bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4332: Evaluation of arachidonic acid pathways with prognosis in patients with surgically resected non-small cell lung cancer
Authors: Su Yinghao , Zhang Ming-Zhi , Wen Wanqing , Zheng Wei , Eisenberg Rosana , Massion Pierre P. , Cai Qiuyin
Published: August 2015

Background: Arachidonic acid (ARA) is a polyunsaturated fatty acid present in the phospholipids of cell membranes. ARA is metabolized through two major pathways, cyclooxygenase (COX) and lipoxygenase (LOX), resulting in various biologically active eicosanoids, such as prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids. Cumulative evidence from both in vitro and animal studies suggests that COX and LOX pathways may be involved in the development and progression of lung cancer by regulating multiple biological processes. However, no direct evidence exists to connect key enzymes of COX and LOX pathways with prognosis of non-small cell lung cancer (NSCLC). We conducted a study to evaluate the association of protein expression of major enzymes in the COX and LOX pathways with prognosis of NSCLC. Materials and Methods: Included in the study are 98 patients with surgically resected NSCLC. The archived paraffin-embedded tumor tissue blocks were retrieved, and tissue microarray were constructed with at least two cores for most cases. Clinical data were obtained from medical records. Expression levels of COX-2, 12-LOX, 15-LOX-1, 15-LOX-2, 5-LOX activating protein (FLAP), and 11β-hydroxysteroid dehydrogenase type I (11βHSD1) and type II (11βHSD2) were evaluated immunohistochemically. Odds ratios (OR) of death were estimated using logistic regression models with adjustment for age at diagnosis, BMI, smoking status, and tumor stage. Results: All seven assayed markers were significantly correlated with one another (r = 0.299 - 0.658, P < 0.01). We observed that a higher level of COX-2 protein expression was associated with advanced tumor stage (P = 0.026). A higher level of 15-LOX-1 protein expression was associated with significantly increased risk of death (OR = 3.27, 95% CI 1.01 - 10.5, P = 0.048) and a higher level of 11βHSD1 protein expression was associated with a marginally significant increased risk of death (OR = 2.67, 95% CI 0.86 - 8.31, P = 0.089). No association of other markers with lung cancer death was found. Conclusions: 15-LOX-1 and 11βHSD1 may be prognostic markers for NSCLC. Validation of the findings in an independent patient cohort is warranted.

Citation Format: Yinghao Su, Ming-Zhi Zhang, Wanqing Wen, Wei Zheng, Rosana Eisenberg, Pierre P. Massion, Qiuyin Cai. Evaluation of arachidonic acid pathways with prognosis in patients with surgically resected non-small cell lung 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 4332. doi:10.1158/1538-7445.AM2015-4332
Abstract 4338: Clinical significance of soluble CD26 in malignant pleural mesothelioma
Authors: Fujimoto Nobukazu , Ohnuma Kei , Aoe Keisuke , Hosono Osamu , Yamada Taketo , Kishimoto Takumi , Morimoto Chikao
Published: August 2015

There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.

Citation Format: Nobukazu Fujimoto, Kei Ohnuma, Keisuke Aoe, Osamu Hosono, Taketo Yamada, Takumi Kishimoto, Chikao Morimoto. Clinical significance of soluble CD26 in malignant pleural mesothelioma. [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 4338. doi:10.1158/1538-7445.AM2015-4338
Abstract 4340: Nuclear expression of antizyme inhibitor is associated with poor prostate cancer prognosis
Authors: Wang Liangzhe , Xu Yingjie , Wu Shulin , Fergus Mary , Wu Chin-Lee , Zetter Bruce
Published: August 2015

Novel molecular markers that are associated with prostate cancer progression are needed to provide more useful information for the diagnosis and treatment of this disease. The antizyme inhibitor (AZI), a non-enzymatic homologue of ornithine decarboxylase (ODC), is upregulated in many cancer types, including: prostate cancer, breast cancer, hepatocellular carcinoma and non-small cell lung cancer. In this study, we examined the distribution of AZI in benign prostate tissues and in prostate cancers at differing stages. We were interested specifically in the possible correlation between AZI expression and patient survival. We found that AZI can reside in the cytoplasm and/or nuclear space in prostate cancer tissue. Nuclear AZI was observed in nearly all of the prostate cancer specimens but not in benign prostate tissue. Cytoplasmic AZI was found both in tumor cells and in adjacent benign prostate tissue. Nuclear AZI was associated significantly with prostate-specific antigen recurrence-free survival but not with overall survival. Further, we found that the presence of nuclear AZI could distinguish poor survival in lower grade patients (Gleason score ≤ 7), especially in samples with non-cribriform tumors. Our results demonstrate a potential role for nuclear AZI as an independent marker of patient outcome in prostate cancer patients.

Citation Format: Liangzhe Wang, Yingjie Xu, Shulin Wu, Mary Fergus, Chin-Lee Wu, Bruce Zetter. Nuclear expression of antizyme inhibitor is associated with poor prostate cancer prognosis. [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 4340. doi:10.1158/1538-7445.AM2015-4340
Abstract 4344: Olfactomedin 4 plays a tumor-suppressor role and is a novel candidate biomarker in the prostate cancer progression and independent of PSA
Authors: Li Hongzhen , Chen Ye , Liu Wenli , Zhu Jianqiong , Kay Chin , Wang Xujing , Rodgers Griffin P.
Published: August 2015

Prostate cancer is the most commonly diagnosed solid tumor and the second leading cause of cancer-related death in the American male population. The olfactomedin 4 gene (OLFM4) plays critical tumor suppressor roles in human and murine prostate cancer. We have previously reported that loss or reduce of OLFM4 expression is associated with the progression of human prostate cancer. We further found that loss of Olfm4 leads to prostate neoplastic progression in the Olfm4-knockout mouse model.

To study the clinical impacts of OLFM4 gene in the prostate cancer, we have performed bioinformatics analysis from the published datasets, GSE35988, GSE21032 and TCGA as well as immunohistochemical analysis with prostate cancer tissue arrays by using OLFM4 antibody. The copy number variations (CNV) of OLFM4 gene were significantly associated with Gleason scores of prostate cancer. The pattern of OLFM4 CNV is similar with other tumor suppressor genes, RB1, PTEN and P53. We have observed consist reduce or loss of mRNA expression in the castrate resistant and metastatic prostate cancer patient samples. To study the relationship between OLFM4 expression and prostate cancer recurrence, we performed Kaplan-Meier Plots and Log-rank statistic analysis for GSE21032 and TCGA data sets. Overall, there was no significant relationship between OLFM4 expression and prostate cancer recurrence. However, when analysis was restricted to the lower quartile of OLFM4 expression, we obtained a highly significant inverse relationship (p = 0.02) between OLFM4 expression and recurrence. We also observed that alteration of CNV and expression of OLFM4 gene has no relationship with the level of (patient) serum prostate specific antigen (PSA).

We performed immunohistochemical analysis with prostate cancer tissue arrays by using OLFM4, PSA and E-cadherin antibodies. Lower or loss of expression of OLFM4 protein is associated with advanced Gleason scores of prostate cancer specimens. The pattern of OLFM4 protein expression in prostate cancer patient samples is similar to that of E-cadherin, but not PSA.

Taken together, these results suggest that OLFM4 plays a tumor-suppressor role, and therefore is a likely therapeutic target for prostate cancer interdiction.

Citation Format: Hongzhen Li, Ye Chen, Wenli Liu, Jianqiong Zhu, Chin Kay, Xujing Wang, Griffin P. Rodgers. Olfactomedin 4 plays a tumor-suppressor role and is a novel candidate biomarker in the prostate cancer progression and independent of PSA. [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 4344. doi:10.1158/1538-7445.AM2015-4344
Abstract 4346: Prognostic gene signature for intermediate risk prostate cancer
Authors: Li Brian , Hallet Robin , Wu Ying , Pong Greg , Hassell John , Hotte Sebastien , Levine Mark , Lukka Himansu , Bane Anita
Published: August 2015

The over treatment of prostate cancer patients is a significant concern, as recent clinical trials suggest that many patients are over treated which can lead to significant patient morbidity. Although the Gleason score is a powerful predictor of lethal or indolent disease, a significant proportion (∼40%) of men present with early stage Gleason score (GS) 7 tumors, for whom prognosis is variable. The goal of this study is to develop and optimize a robust prognostic gene signature that can be utilized on formalin fixed paraffin embedded (FFPE) core biopsy tumor material to better classify patients with intermediate risk, GS 7 tumors into good and poor outcome groups.

Three gene signatures were derived from publicly available gene expression profiles of the Swedish Watchful Waiting cohort. The Genomic Grade Index consisted of the top 25 molecular signatures discriminating between high (8, 9 & 10) and low (≤ 6) GS tumors. The Lethal Gene Score consisted of the top 25 molecular signatures discriminating between lethal and indolent disease within GS 7 tumors only. A network-based gene signature consisted of 88 genes which accurately stratified GS 7 patients into high risk and low risk groups, resembling the survival curves of high GS and low GS patients. The prognostic capacity of the combined gene signature was tested in silico on the gene expression profiles of the Mayo cohort. Results demonstrated the gene signature's highly robust capacity for differentiating low risk and high risk patients within GS 7 patients.

The NanoString nCounter System will be used to quantify mRNA from prostate FFPE blocks to assess the expression of the 138 prognostic genes. 156 archived prostate tumor blocks will be collected from intermediate risk, GS 7 patients enrolled in the 2005 PR5 prostate trial, which also collected 12 years of clinical follow-up information. Results will be correlated with biochemical (PSA) failure rates and overall survival.

In short, our findings provide proof-of-principle that through the use of gene signatures it is possible to separate prostate cancer patients of intermediate risk into good and poor outcome groups. Furthermore, they also identify multiple gene candidates whose expression could likely be formulated into a clinically applicable assay, the implementation of which could serve to stratify prostate cancer patients with tumors of intermediate risk into more accurate high and low risk groups.

Citation Format: Brian Li, Robin Hallet, Ying Wu, Greg Pong, John Hassell, Sebastien Hotte, Mark Levine, Himansu Lukka, Anita Bane. Prognostic gene signature for intermediate risk prostate 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 4346. doi:10.1158/1538-7445.AM2015-4346
Abstract 4356: Factors predicting lymph node metastasis in resected lung adenocarcinoma of 2cm or smaller
Authors: Hung Jung-Jyh , Chou Teh-Ying , Wu Yu-Chung , Hsu Wen-Hu
Published: August 2015

Objective: The predictive value of the new International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) classification of lung adenocarcinoma predicting lymph node metastasis in lung adenocarcinoma has not been well demonstrated.

Methods: Histological classification of 246 patients undergoing anatomical resection for lung adenocarcinoma of 2cm or smaller was determined according to the IASLC/ATS/ERS classification with recording of the percentage of each histologic component (lepidic, acinar, papillary, micropapillary, and solid). Their predictive value of lymph node metastasis was investigated.

Results: Among the 246 patients, there were 215 (87.4%) patients with N0 status, 13 (5.3%) with N1 status, and 18 (7.3%) with N2 status. Greater tumor size (P < 0.001) and predominant pattern group (micropapillary/solid predominant) (P = 0.001) were significantly associated with higher percentage of N1 or N2 lymph node metastasis. In multivariate analysis, greater tumor size (P < 0.001), and micropapillary/solid predominant pattern (P = 0.029) were significant predictors of N1 or N2 lymph node metastasis in tumors of 2cm or smaller. Micropapillary/solid predominant pattern (P = 0.031) was also a significant predictor of N2 lymph node metastasis in multivariate analysis.

Conclusions: The IASLC/ATS/ERS classification has significantly predictive value on lymph node metastasis in lung adenocarcinoma of 2cm or smaller. Micropapillary/solid predominant pattern is a predictor of lymph node metastasis.

Note: This abstract was not presented at the meeting.

Citation Format: Jung-Jyh Hung, Teh-Ying Chou, Yu-Chung Wu, Wen-Hu Hsu. Factors predicting lymph node metastasis in resected lung adenocarcinoma of 2cm or smaller. [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 4356. doi:10.1158/1538-7445.AM2015-4356
Abstract 4373: Targeting lung cancer stem cells with inhibition of multiple drug resistance by demethoxylcurcumin-carrying chitosan-antibody core-shell nanoparticles
Authors: Chiou Shih-Hwa
Published: August 2015

Lung adenocarcinoma (LAC) has been clinically realized to be one of the most deadly malignant tumors with relatively low in 5-year survival rate. High recurrence rates and drug-resistance potential have been reported in LAC even after completion of combined therapy. Herein we demonstrate that cisplatin treatment selecting for resistance with high self-renewal and invasive capabilities in cisplatin-resistant LAC cell (CisR-LAC). For overcoming the multi-drug resistance (MDR) in CisR-LAC, we designed a multifunctional nanocarrier with enhanced targeting ability and inhibition of MDR inhibition in CisR-LAC. The platform provide a high anti-MDR efficacy via a facile synthesis scheme using an amphiphilic chitosan to encapsulate a demethoxylcurcumin (DMC), as a core phase, following surface modification of an anti-EGFR layer, forming a CHC-DMC/anti-EGFR core-shell nanostructure. Experimental outcomes revealed an enhanced therapeutic efficacy of the DMC, forming DMC nano-precipitates in lysosome and endosome, as a result of efficient cellular endocytosis of the core-shell nanoparticles, by a synergistic action of both MDR inhibition and efficacious cell killing. Animal study showed a significant therapeutic efficacy against CisR-LAC-xenograft lung tumor using the core-shell nanocarriers, by a reduction of as high as 5-folded tumor volume compared with control groups. This result indicated the multi-therapeutic efficacy of the multifunctional CHC-DMC/anti-EGFR core-shell nanoparticle, providing a potential capability in anti-MDR LAC for better clinical translation.

Note: This abstract was not presented at the meeting.

Citation Format: Shih-Hwa Chiou. Targeting lung cancer stem cells with inhibition of multiple drug resistance by demethoxylcurcumin-carrying chitosan-antibody core-shell nanoparticles. [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 4373. doi:10.1158/1538-7445.AM2015-4373
Abstract 4374: DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma
Authors: Weygant Nathaniel , Qu Dongfeng , May Randal , Tierney Ryan M. , Berry William L. , Zhao Lichao , Agarwal Shweta , Chandrakesan Parthasarathy , Sureban Sripathi M. , Schlosser Michael J. , Tomasek James J. , Houchen Courtney W.
Published: August 2015

Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and the 8th most common cancer overall in the US. RCC survival rates drop precipitously with regional and distant spread and recent studies have demonstrated that RCC presents an epithelial-mesenchymal transition (EMT) phenotype linked to increased recurrence and decreased survival. EMT is a key characteristic of tumor stem cells (TSCs) along with chemo-resistance and radio-resistance, which are also phenotypic of RCC.

Targeting these factors is key to increasing the survival of RCC patients.

Doublecortin-like kinase 1 (DCLK1) marks TSCs in pancreatic and colorectal cancer and regulates EMT and stemness. Analysis of the Cancer Genome Atlas’ RCC dataset revealed that DCLK1 is overexpressed and dysregulated on the mRNA and epigenetic level in more than 93% of RCC tumors relative to adjacent normal tissue. Immunohistochemistry using α-DCLK1 antibody confirmed overexpression and demonstrated a major increase in immunoreactivity in stage II-III tumors compared to normal kidney and stage I tumors. Small-interfering RNA (siRNA) mediated knockdown of DCLK1 resulted in decreased expression of EMT and pluripotency factors and significantly reduced invasion, migration, focal adhesion, drug-resistance, and clonogenic capacity. These findings suggest that DCLK1 is a novel, overexpressed factor in RCC progression that may be targeted to suppress EMT, metastasis, and stemness in early-stage and advanced RCC to increase patient survival. Moreover, the possibility that DCLK1 may mark a population of tumor stem-like cells in RCC should be further investigated in light of these findings.

Citation Format: Nathaniel Weygant, Dongfeng Qu, Randal May, Ryan M. Tierney, William L. Berry, Lichao Zhao, Shweta Agarwal, Parthasarathy Chandrakesan, Sripathi M. Sureban, Michael J. Schlosser, James J. Tomasek, Courtney W. Houchen. DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma. [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 4374. doi:10.1158/1538-7445.AM2015-4374
Abstract 4375: Podoplanin (PDPN): novel biomarker and chemotherapeutic target
Authors: Krishnan Harini , Ochoa-alvarez Jhon , Shen Yongquan , Nevel Evan , Kephart David , Nguyen Angels , Han Min , Acharya Nimish , Nagele Robert , Ramirez Maria , Miller W. Todd , Kalyoussef Evelyne , Baredes Soly , Fatahzadeh Mahnaz , Jensen Lasse , Shienbaum Alan , Goldberg Gary
Published: August 2015

Cancer is a leading cause of death. In fact, cancer killed over 8 million people around the world in 2012. Over 90% of these cancer deaths are due to metastasis, which results from tumor cell migration and invasion. Specific cancer biomarkers need to be identified in order to effectively target these motile cells. The transmembrane glycoprotein receptor podoplanin (PDPN) promotes tumor cell motility and metastasis in many aggressive cancers. Indeed, PDPN has emerged as a prime cancer biomarker and chemotherapeutic target. Here, we describe how PDPN can be targeted to inhibit the growth and motility of melanoma and oral cancer cells. PDPN has a short intracellular domain of 9 amino acids which include two conserved serine residues. PDPN also has a large extracellular domain that is extensively O-glycosylated with α2,3-sialic acid linked to galactose. We are developing novel methods to target the intracellular and extracellular domains of PDPN to combat cancer progression. For example, we have found that some activators of protein kinase A can induce phosphorylation of the intracellular serine residues of PDPN to inhibit tumor cell migration. In addition, we have found that Maackia amurensis seed lectin (MASL) can target the extracellular domain of PDPN to inhibit tumor cell growth, migration, and tumor progression in cell culture and animal models. Furthermore, we utilized live cell imaging to find that PDPN expression can be modulated in cancer associated fibroblasts to inhibit neighboring tumor cell migration and survival. Thus, reagents can be used to target PDPN from inside of the cell and outside of the cell to inhibit tumor cell migration and combat cancer progression. This work illuminates novel strategies designed to exploit PDPN as a functionally relevant biomarker and chemotherapeutic target.

Citation Format: Harini Krishnan, Jhon Ochoa-alvarez, Yongquan Shen, Evan Nevel, David Kephart, Angels Nguyen, Min Han, Nimish Acharya, Robert Nagele, Maria Ramirez, W. Todd Miller, Evelyne Kalyoussef, Soly Baredes, Mahnaz Fatahzadeh, Lasse Jensen, Alan Shienbaum, Gary Goldberg. Podoplanin (PDPN): novel biomarker and chemotherapeutic target. [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 4375. doi:10.1158/1538-7445.AM2015-4375
Abstract 438: Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis of uterine cervical cancer by recruiting myeloid-derived suppressor cells (MDSCs) via CXCL12-CXCR4 axis
Authors: Sasano Tomoyuki , Mabuchi Seiji , Takahashi Ryoko , Kuroda Hiromasa , Sawada Kenjiro , Kimura Tadashi
Published: August 2015

Objectives: Granulocyte-colony stimulating factor (G-CSF) is known to induce the myeloid-derived suppressor cells (MDSCs) to stimulate the progression of uterine cervical cancer. The aim of this study was to investigate the role of G-CSF and the MDSCs in the invasion and the metastasis of uterine cervical cancer.

Methods: We first established cervical cancer cell lines stably transfected with G-CSF expression vector (ME180-GCSF) or control vector (ME180-control). Then, using mice subcutaneously inoculated with ME180-control or ME180-GCSF cells, the effect of G-CSF on the induction of MDSCs (CD11b+Gr1+ cells) and the metastatic activity of cervical cancer cells. The association of MDSCs infiltration and the clinical outcome was also assessed immunohistochemically using tumor samples obtained from cervical cancer patients. Finally, using MDSCs isolated from the spleen of the ME180-GCSF-bearing mice, we investigated whether the MDSCs facilitate the invasive or metastatic activities of uterine cervical cancer in vitro and in vivo.

Results: 1) ME180-GCSF-derived tumors contain greater number of MDSC, more frequently develop lymphovascular space invasion, and developed greater number of metastatic tumors than ME180-control-tumors. 2) Immunohistochemical analyses using human samples revealed that increased MDSC counts were significantly associated with deep stromal invasion and lymphovascular space invasion. 3) MDSCs were recruited into cervical cancer via CXCL12-CXCR4 axis. 4) Coincubation of MDSCs with ME180 cells increased the invasive activity of ME180 cells. 5) The depletion of MDSCs significantly decreased the invasive and metastatic activities of ME180 cells.

Conclusions: Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis by recruiting MDSCs. MDSCs and CXCL12-CXCR4 axis might be promising therapeutic targets in patients with uterine cervical cancer.

Citation Format: Tomoyuki Sasano, Seiji Mabuchi, Ryoko Takahashi, Hiromasa Kuroda, Kenjiro Sawada, Tadashi Kimura. Granulocyte-colony stimulating factor (G-CSF) facilitates metastasis of uterine cervical cancer by recruiting myeloid-derived suppressor cells (MDSCs) via CXCL12-CXCR4 axis. [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 438. doi:10.1158/1538-7445.AM2015-438
Abstract 4380: IACS-10759: A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities
Authors: Protopopova Marina , Bandi Madhavi , Bardenhagen Jennifer , Bristow Christopher , Carroll Christopher , Chang Edward , Feng Ningping , Gay Jason , Geck Do Mary , Greer Jennifer , Konopleva Marina , Matre Polina , Kang Zhijun , Liu Gang , Muller Florian , Lofton Timothy , McAfoos Timothy , Sun Yuting , Smith Melinda , Theroff Jay , Wu Yuanqiang , Chin Lynda , Draetta Giulio , Jones Philip , Toniatti Carlo , Di Francesco M. Emilia , Marszalek Joseph R.
Published: August 2015

Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks needed to enable continued tumor cell growth. Genetic or epigenetic inactivation of one of these two redundant pathways represents a metabolic vulnerability that should be susceptible to an inhibitor of the other pathway. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent inhibitor of complex I of oxidative phosphorylation. In isolated mitochondria or permeabilized cells, ATP production or oxygen consumption was inhibited at single digit nM concentrations in the presence of malate/glutamate, but not succinate. More directly, IACS-10759 inhibited the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations. Using genetic and pharmacological approaches, the specific complex I subunit inhibited by IACS-10759 has been identified and the mechanism of complex I inhibition is being investigated. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species and achieved significant in vivo efficacy with daily oral dosing of 10-25 mg/kg. Specifically, there was a >50 day extension of median survival in an orthotopic AML cell line xenograft and robust regression in DLBCL and GBM xenograft models. In light of these results, as well as its drug like profile IACS-10759 has entered IND enabling studies with first-in-human studies targeted for third quarter of 2015.

Citation Format: Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Yuting Sun, Melinda Smith, Jay Theroff, Yuanqiang Wu, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-10759: A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities. [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 4380. doi:10.1158/1538-7445.AM2015-4380
Abstract 4383: Vitamin E delta-tocotrienol inhibits metastasis and targets cancer stem cell signaling in human pancreatic cancer
Authors: Husain Kazim , Sebti Said M. , Malafa Mokenge P.
Published: August 2015

Background: Pancreatic cancer, a lethal and aggressive malignancy is the fourth leading cause of cancer-related deaths in the United States. One of the main reasons for this outcome includes the lack of effective prevention strategies for recurrent disease. Pancreatic cancer stem cells (CSCs) have been implicated in the development of pancreatic cancer metastasis, resistance to chemotherapy and its recurrence following surgical extirpation. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the effect of δ-tocotrienol on tumor metastatic EMT, migration, invasion, angiogenesis and CSCs signaling in metastatic human pancreatic cancer cells.

Methods: Human metastatic pancreatic cancer cells L3.6pl expressing luciferase were orthotopically implanted into pancreas of Athymic nude mice (n = 10) and after one week they were randomized in two groups: 1) vehicle control (ethanol extracted olive oil) and 2) δ-tocotrienol (200 mg/kg, orally twice a day) for 4 weeks. The tumor volume, tumor weight, liver and lung metastasis were recorded. The tumor tissues were analyzed for metastasis markers, epithelial to mesenchymal transition (EMT), and angiogenesis. In vitro L3.6pl cells were treated with δ-tocotrienol (50 μM) and used for migration and invasion assay, isolation of CSCs and spheroid formation, transcription factors and CSCs signaling markers were determined by Western blotting.

Results: Vitamin E δ-tocotrienol significantly inhibited the pancreatic tumor growth [tumor volume (50%) and weight (60%)] and metastasis in the liver and lung, CSCs spheroid formation, migration and invasion compared to control. δ-tocotrienol induced apoptosis (PARP1 cleavage and Bax expression) compared to control. δ-tocotrienol also inhibited EMT (E-cadherin to vimentin), metastasis (MMP9), angiogenesis (VEGF), CSCs transcription factors (Nanog, Oct4, Sox2 and KLF4) and oncogenic signaling (Notch-1 and pERK) compared to control.

Conclusion: Vitamin E δ-tocotrienol inhibited metastasis of human pancreatic tumor through inhibition of EMT, migration, invasion, angiogenesis, cancer stem cell signaling and induction of apoptosis.

Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Vitamin E delta-tocotrienol inhibits metastasis and targets cancer stem cell signaling in human pancreatic 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 4383. doi:10.1158/1538-7445.AM2015-4383
Abstract 4397: Preclinical development of a novel hypoxia-activated EGFR inhibitor using a cobalt(III)-based prodrug design
Authors: Heffeter Petra , Karnthaler-Benbakka Claudia , Groza Diana , Kryeziu Kushtrim , Berger Walter , Keppler Bernhard K. , Kowol Christian R.
Published: August 2015

Chemotherapy and therapy with small targeted molecules are two major strategies for therapy of human cancer at the disseminated stage. During the last decades, thousands of compounds have been developed and, consequently, have improved therapy effectiveness. Especially the development of receptor tyrosine kinase inhibitors such as erlotinib or imatinib were major step forwards in cancer treatment. However, despite its success EGFR inhibitor therapy is still limited by strong side effects, resistance development and insufficient tumor accumulation. Aim of the here presented study was the development of novel EGFR inhibitors, which are specifically activated in the malignant tissue. To this end a cobalt(III)-based prodrug strategy was used, which allows targeted release of the active EGFR inhibitor triggered by hypoxic conditions of the solid tumor. As a first step, new inhibitors with bis-chelating moieties were prepared and tested for their efficacy against several cell models with differing EGFR status. The most promising lead candidate was selected based on potent kinase inhibition (confirmed by in vitro kinase assays as well as Western blotting) resulting in activity against EGFR-driven cells in the nM range (MTT assay). Subsequently, the respective cobalt complex was prepared and its activity tested in hypoxia vs. normoxia revealing that the new complex was distinctly more active under hypoxic conditions. Finally, the anticancer activity of the new complex was tested in two xenografts indicationg potent and hypoxia-dependent anticancer activity also in vivo. Summarizing, cobalt(III)-based tumor-targeting represents a promising strategy to reduce the side effects of tyrosine kinase inhibitors such as erlotinib.

Acknowledgements. This work was performed in course of the research platform “Translational Cancer Therapy Research” Vienna, Austria and the COST action CM1105 and supported by “Fonds der Stadt Wien für innovative interdisziplinäre Krebsforschung”.

Citation Format: Petra Heffeter, Claudia Karnthaler-Benbakka, Diana Groza, Kushtrim Kryeziu, Walter Berger, Bernhard K. Keppler, Christian R. Kowol. Preclinical development of a novel hypoxia-activated EGFR inhibitor using a cobalt(III)-based prodrug design. [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 4397. doi:10.1158/1538-7445.AM2015-4397
Abstract 4399: Utilizing cobalt coordination chemistry as a traceless prodrug strategy in targeted drug delivery
Authors: Petros Robby A. , Nguyen Duong T. , Cavazos Ronaldo J. , Morrison Clifford S. , Lampe Jana B. , Harris Alesha N. , McFarlin Brian K.
Published: August 2015

We recently reported the synthesis of albumin nanoparticles using cobalt as a traceless, reductively labile crosslinker. Here, we report in vitro characterization of particle uptake for fluorescently labeled cobalt crosslinked albumin nanoparticles (Co-Alb-FITC NPs) via image-based flow cytometry as well as preliminary toxicity data. Uptake of Co-Alb-FITC NPs by gastric carcinoma cells (SNU-5) was rapid, but could be dramatically reduced through the addition of an inhibitor of macropinocytosis. High levels of non-specific uptake of other particle types were also observed suggesting SNU-5 cells possess high macropinocytic activity. Cancers harboring mutated Ras (>20% of all cancers) are known to take up protein via macropinocytosis to satisfy metabolic demands. Because SNU-5 cells are not known harbor mutated Ras, our findings may indicate that other cancers rely on this mechanism as well, which would have important implications for observing selectivity in active nanoparticle targeting strategies. The Co-Alb NPs themselves were found to exhibit no inherent toxicity. Based on these initial findings, Co-Alb NPs were loaded with the active metabolite of camptothecin, SN-38, to explore their potential as a delivery vector for hydrophobic drugs. An albumin-topotecan prodrug conjugate was also synthesized by crosslinking the amine group in topotecan with lysine residues in the protein, which should be applicable to other amine-containing therapeutics. Characterization of drug loading and release will be discussed along with preliminary in vitro characterization.

Citation Format: Robby A. Petros, Duong T. Nguyen, Ronaldo J. Cavazos, Clifford S. Morrison, Jana B. Lampe, Alesha N. Harris, Brian K. McFarlin. Utilizing cobalt coordination chemistry as a traceless prodrug strategy in targeted drug delivery. [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 4399. doi:10.1158/1538-7445.AM2015-4399
Abstract 4405: Tumor-targeted nanotherapeutics
Authors: Garbuzenko Olga B. , Kuzmov Andriy , Sapiezynski Justin E. , Taratula Oleh , Shah Vatsal , Zhang Min , Savla Ronak , John Shali , Rodriguez-Rodriguez Lorna , Minko Tamara
Published: August 2015

Directing anticancer agents specifically to tumors and/or cancer cells by targeting specific extracellular receptors fulfills the following three most important tasks: (1) preventing or at least substantially limiting adverse side effects on healthy tissues, (2) enhancing drug internalization by cancer cells, and (3) overcoming (at least in part) resistance mechanisms that are based on the active efflux of exogenous drugs from cancer cells.

We developed several tumor-targeted nanoscale-based formulations: various nanocarriers (liposomes, lipid nanoparticles, dendrimers, polymers, quantum dots, mesoporous silica and supermagnetic iron oxide nanoparticles); different anticancer drugs (doxorubicin, paclitaxel, camptothecin, and cisplatin); suppressors of cellular drug resistance and tumor grows (antisense oligonucleotides or siRNA targeted to BCL2, MDR1, MRP1, HIF1A, CD44 mRNA); and tumor-targeting agent - luteinizing hormone-releasing hormone (LHRH).

The proposed nanotherapeutics were tested in vitro and in vivo using established lung and ovarian cancer cell lines and highly metastatic cancer cells isolated from malignant intraperitoneal ascites from patients with advanced ovarian carcinoma. These cells were used to initiate orthotopic models of lung and ovarian cancers in nude mice that were often accompanied by the development of metastases. Tumor-targeted nanoscale-based drug formulations were delivered intravenously and intraperitoneally (for ovarian cancer) or intravenously and by inhalation (for lung cancer). Treatment with the developed therapeutics led to the suppression of targeted proteins, efficient induction of cell death, effective tumor shrinkage, prevention the development of metastases and limitation of adverse side effects.

Acknowledgements: The work was supported by R01CA100098, R01CA111766, and R01CA138533 grants from NIH.

Note: This abstract was not presented at the meeting.

Citation Format: Olga B. Garbuzenko, Andriy Kuzmov, Justin E. Sapiezynski, Oleh Taratula, Vatsal Shah, Min Zhang, Ronak Savla, Shali John, Lorna Rodriguez-Rodriguez, Tamara Minko. Tumor-targeted nanotherapeutics. [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 4405. doi:10.1158/1538-7445.AM2015-4405
Abstract 441: IL-17 and IL-17-producing cells associated with advanced stage or poor prognosis in oral cancers, through enhancing tumor progression
Authors: Lee Meng Hua
Published: August 2015

Introduction: Interleukin 17 (IL-17) majorly produced by Th17 and Tc17 cells, contributes greatly in inflammatory associated diseases. However, its presence was reported to suppress tumor growth by enhancing cytotoxic T cell responses. On the contrary, through inducing angiogenesis, IL-17 appeared to promote tumor progression. Here we demonstrated IL-17 and their producing cells directly correlating with advanced stage or poor prognosis of oral cancer patients.

Methods: Peripheral blood samples were obtained from the oral patients in Chang Gung Memorial Hospital, and the multi-color flow cytometric analysis and enzyme conjugated immunoassays were utilized to identify the IL-17 producing T cell subsets and to quantify the production of inflammation-associated cytokines. The effects of IL-17 on the growth and invasion of oral cancer cells were determined with the supplement with recombinant IL-17 (γhIL-17) and cell culture supernatant.

Results: The significantly increased prevalence of IL-17-producing T cells was correlated with clinical stage and the patients’ peripheral blood mononuclear cells secreted higher amount of IL-17 and other related factors. Such responses also appeared to be associated with poor prognosis. Moreover, the stimulation of γhIL-17 apparently induced cell proliferation, migration and invasion in oral cancer cells, indicating that IL-17 directly contribute to tumor progression.

Conclusion: These findings suggest IL-17 and its related factors are crucial to tumor development, and such responses may therefore lead to the clinical impact of advanced stage or poor prognosis in oral cancer.

Citation Format: Meng Hua Lee. IL-17 and IL-17-producing cells associated with advanced stage or poor prognosis in oral cancers, through enhancing tumor 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 441. doi:10.1158/1538-7445.AM2015-441
Abstract 4411: Oral drug formulations containing microspheres
Authors: Do Duc P. , Kar Alexander
Published: August 2015

Oral anticancer drug formulations are considerably favorable not only for patient adherence, but also for ease of administration. The main objective of the present research was to develop extended-release capsule formulations containing doxorubicin hydrochloride-encapsulated albumin microspheres. Albumin-based polymeric microspheres were evaluated as a potential platform technology for providing extended-release of oral dosage formulations. Bovine serum albumin microspheres were prepared by spray drying and characterized for their physicochemical properties. Scanning electron microscopy (SEM) was used to analyze the size, surface morphology, and size distribution of the drug-loaded microspheres. Zeta potential measurements were carried out to assess the surface properties and stability of the microsphere formulations. Dissolution studies were conducted to analyze the release profiles of the microspheres and capsule-containing microsphere drug formulations. SEM analysis indicated that microspheres were less than 2-μm in size, which is considered to be optimal for uptake by the enterocytes. The average Zeta potential measurements were approximately -30 mV. Additionally, the data showed that microspheres, which contained 1% BSA and 0.1% glutaraldehyde, provided a drug release profile that is desirable for cancer therapy. Both microsphere and capsule-encapsulating microsphere formulations were shown to provide extended-release of the drug over 36 hours. Thus, capsules containing biodegradable microspheres show potential for effective delivery of oral drug formulations.

Citation Format: Duc P. Do, Alexander Kar. Oral drug formulations containing microspheres. [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 4411. doi:10.1158/1538-7445.AM2015-4411
Abstract 4417: Vatalanib targets ABCG2-overexpressing multidrug resistant colon cancer cells under hypoxia
Authors: To Kenneth K. , Poon Daniel C. , Wei Yuming , Wang Fang , Lin Ge , Fu Li-wu
Published: August 2015

Cancer microenvironment is characterized by significantly lower oxygen concentration. This hypoxic condition is known to reduce drug responsiveness to cancer chemotherapy via multiple mechanisms, among which the upregulation of an efflux transporter ABCG2 confers resistance to a wide variety of structurally unrelated anticancer drugs. Vatalanib (PTK787) is a multitargeted tyrosine kinase inhibitor for VEGFR2, Flt and c-Kit, which exhibit potent anticancer activity in vitro and in vivo. We investigated the potentiation effect of vatalanib on the anticancer activity of conventional cytotoxic drugs in colon cancer cell lines under both normoxic and hypoxic growth conditions. More significant synergistic anticancer activity was observed under hypoxic condition. Mechanistically, vatalanib was found to inhibit ABCG2 and P-gp efflux activity, probably by acting as an uncompetitive inhibitor and interfering with their ATPase activity. Under hypoxic growth condition, ABCG2-overexpressing cells sorted out by FACS technique as side population cells (SP) were found to be significantly more responsive to irinotecan (an ABCG2 substrate anticancer drug) in the presence of vatalanib. The colony formation capactiy of these SP cells was remarkably reduced upon treatment with a combination of irinotecan and vatalanib, compared to irinotecan alone. However, vatalanib, at concentrations that produced the circumvention of ABCG2-mediated resistance, did not appreciably alter ABCG2 mRNA or protein expression levels or the phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2). Vatalanib was also evaluated for potential interference with the cytochrome P450 metabolic enzymes by a rapid N-in-one in vitro interaction screening assay. The result indicates that vatalanib is only a mild inhibitor of both CYP34A and CYP2D, two major drug-metabolizing P450 enzymes, which presumably may avoid the undesirable drug-drug interactions in combination therapy. Our study thus advocates the further investigation of vatalanib for use in combination chemotherapy to circumvent hypoxia-mediated drug resistance.

Citation Format: Kenneth K. To, Daniel C. Poon, Yuming Wei, Fang Wang, Ge Lin, Li-wu Fu. Vatalanib targets ABCG2-overexpressing multidrug resistant colon cancer cells under hypoxia. [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 4417. doi:10.1158/1538-7445.AM2015-4417