossed one. There was evidence of a dose-response relationship and subgroup analysis revealed a protective effect of high zinc intake among advanced prostate cancer cases.

Conclusions: Although the level of zinc in prostate cancer tissue is reduced, studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. We performed a systematic review to assess the role of zinc in prostate cancer. As a result of this systematic review, the evidence is still insufficient to recommend zinc supplementation for cancer patients in clinical practice.

Citation Format: Abeer M. Mahmoud, Umaima Al-alem, Ebony Shah, Ken Batai, Firas Dabbous, Mohamed Ali, Rick Kittles. Zinc and prostate cancer: a systematic review. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4883. doi:10.1158/1538-7445.AM2013-4883
Abstract 4909: Olig2 phosphorylation by CDK2 implicated in glioma proliferation.
Authors: Fu Jun , Koul Dimpy , Zheng Siyuan , Singh Vivek , Yao Jun , Zheng Yanhua , Lu Zhimin , Sulman Erik P. , Lang Frederick F. , Yung Alfred W.K
Published: August 2014

Oligodendrocyte transcription factor 2 (Olig2) is an important proneural transcription factor that regulates early development of the central nervous system and formation of glioma. Although recent studies established the role of developmentally regulated Olig2 phosphorylation in promoting the proliferation of both normal and malignant neural stem/progenitor cells, the molecular mechanisms by which Olig2 phosphorylation is regulated and functions as a pro-proliferative factor are not completely understood. Here we identified Olig2 as a critical phosphorylation target for cyclin-dependent kinase 2 (CDK2). CDK2 stabilizes and activates Olig2, thereby regulating G1-to-S phase progression by repressing the expression of Cyclin-dependent kinase inhibitor p27kip1. After phosphorylation by CDK2, Olig2 exerts pro-proliferative effects that are reflected in normal neural/glioma stem cells and in murine xenograft models of glioma. Olig2 phosphorylation regulates its binding to E-box sequence in p27 gene promoter and represses p27 expression. We show that constitutive p27 expression antagonizes CDK2-mediated Olig2 phosphorylation and attenuates cell proliferation both in in-vitro and in-vivo glioma models. Expression analysis of TCGA GBM samples also showed that high Olig2 expression is always accompanied with high CDK2 expression in the proneural, classical, and neural subclasses, which could provide a convincing evidence to use a CDK2 inhibitor to treat Olig2-high gliomas. Treatment with CDK2 inhibitor preferentially suppresses proliferation of Olig2-high glioma cells. Thus, we conclude that a CDK2 inhibitor could be of great therapeutic value in patients with Olig2-high glioma and Olig2 might be used as a biological marker for CDK2 inhibitors in the future studies.

Citation Format: Jun Fu, Dimpy Koul, Siyuan Zheng, Vivek Singh, Jun Yao, Yanhua Zheng, Zhimin Lu, Erik P. Sulman, Frederick F. Lang, Alfred W.K Yung. Olig2 phosphorylation by CDK2 implicated in glioma proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4909. doi:10.1158/1538-7445.AM2013-4909
Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy.
Authors: Mautino Mario R. , Jaipuri Firoz A. , Waldo Jesse , Kumar Sanjeev , Adams James , Van Allen Clarissa , Marcinowicz-Flick Agnieszka , Munn David , Vahanian Nicholas , Link Charles J.
Published: August 2014

The IDO pathway mediates immunosuppressive effects through the metabolization of tryptophan (Trp) to kynurenine (Kyn), triggering downstream signaling through GCN2, mTOR and AHR that can affect differentiation and proliferation of T cells. Expression of the IDO1 gene by tumor cells or host APCs can inhibit tumor-specific effector CD8+ T cells and enhance the suppressor activity of Tregs, and high expression of IDO correlates with worse clinical prognosis in patients with a variety of malignancies. Therefore, targeting the IDO pathway via inhibition of the IDO enzyme or blocking its downstream signaling effects is a prime target for small-molecule immunomodulatory drugs in cancer.

Here we describe the pharmacological and biological properties of NLG919, a novel small-molecule IDO-pathway inhibitor. NLG919 potently inhibits this pathway in vitro and in cell based assays (Ki=7 nM; EC50 =75 nM). It is orally bioavailable (F>70%); and has a favorable pharmacokinetic and toxicity profile. In mice, a single oral administration of NLG919 reduces the concentration of plasma and tissue Kyn by ∼ 50%. Using IDO-expressing human monocyte-derived DCs in allogeneic MLR reactions, NLG919 potently blocked IDO-induced T cell suppression and restored robust T cell responses with an ED50=80 nM. Similarly, using IDO-expressing mouse DCs from tumor-draining lymph nodes, NLG919 abrogated IDO-induced suppression of antigen-specific T cells (OT-I) in vitro, with ED50=120 nM. In vivo, in mice bearing large established B16F10 tumors, administration of NLG919 markedly enhanced the anti-tumor responses of naïve, resting pmel-1 cells to vaccination with cognate hgp100 peptide plus CpG-1826 in IFA. In this stringent established-tumor model, NLG919 plus pmel 1/vaccine produced a dramatic collapse of tumor size within 4 days of vaccination (∼95% reduction in tumor volume compared to control animals receiving pmel-1/vaccine alone without NLG919).

In conclusion, NLG919 is a potent IDO pathway inhibitor with desirable pharmacological properties, suitable for the treatment of immunosuppression associated with cancer.

Citation Format: Mario R. Mautino, Firoz A. Jaipuri, Jesse Waldo, Sanjeev Kumar, James Adams, Clarissa Van Allen, Agnieszka Marcinowicz-Flick, David Munn, Nicholas Vahanian, Charles J. Link. NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 491. doi:10.1158/1538-7445.AM2013-491
Abstract 4921: Essential role of MMP-2 in carbon nanotube-induced invasion of human pleural mesothelial cells.
Authors: Lohcharoenkal Warangkana , Liu Yuxin , Stueckle Todd A. , Dinu Cerasela-Zoica , Wang Liying , Rojanasakul Yon
Published: August 2014

Carbon nanotubes (CNTs) have increasingly been used in a wide variety of applications. However, because of their needle-shape morphology, biopersistence and mode of exposure similar to those of asbestos which is a known carcinogen causing lung mesothelioma, there has been a great concern about their potential carcinogenicity. In this study, we investigated the effect of long-term exposure of CNT on proliferative and invasive properties of human pleural mesothelial cells. We found that chronic exposure of human mesothelial Met5A cells to low-dose non-cytotoxic concentration of single-walled CNT (0.02 μg/cm2 for 25 weeks) in culture induced malignant transformation of the cells as indicated by their increased cell invasion and migration. Analysis of gene expression by real-time PCR array showed a 50-fold increase in MMP-2 expression in CNT-transformed cells as compared to passage-matched control cells. Western blot analysis of the protein expression confirmed the upregulation of MMP-2 in the transformed cells. Downregulation of MMP-2 in the transformed cells by short-hairpin RNA stable transfection effectively inhibited the MMP-2 activity in these cells as well as their invasive and migratory activities. These results indicate MMP-2 as a key regulator of the aggressive phenotype of mesothelial cells after chronic CNT exposure. This study fortifies the carcinogenic potential of CNT and reveals a novel mechanism that may be important in CNT-induced mesothelioma.

Citation Format: Warangkana Lohcharoenkal, Yuxin Liu, Todd A. Stueckle, Cerasela-Zoica Dinu, Liying Wang, Yon Rojanasakul. Essential role of MMP-2 in carbon nanotube-induced invasion of human pleural mesothelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4921. doi:10.1158/1538-7445.AM2013-4921
Abstract 4942: Deletion of the asymmetry regulator Lgl1 contributes to tumor stemness and invasiveness.
Authors: Lerner Robin G. , Nguyen Loan , Petritsch Claudia
Published: August 2014

In the developing and adult brain asymmetric cell division (ACD) maintains a balance between self-renewing and differentiated progeny of neural stem and progenitor cells. The WD protein lethal giant larvae 1 (Lgl1) regulates the distribution of polarity proteins in dividing cells and thereby establishes an axis of polarity, which is crucial for proper asymmetric divisions to occur (Baek et al. Mutat Res. 1999; 436; 131-6). Lgl, along with other asymmetry regulators, have been identified as a putative tumor suppressor gene in Drosophila.

There remains debate as to whether disrupting ACD by itself is sufficient to cause tumor initiation by mammalian stem and progenitor cells. We have previously shown that expression of multiple asymmetry regulators is disrupted in human glioma (Sugiarto et al. Cancer Cell; 2011; 20; 320-340). Here we address our hypothesis that ACD defects are crucial for tumorigenesis, by delineating the role of Lgl1 in tumor initiation and progression.

Using mouse neural stem cells (NSCs) isolated from genetically modified Lgl1lox/lox mice (Klezovitch et al. Genes Dev. 2004; 18; 559-71) we investigated the contribution of Lgl1 to various hallmarks of cancer in vitro and in vivo.

We demonstrate that loss of Lgl1 in mouse NSC and oligodendrocyte precursor cells disrupts ACD and increases the expression of early-stage precursor cell markers. Deletion of Lgl1 does not increase proliferation in vitro and deletion of Lgl1 alone does not transform cells transplanted into immunocompromised mice. However properties associated with a high-grade tumor, including invasiveness and stem cell marker expression, are increased when Lgl1 is deleted in the context of oncogenic EgfrVIII expression.

Increase in tumor invasiveness has previously been demonstrated to be associated with an increase in stem cell marker expression (Molina et al. Neoplasia. 2010; 12; 453-63). Our data suggest that loss of asymmetry in tumor precursor cells blocks differentiation and contributes to tumor progression by increasing stemness and hence invasiveness.

Citation Format: Robin G. Lerner, Loan Nguyen, Claudia Petritsch. Deletion of the asymmetry regulator Lgl1 contributes to tumor stemness and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4942. doi:10.1158/1538-7445.AM2013-4942