bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1789: Auristatin-based antibody-drug conjugates are synergistic in combination with PI3K-AKT-mTOR pathway inhibitors in hematologic malignancies and carcinoma
Authors: Lewis Timothy S. , McCormick Renee S. , Zeng Weiping , Miyamoto Jamie B. , Kennedy Dana , Sievers Eric L. , McEarchern Julie A. , Law Che-Leung 
Published: June 2012

Abstract
Antibody-drug conjugates (ADCs) that couple the potent anti-mitotic agents monomethyl auristatin E or F (MMAE or MMAF) to tumor antigen specific monoclonal antibodies have demonstrated antitumor activity in preclinical models. We report that the combination of auristatin-based ADCs with inhibitors of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway improves cytotoxic activity in Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and renal cell carcinoma (RCC) cell line models. Implicated in tumor cell growth and survival, the PI3K-AKT-mTOR pathway is frequently hyperactivated in carcinomas and hematologic malignancies with elevated AKT activity reported in ∼64% of Hodgkin Reed-Sternberg (HRS) cells and 25-52% of primary patient diffuse large B-cell lymphomas. We produced dose response curves for auristatin ADCs and PI3K-AKT-mTOR pathway inhibitors, alone and in combination, and then performed combination index (CI) analysis using the Chou-Talalay method. The CD30-targeting ADC brentuximab vedotin (SGN-35) and the CD19-targeting ADC (SGN-19A) were synergistic (CI &lt; 0.7) with the allosteric mTORC1 inhibitors sirolimus and temsirolimus in panel of lymphoma cell lines. Similarly, a CD70 targeting ADC (SGN-75) was synergistic with sirolimus and temsirolimus in RCC cell lines. Unconjugated MMAE drug was synergistic in combination with sirolimus and temsirolimus, proving the auristatin component of the ADC is responsible for enhanced combinatorial activity. Next, we found that brentuximab vedotin, SGN-19A, and SGN-75 were each synergistic with NVP-BEZ235, a dual specificity PI3K and mTORC1/2 catalytic site inhibitor. Therefore, the synergy observed with auristatin ADCs is generalizable to inhibitors of the PI3K-AKT-mTOR pathway and not unique to rapamycin analogs. Finally, the brentuximab vedotin combination with temsirolimus was evaluated in a L428 mouse xenograft model of B-like HL. Temsirolimus and brentuximab vedotin alone showed antitumor activity in the L428 model; however, the brentuximab vedotin plus temsirolimus combination had significantly greater (P-value = 0.001) antitumor activity than either drug alone. The mechanism for the synergy observed in these combinations may involve reduced expression of antiapoptotic proteins by mTOR pathway inhibitors, which sensitizes cancer cells to auristatin ADCs. Collectively, these data suggest the potential for auristatin ADC plus mTOR inhibitor cotherapy in PI3K-AKT-mTOR pathway hyperactivated lymphomas and carcinomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1789. doi:10.1158/1538-7445.AM2011-1789
Abstract 179: Histone deacetylase inhibitor; CG005, is a novel anticancer drug; as a combination drug with docetaxel in prostate cancer
Authors: Kim Yong Sook , Kim Mi Joung , Choi Jene , Jang Sejin , Lee Je-hwan , Ro Seonggu , Kim Choung-soo , Hwang Jung Jin 
Published: June 2012

Abstract
We synthesized a novel hydroxamate-based HDACi, CG0005 {(E)-2-(Naphthalen-1-yloxymethyl)-oct-2-enedioic acid 1-[(3-dimethylamino-propyl)-amide] 8-hydroxyamide]}. Like other inhibitors, for example SAHA and PXD 101, CG0005 has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. The aliphatic chain of CG0005, which is presumed to be positioned at the narrow channel of pocket, is less flexible than that of SAHA and less rigid than that of PXD101. Of the other moieties, the tertiary amine was adopted to improve water solubility. Firstly, we analyzed its activity in hormone-dependent LNCaP cells and hormone-refractory DU145 and PC3 cells. CG0005 inhibited deacetylation of histone3 and tubulin as much as vorinostat and belinostat. CG0005 also inhibited growth of prostate cancer cells and increased sub-G1 population and activated caspase-9, -3 and -8. These results indicated that CG0005 induced apoptosis in prostate cancer cell lines. Next, we examined the effect of CG0005 on cell death induced by docetaxel in DU145 cells in vitro and in vivo. Pre-treatment of DU145 cells with docetaxel followed by CG0005 showed synergistic cytotoxicity, and increased the apoptotic sub-G1 population, caspase activation, and tubulin acetylation, compared with docetaxel alone. Moreover, the combination treatment decreased Mcl-1, Bcl-xl and cyclin D1. Docetaxel and CG0005 combination reduced tumor size in the DU145 xenograft model. These preclinical results show that post-treatment with CG0005 potentiated anti-tumor effect of docetaxel in hormone-refractory prostate cancer (HRPC) cells via intrinsic and extrinsic apoptotic pathway in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 179. doi:10.1158/1538-7445.AM2011-179
Abstract 1804: Immuno-chemoradiotherapy for oral cancer: Augmentation of OK-432-induced anti-tumor immunity by tegafur and radiation
Authors: Okamoto Masato , Tano Tomoyuki , Shin Kan , Mitsunobu Sato 
Published: June 2012

Abstract
In the current study, we have evaluated the anti-cancer effect of OK-432 in combination with UFT, an oral preparation combining the 5-FU pro-drug tegafur and uracil in a 1:4 ratio, and radiation therapy (RT). RT+UFT+OK-432 therapy elicited better clinical response and longer survival time than only RT+UFT. Next, we conducted the in vitro study to examine the effect of 5-FU and X-ray irradiation in the OK-432-induced cytokines. Human peripheral blood mononuclear cells (PBMCs) were stimulated with OK-432, 5-FU or X-ray for 24 hr. OK-432 induced Th1-type cytokines (IFN-γ, IL-12, IL-18) as well as IL-10 and TGF-β. When PBMCs were stimulated by 5-FU and/or X-ray in combination with OK-432, production of IL-10 and TGF-β was significantly inhibited. Gene expression of negative regulators, SOCS-1 and -3, was augmented by OK-432, however, this was also inhibited by 5-FU and X-ray irradiation. OK-432-induced IL-10 and TGF-β, but not Th1-type cytokines, was significantly reduced by addition of antisense oligonucleotide for SOCS-1 or that for SOCS-3. Radiation and 5-FU induce Th1-dominant state by inhibiting the OK-432-induced production of IL-10 and TGF-β mediated by regulation of negative regulators, SOCS-1 and -3.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1804. doi:10.1158/1538-7445.AM2011-1804
Abstract 1806: TLR2 agonist PSK activates NK cells and enhances the anti-tumor effect of HER2-targeted monoclonal antibody therapy
Authors: Lu Hailing , Yang Yi , Gad Ekram , Disis Mary L. 
Published: June 2012

Abstract
Purpose: The therapeutic effect of trastuzumab, the anti-HER2 monoclonal antibody (mAb), is dependent on functional NK cells which mediates antibody-dependent cell-mediated cytotoxicity (ADCC). Novel agents that enhance NK cell function could potentially improve the therapeutic effect of trastuzumab. We recently identified polysaccharide krestin (PSK), a natural product extracted from medicinal mushroom, as a novel TLR2 agonist. The current study was undertaken to evaluate the effect of PSK on human NK cells and the potential of PSK to enhance HER2-targeted mAb therapy.
Experimental Design: Human PBMC were stimulated with PSK to evaluate the effect of PSK on NK cell activation and IFN-g secretion. K 562 was used as a target to measure the lytic function of NK cells. Effect of PSK on ADCC was also measured using trastuzumab-coated SKBR3 and MDA-MB-231 breast cancer cells. Finally, in vivo experiment in neu transgenic mice was carried out to determine the potential of PSK to augmented HER2-targeted mAb therapy.
Results: PSK upregulated the expression of activation markers, CD25 and CD69, on NK cells, and stimulated IFN-g production by NK cells. The cytolytic potential of NK cells, as shown by CD107a degranulation and lysis of K562, was also augmented by PSK treatment. PSK enhanced trastuzumab-mediated ADCC in lysing both SKBR3 and MDA-MB-231 breast cancer cells. In vivo treatment in neu transgenic mice showed that oral administration of PSK significantly potentiated the anti-tumor effect of anti-rat neu/HER2 mAb therapy.
Conclusion: These results demonstrated that natural product PSK activates human NK cells and potentiates trastuzumab-mediated ADCC. Concurrent treatment of PSK and trastuzumab may be a novel way to augment the anti-tumor effect of trastuzumab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2011-1806
Abstract 181: The combination of a novel retinoid compound with standard chemotherapy increases cytotoxicity in an ovarian cancer cell line
Authors: Whitworth Jenny M. , Oliver Patsy J. , Muccio Donald D. , Straughn J. Michael , Buchsbaum Donald J. 
Published: June 2012

Abstract
Background: Retinoids are a class of chemotherapeutic agents that have been studied in a variety of malignancies and are known to play an important role in cellular proliferation and apoptosis. 9cUAB30 is a novel retinoid compound that has been shown to demonstrate anti-tumor activity in breast cancer and in acute promyelocytic leukemia. The objective of this study was to determine if 9cUAB30, alone and in combination with carboplatin, has cytotoxic effects on ovarian cancer cells.
Methods: The ovarian cancer cell line A2780 was cultured in 96-well plates for 24 hours. Carboplatin at doses of 15 and 30 µM was added 24 hours after plating (Day 1). 9cUAB30 at doses of 0.5, 1, and 3 µM was also added at 24, 72, and 120 hours after plating (Days 1, 3 and 5). On Day 7, cell viability was assessed using adenosine triphosphate (ATP) assays.
Results: Mean cytotoxic values (expressed as % of untreated control) were calculated for 9cUAB30 monotherapy. On average, 6% cytotoxicity was observed at the lowest dose (0.5 µM,) compared to 48% cytotoxicity at the medium dose (1 µM) and 66% cytotoxicity at the highest dose (3 µM). Addition of 9cUAB30 at doses of 1 and 3 µM significantly reduced cell viability (p&lt;0.01) compared to controls. When used in combination with carboplatin (30 µM), 9cUAB30 at doses of 0.5, 1 and 3 µM resulted in 71%, 85% and 91% cytotoxicity, respectively. When used in combination with a lower dose of carboplatin (15 µM), 9cUAB30 at doses of 0.5, 1 and 3 µM resulted in cytotoxicity of 67%, 83% and 89%, respectively. Addition of 9cUAB30 to carboplatin at either 15 or 30 µM significantly reduced cell viability when compared to carboplatin alone (p&lt;0.01).
Conclusion: In previous studies of acute promyelocytic leukemia, a dose of 5 µM 9cUAB30 was commonly used for in vitro studies. In ovarian cancer, lower doses of this novel retinoid can be used to achieve significant cytotoxicity. The combination of carboplatin and 9cUAB30 provided additional ovarian cancer cellular cytotoxicity. Further in vivo studies in ovarian cancer xenografts models are underway to determine if this novel retinoid compound enhances efficacy in combination with standard chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 181. doi:10.1158/1538-7445.AM2011-181
Abstract 1812: Effects of vitamin D on obesity-induced increase in ER-positive and ER-negative mammary cancer in mice
Authors: Yu Wei , Kim Dominic , Sumis Allison , Hilakivi-clarke Leana 
Published: June 2012

Abstract
We have previously found that dietary exposure to vitamin D (VD3) reverses the increase in endometrial cancer in obese Pten+/- mice. Since obesity also increases breast cancer risk and recurrence, this study investigated whether VD3 supplementation may inhibit development of mammary cancer in obese mice. As the protective effect of VD3 in the endometrium was not related to the estrogen receptor (ER), we pursued another potential pathway and determined whether VD3 reverses obesity-induced insulin resistance. Methods: Two mouse models were used: DMBA-treated C57BL/6 mice developing ER positive (ER+) mammary tumors, and Pten+/- mice which develop triple negative mammary tumors. C57BL/6 mice were wild type littermates of the Pten+/- mice. Mice in the two models were divided into four groups after weaning, and they were fed (a) AIN93G based control diet, (b) diet supplemented with 20K IU VD3, (c) obesity-inducing diet (OID), or (d) OID supplemented with 25K IU VD3. Results: OID induced insulin resistance and increased mammary tumorigenesis in both C57BL/6 and Pten+/- mice. VD3 significantly inhibited ER+ (p&lt;0.05) and ER- (p&lt;0.04) mammary cancer, but did not reverse the obesity-induced increase in cancer risk. Results obtained in the insulin tolerance test, however, indicated that VD3 prevented the development of insulin resistance in the OID fed obese C57BL/6 and Pten+/- mice. Conclusions: Dietary exposure to VD3 protects against development of ER+ and triple negative mammary cancer, but only in lean mice. VD3 supplementation also prevents insulin resistance in obese mice, but this is not sufficient to reduce mammary cancer risk in either C57BL/6 or Pten+/- mice
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1812. doi:10.1158/1538-7445.AM2011-1812
Abstract 1819: Fecal RNA test using microRNA expressions of exfoliated colonocytes for colorectal cancer screening
Authors: Koga Yoshikatsu , Yasunaga Masahiro , Takahashi Amane , Kuroda Junichiro , Matsumura Yasuhiro 
Published: June 2012

Abstract
Background & Aims: To reduce the mortality rate of colorectal cancer (CRC), the development of a screening test for its early diagnosis is needed. We have been developing new CRC screening methods by applying molecular biological tools to exfoliated colonocytes. As part of this development, we have reported in the last few years the fecal RNA test using CRC-related gene expression analysis for CRC screening. In this study, we conducted microRNA (miRNA) expression analysis in exfoliated colonocytes isolated from feces for CRC screening.
Methods: We initially analyzed CRC-related oncogenic miRNAs (miR-17-92, miR-21, and miR-135) in CRC tissue and exfoliated colonocytes. We subsequently selected other oncogenic miRNAs for CRC detection using TaqMan MicroRNA Array v3.0 (corresponds to miRBase release 14). We finally analyzed all oncogenic miRNA expressions in colonocytes isolated from feces from 197 CRC patients and 119 healthy volunteers by quantitative real-time PCR.
Results: miR-17-92, miR-21, and miR-135 showed a significantly higher expression in CRC tissue than in normal tissue. The overall sensitivity of miRNA expression analysis in the exfoliated colonocytes was 74.1% (146/197, 95% CI; 67.4-80.1) and the specificity was 79.0% (94/119, 95% CI; 70.6-85.9). Because the sensitivity and specificity using CRC-related oncogenic miRNA expressions were relatively low, we selected 12 miRNAs as candidates of CRC detection using TaqMan MicroRNA Array v3.0. Conclusions: We have indentified suitable miRNAs for CRC detection in exfoliated colonocytes. Additionally, we report the overall sensitivity and specificity of miRNA expression analysis in exfoliated colonocytes using these oncogenic miRNAs in this annual meeting. miRNA expression analysis of colonocytes isolated from feces may be useful for CRC screening.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1819. doi:10.1158/1538-7445.AM2011-1819
Abstract 1821: Marital status and adherence to scheduled free breast cancer screening among uninsured inner city women
Authors: Spencer Cherie , Higginbotham Kimberly , Williams Carla , Miller Kim , Lea Kelda , Anders Kyle B. , Frederick Wayne A.I. , Laiyemo Adeyinka O. 
Published: June 2012

Abstract
Background: Mammography screening is associated with reduction in mortality from breast cancer. Women with lower socioeconomic status have increased burden from breast cancer which may be attributable to lower access and uptake of screening. The impact of family support in promoting uptake of breast cancer screening among women with low socioeconomic status is not well understood.
Aim: We sought to examine whether marital status influences adherence to scheduled free breast cancer screening with clinical breast examination and mammography among uninsured inner city women.
Methods: Howard University Cancer Center offered free breast cancer screening (clinical breast examination and mammogram) for uninsured women who are aged 40 and older in the Washington DC area. Participants were referred from community health organizations’ outreach programs in Maryland, District of Columbia and Maryland. Our analytic cohort comprises patients who were scheduled for free breast cancer screening from July 2009 to June 2010. The participants were categorized as non-adherent (no shows) if they did not cancel their appointments and did not show up for the breast cancer screening. We used Poisson regression models to evaluate the association of race with adherence to the scheduled breast cancer screening and adjusted for potential confounders. We calculated Relative Risks (RR) for no shows and 95% Confidence Intervals (CI).
Results: A total of 460 patients were scheduled for screening. The mean age was 49.7 years; 195 (43.4%) were Hispanic and 215 (47.9%) were black. 186 (41.3%) patients were married and 264 (58.7%) were not. Married patients were less likely to be born in the United States (6% vs 21%; P &lt; 0.0001) but were comparable in age with unmarried patients (mean age = 49.4 years vs 50.4 years; P = 0.239). 345 (75%) patients showed up but 115 (25%) were non-adherent for their scheduled appointment. When compared with unmarried patients, married patients were less likely to be non-adherent to their breast cancer screening appointment, adjusted RR = 0.58; 95%CI: 0.40 – 0.84, P value = 0.004.
Conclusions: Although a quarter of uninsured women are non-adherent for their free breast cancer screening appointments, married women are less likely to be non-adherent. This suggests that educational outreach programs targeting men may be a potential mechanism to increase uptake of breast cancer screening among underserved women.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1821. doi:10.1158/1538-7445.AM2011-1821
Abstract 1824: Effects of high-fat diet feeding on solid tumor growth and lung metastasis in the Lewis lung cancer allograft model
Authors: Song Hyerim , Park Heesook , Park Jung Han Yoon 
Published: June 2012

Abstract
Epidemiological studies indicate that overweight and obesity are associated with increased risk of developing several cancers. In the present study, we determined whether a chronic consumption of a high-fat diet increases solid tumor growth and metastasis in the C57BL/6N mouse lung cancer allograft model. Four-week old, male C57BL/6N mice were fed a purified diet containing 34.9% (w/w) fat (high fat diet) or 4.3 % fat (control diet) for 16 weeks, and then Lewis lung carcinoma cells were subcutaneously injected at 5 × 104 cells per mouse into the animals’ left flank. The primary tumor was resected 3 weeks later, and all animals were killed 21 days after the surgery. The high-fat diet feeding significantly increased the body weights and energy intakes as compared with those in the control diet group. The weights of the liver, spleen, epididymal fat pad, and mesenteric fat pad were increased in the high-fat diet group compared to the control group. The high fat diet increased solid tumor growth as well as the number and the size of colonies in the lung. Immunohistochemical staining of tumor tissues revealed that the expression of Ki67 (prototypic cell cycle related nuclear antigen), CD45 (phospho-tyrosine phosphatase), CD31 (platelet endothelial cell adhesion molecule-1), vascular endothelial growth factor (VEGF), cyclin-dependent kinase 4, cyclin A, and cyclin D1 was significantly increased in the high-fat diet group compared to the control group. The high-fat diet feeding significantly increased the blood levels of leptin, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), granulocyte-colony stimulating factor (G-CSF), triggering receptor expressed on myeloid cells-1 (TREM-1), angiopoietin-1 (Ang-1), chemokine ligand 16 (CXCL16), plasminogen activator inhibitor-1 (PAI-1), and stromal cell-derived factor-1 (SDF-1) compared to the control group. Results of the present study indicate that the prolonged consumption of a high-fat diet enhances the secretion of cytokines, chemokines, matrix metalloproteinases, and angiogenesis-related proteins and increases the infiltration of macrophages into tumor tissues which, in turn, stimulate the proliferation and metastasis of lung cancer cells. The increased angiogenesis probably contributes to increased tumor growth and metastasis in mice fed on a high-fat diet.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1824. doi:10.1158/1538-7445.AM2011-1824