bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3125: Upregulation of gap junctions with substituted quinolines in colon cancer cells
Authors: Bigelow Kristina M. , Nguyen Thu Annelise
Published: June 2012

Colon cancer is one of the most common cancers in the United States with a high predisposition to metastasize. Furthermore, 30-40% of patients have metastatic disease at the initial diagnosis. Cancer cells exhibit many deficiencies in cell-to-cell communication, particularly gap junctional intercellular communication (GJIC). GJIC has been reported to diminish as cancer cells progress. Gap junctions are intercellular channels composed of connexin proteins, which mediate the direct passage of small molecules from one cell to the next. They are involved in the regulation of cell cycle, cell differentiation, and cell signaling. Previous work demonstrated that connexin proteins such as Cx43, Cx32 and Cx26 have a distinct pattern in SW480, SW620, HT29 and Caco-2 human colon cancer cell lines. The findings suggest that the lack of GJIC, in part due to low level of connexin, may contribute to facilitate colon cancer progression. Since the regulation of gap junction is lost in colon cancer cells, the goal of this study is to restore GJIC in colon cancer cells. Recently, substituted quinolines (PQs), gap junction enhancers, have been shown to increase gap junction activity in breast cancer cells. The level of Cx43 is low in SW620 and SW480 human colon cancer cells. Transfected Cx43 cells have a 6-fold increase of gap junction activity compared to control using scrape load/dye transfer assay. Western blot analysis confirmed that a significant level of Cx43 was expressed in transfected Cx43 cells compared to control. This suggests that overexpressing Cx43 can restore GJIC. Interestingly, 200 nM PQ1 causes a 4-fold increase of gap junction activity as well and subsequently causes a decrease in cell proliferation by 15%. However, TPA, GJIC inhibitor, can reverse the gap junction activity of transfected Cx43 or treated PQ1 cells. Further analysis of Cx43, survivin, and cyclin D1 in treated cells was observed. Overall, the results show that substituted quinolines can directly enhance gap junction activity and attenuate cell proliferation in colon cancer cells. The findings provide an important implication in which restoration of gap junction activity can be targeted for drug development.

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 3125. doi:10.1158/1538-7445.AM2011-3125
Abstract 3134: Neoadjuvant chemotherapy in ER+HER2- breast cancer: Response prediction based on immunohistochemical and molecular characteristics
Authors: Lips Esther H. , Mulder Lennart , De Ronde Jorma J. , Mandjes Ingrid A.M. , Vincent Andrew A. , Vrancken-Peeters Marie-Jeanne T.F.D , Nederlof Petra M. , Wesseling Jelle , Rodenhuis Sjoerd
Published: June 2012

Introduction: A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy (NAC) in ER+HER2- tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be withheld from NAC, we tested standard pathology and molecular markers in ER+HER2- breast tumors.

Methods: Pre-treatment biopsies were available from 211 ER+HER2- tumors, which had been treated with NAC. mRNA expression and aCGH data were available for 132 tumors. We determined progesterone receptor (PR)expression, endocrine responsiveness, histology, proliferation, molecular subtypes and BRCAness aCGH profiles. We correlated these data with chemotherapy response using pCR rates and the neoadjuvant response index (NRI).

Results: PR-negative tumors (n = 65, 30.8%) and Luminal B type tumors (n=43, 20.4%) responded significantly better to NAC than other tumors, for both pCR breast and the NRI as outcome measure (table 1). The associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate (tumors with both a positive PR and of the Luminal A type (n=58, 44 %)), the majority showed downstaging (median NRI=0.25)(table 1). For endocrine responsiveness and the BRCAness aCGH profile only an association with pCR breast was observed. Histology (lobular versus ductal) and proliferation did not show an association with chemotherapy response (table 1).

Discussion: PR expression and molecular subtype are associated with a better response to NAC. However, both markers had only weak predictive power and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain patients from NAC in ER+HER2- breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis.

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 3134. doi:10.1158/1538-7445.AM2011-3134
Abstract 3137: E-cadherin is a useful surrogate maker to predict chemosensitivity of neoadjuvant chemotherapy for breast cancer
Authors: Aomatsu Naoki , Yashiro Masakazu , Kashiwagi Shinichiro , Takashima Tsutomu , Kawajiri Hidemi , Onoda Naoyoshi , Ishikawa Tetsuro , Hirakawa Kosei
Published: June 2012

Background: Current studies have demonstrated that neoadjuvant chemotherapy (NAC) improves the prognosis of patients with breast cancer, however, no reliable maker to predict chemosensitivity of NAC is not available. Although E-cadherin is one of the markers for chemosensitivity in several types of carcinomas, the significance of E-cadherin for chemosensitivity of NAC remains unclear. The aim of this study was to evaluate the value of E-cadherin as a surrogate maker of NAC for breast cancer.

Experimental Design: A total of 104 patients with breast cancer of stage II and III, as evaluated by core needle biopsy and ultrasonography, was treated with NAC, including FEC (5-fluorouracil + epirubicin + cyclophosphamide) followed by weekly paclitaxel. Expressions of E-cadherin, estrogen receptor, progesterone receptor, and HER2 were assessed by immunohistochemistry. Clinical responses and pathological responses were classified according to WHO criteria or The General Rules for Breast Cancer.

Results: A clinical response (responder; complete response + partial response) was observed in 93 (89%) of 104 patients. The pathological complete response rate (pCR) was 29% (30/104). E-cadherin was positive in 60 (57%) of 104 breast cancer. Fifty-eight (96%) of 60 E-cadherin-positive tumors were responders, while 35 (80%) of 44 E-cadherin-negative tumors were non-responders (p=0.005). The pCR rate (37%; 22/60) of E-cadherin-positive tumors also was significantly (p=0.04) higher than that (18%; 8/44) of E-cadherin-negative tumors. Among the 104 breast cancer cases, 32 (31%) revealed a triple-negative phenotype (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative). The pCR of triple-negative breast cancer was 34% (11/32). In the 32 triple-negative breast cancers, the pCR rate (64%; 7/11) of E-cadherin-positive tumors was significantly (p=0.004) higher than that (19%; 4/21) of E-cadherin-negative tumors.Conclusion: E-cadherin might be a clinically useful maker to predicting the response to NAC in breast cancer, especially in triple-negative breast cancer.

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 3137. doi:10.1158/1538-7445.AM2011-3137
Abstract 3138: FOXC1 represses estrogen receptor-α expression via increasing NF-κB activity in breast cancer: A novel mechanism to explain antiestrogen resistance
Authors: Wang Jinhua , Li Guifa , Ray Partha , Sim Myung-Shin , Walter Michael A. , Giuliano Armando E. , Cui Xiaojiang
Published: June 2012

The Forkhead-box transcription factor FOXC1 has recently been identified as a critical marker for human basal-like breast cancer, which lacks or under-expresses estrogen receptor-α (ERα). Here we show a consistent inverse correlation between FOXC1 expression and ERα expression in multiple cDNA microarray data sets of human breast cancer. Overexpression of FOXC1 in ERα-positive breast cancer cells induces cell growth, migration, and invasion, but downregulates ERα mRNA and protein levels and consequently reduces cellular responses to estradiol and tamoxifen. This could explain why tamoxifen-refractory breast cancer cells exhibit higher FOXC1 levels as compared with tamoxifen-sensitive parental cells. We also found that FOXC1 induces NF-κB activation, which is known to be associated with ER-negative breast cancer, by increasing Pin1-mediated p65 protein stability and thus p65 protein levels. NF-κB mediates, at least in part, the regulation of ERα by FOXC1, because inhibition of NF-κB by an IκBα super-repressor and small-molecule inhibitors attenuated the suppression of ERα expression by FOXC1. Furthermore, the importance of the NF-κB pathway in FOXC1-stimulated cell growth was demonstrated by increased cell sensitivity to pharmacologic inhibition of NF-κB. Taken together, these results reveal a novel ERα-regulating mechanism that may explain the loss or low expression of ERα in basal-like breast cancer and also may provide new insight into mechanisms for antiestrogen resistance in breast cancer.

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 3138. doi:10.1158/1538-7445.AM2011-3138
Abstract 3151: Navitoclax enhances the activity of chemo-therapeutic and targeted agents across a large panel of epithelial cancer cell lines
Authors: Wong Maureen , Tan Nguyen , Kassees Robert , Berry Megan , Nannini Michelle , Sampath Deepak , Belmont Lisa
Published: June 2012

Navitoclax (formerly ABT-263), a potent inhibitor of Bcl-2, Bcl-xL, and Bcl-w, has shown promising activity in CLL, a disease in which Bcl-2 is highly expressed. In this study, we wished to explore its potential as a Bcl-xL inhibitor. Bcl-xL is thought to contribute to resistance to cancer therapy in epithelial cancers. Navitoclax and the related molecule, ABT-737, potentiate the activity of chemotherapy and targeted agents in cell lines and mouse models. In order to identify predictive biomarkers of synergy and identify combinations most likely to translate to the clinical setting, we performed combination studies on a panel of 100 cell lines derived from breast, lung, ovarian and pancreatic cancer. We evaluated the combination of navitoclax with gemcitabine, paclitaxel, as well as targeted agents that inhibit EGFR, phosphatidylinositol-3-kinase and MAP kinase pathways. These studies demonstrate that navitoclax is broadly synergistic with these agents as evaluated by a Bliss independence model. The majority of cell lines and combinations exhibited Bliss scores that exceeded the values predicted for two independent agents. Correlative marker analysis revealed that levels of proteins within the Bcl-2 family correlated with synergy scores for chemotherapy combinations, while activation of the EGFR/Ras/Raf pathway was a better predictor for the combinations of navitoclax with targeted agents. Combination studies in xenograft models demonstrate that navitoclax can enhance the activity of chemotherapy and targeted agents in vivo. Furthermore, biomarker expression correlated with response in vivo. These studies suggest distinct strategies for patient selection that are dependent upon the combination agent.

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 3151. doi:10.1158/1538-7445.AM2011-3151
Abstract 3158: Stathmin expression predicts response to taxanes in metastatic endometrial cancer
Authors: Werner Henrica MJ , Trovik Jone , Wik Elisabeth , Akslen Lars A. , Salvesen Helga B.
Published: June 2012

Introduction: Endometrial cancer is the most frequent gynecological cancer in industrialized countries. Although the majority have a good prognosis, up to 20% recurs. To date there are few markers available to predict response to treatment of metastatic endometrial cancer. Patients with tumors expressing estrogen- and progesterone receptors have the best response to antihormonal treatment. Still, more markers are needed to predict response to other therapy modalities in patients with metastatic endometrial cancer. Stathmin is known to have a role in microtubule dynamics. In ovarian cancer it was recently shown that high stathmin expression predicted unfavorable prognosis in patients treated with paclitaxel/platinum chemotherapy. We therefore hypothesize that level of stathmin expression may predict response to microtubule-stabilizing chemotherapy in endometrial cancer.

Material and methods: Between 2001 and 2010, 603 patients treated for endometrial cancer were recruited prospectively in a population based setting. Stathmin expression in primary tumors was measured by immunohistochemistry and linked to treatment response to taxanes in patients with metastatic disease. Response was evaluated by the RECIST criteria and analyzed as partial-/complete response versus stable disease/progression.

Results: Of the 603 patients, a total of 117 either relapsed (n=80) or progressed (n=37) after their first line of treatment. Of these, 87 were treated; with chemotherapy (n=34), radiation (n=38) or hormonal therapy (n=15). The remainder did not receive any further treatment or underwent surgery. Complete information regarding response to therapy according to the RECIST criteria was available in 57 patients. Stathmin expression in primary tumors predicted response to microtubule-stabilising chemotherapy (p=0.02, Fisher Exact test): Amongst patients with low expression of stathmin 11 of 12 (92%) had partial-/complete response, whereas only 2 of 6 (33%) patients with a high level of stathmin had partial-/complete response. Stathmin expression was not associated with response to other treatment modalities.

Conclusion: Stathmin expression in primary tumors predicts response to microtubule-stabilizing chemotherapy in metastatic endometrial cancer. Biologically, this is plausible due to the known function for stathmin in microtubule dynamics. A larger cohort is needed to confirm these data and the usefulness of stathmin expression as a marker for treatment of metastatic endometrial cancer.

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 3158. doi:10.1158/1538-7445.AM2011-3158
Abstract 3168: An antioxidant and DNA repair gene expression pattern associated with lung cancer risk is also associated with COPD risk
Authors: Willey James C.
Published: June 2012

Lung cancer and Chronic Obstructive Pulmonary Disease (COPD) are leading causes of morbidity and mortality both in the United States and worldwide. Inhalation of cigarette smoke is the primary known and preventable cause but only 10-15% of heavy smokers develop these diseases. This suggests that cigarette smoke exposure interacts with inherited susceptibility factors to determine risk. While some susceptibility genes are known, they account for less than 5% of risk for either disease. There is urgent need to identify additional heritable susceptibility factors for these diseases that explain the majority of COPD and lung cancer risk. For example, the National Lung Screening Trial (NLST) recently reported a 20% reduction in mortality from lung cancer. Because there are over 50 million individuals in the US who meet the criteria for the NLST, at a cost of $400/CT scan, the yearly cost of screening could be $20 billion. The objective in this study is to determine the role of inter-individual variation in antioxidant and DNA repair gene transcript regulation in conferring risk for both COPD and lung cancer. The central hypothesis is that inherited DNA variants are associated with increased risk for both COPD and lung cancer and that many of these manifest as increased transcript abundance dispersion in key antioxidant, DNA repair, and transcription factor genes. In support of our hypothesis, we recently identified a lung cancer risk test (LCRT) that comprises transcript abundance values of 14 genes, including nine anti-oxidant, three DNA repair, and two transcription factor genes. For each of these genes, transcript abundance values were dispersed over a greater range in lung cancer compared to matched controls (Blomquist et al, 2009). In addition, inherited DNA variation causes variation in transcript regulation of genes comprised by the LCRT (Crawford et al, 2007;Blomquist et al, 2010). Here we report that in a small number of non-lung cancer cases studied thus far N=13), a subject with positive LCRT value has a 6.7-fold increased likelihood of having COPD (defined by FEV1/FVC<0.7). Development of biomarkers for lung cancer and/or COPD risk will enable prioritization for screening and/or chemoprevention trials and provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals. These developments are expected to reduce mortality and health care costs.

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 3168. doi:10.1158/1538-7445.AM2011-3168
Abstract 3170: Early detection and follow up of head and neck squamous cell carcinoma – A longitudinal serum based biomarker study
Authors: Soudry Ethan , Brait Mariana , Adam Bao-Ling , Gourin Christine , Sidransky David
Published: June 2012

Head and neck squamous cell carcinoma (HNSCC) accounts for more than 37,000 new cases in the US each year. More than half of the patients present in an advanced stage, which confers a poor prognosis. However if detected early this cancer maybe highly curable. Currently there is no biomarker in clinical practice for early detection or prognosis prediction. Many studies are attempting to discover potential biomarkers in tissue, saliva and serum. Promoter methylation suppresses gene expression in cancer and several candidates have been demonstrated to be cancer specific biomarkers. Increased mitochondrial content is another feature that has been demonstrated related to cancer. Our goal is to validate potential biomarkers previously described by our group and others to be linked to HNSCC, in serum samples from a cohort of patients with longitudinal follow up and a subset of normal subjects’ samples. We assessed mitochondrial DNA content (Cox I and Cox II) and methylation status of EDNRB and KIF1a by quantitative PCR in an evaluation set of samples consisting of 75 pre and post treatment serum samples from HNSCC patients and from 11 healthy cancer-free subjects. In tumors, the observed methylation frequencies were 17%, 22% for EDNRB and KIF1a, respectively. There was no observed methylation for EDNRB and KIF1a in normal samples. Increased mitochondrial DNA content was observed in 54% and 59% of the HNSCC samples, by COX1 and COX2, respectively. And no increased content was noted in the normal set. Combining all the markers and analyzing as a panel (at least one positive), we obtained a sensitivity of 83% with specificity of 100%. When we compared post treatment samples to pre treatment samples, we noticed a decreased mitochondrial DNA content in patients without recurrence, and an increase in patients that recurred, however, due to the small number of samples, these associations needs to be confirmed. Our findings indicate that a serum based panel that includes mitochondrial DNA content analysis and cancer specific methylation markers may serve as a high quality detection tool for HNSCC, as well as recurrence prediction. Validation of these preliminary data is ongoing in a larger independent cohort with comprehensive clinical and follow up data.

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 3170. doi:10.1158/1538-7445.AM2011-3170
Abstract 3175: Detection of hypermethylated vimentin gene in urine of colorectal cancer patients
Authors: Song Benjamin P. , Jain Surbhi , Lin Selena Y. , Block Timothy M. , Brenner Dean E. , Su Ying-Hsiu
Published: June 2012

Although the success of cancer treatment often depends on the early detection of cancer, colorectal cancer (CRC) screening is hindered by low compliance rates (40%) of inconvenient, invasive screening tests. Previous studies have demonstrated that urine contains circulation-derived low-molecular-weight (LMW) DNA (<300 bp) and suggested that LMW urine DNA could be used to detect CRC associated genetic alterations. Aberrant hypermethylation of the vimentin gene (mVIM) has been shown to be a potential stool DNA marker for CRC screening. It was of interest to see whether mVIM could be detected in urine of patients with CRC. In this study, we developed a quantitative MethyLight assay targeting a 39 bp DNA template for mVIM. A locked nucleic acid was incorporated at the CpG sites of the reverse primer of the assay to increase the assay sensitivity and specificity for methylated templates. A blinded concordance study between urine and matched CRC tissue was performed. Twenty matched sets of urine and CRC tissue were collected and subjected to DNA isolation. Total urine DNA was further fractionated into both LMW DNA (< 1 kb) and high-molecular-weight (HMW) DNA (>1 kb) fractions. The MethyLight assay was used to quantify the amount of mVIM in each DNA sample. mVIM was detected in 75% (15/20) of the LMW urine DNA fraction, 0% (0/20) of the HMW urine DNA fraction and 85% (17/20) of the CRC tissue DNA. There was a 60% concordance in detecting mVIM between the CRC tissues and their corresponding urine samples. As negative controls, twenty LMW urine DNA fractions from subjects with no known neoplasia were also tested for mVIM and only 10% (2/20) of control samples contained detectable mVIM. mVIM may be a useful part of a urine based genetic biomarker panel for the early detection of CRC.

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 3175. doi:10.1158/1538-7445.AM2011-3175
Abstract 3187: Utility of serum p53 antibodies in patients with various types of malignant tumors
Authors: Hagiwara Nobutoshi , Miyashita Masao , Yamashita Naoyuki , Iida Shinya , Nomura Tsutomu , Makino Hiroshi , Okawa Keiichi , Takahashi Ken , Akagi Ichiro , Shinozuka Eriko , Fujita Itsuro , Kanazawa Yoshiichi , Sakurazawa Nobuyuki , Onodera Hiroyuki , Uchida Eiji
Published: June 2012

Background: Circulating anti-p53 antibody(p53-Ab) in blood can be detected in various cancers. Serum p53-Ab has been applied as a tumor marker in clinical practice. We studied the clinical significance of p53-Ab in patients with esophageal, colorectal, and breast carcinoma.

Methods: p53-Ab in serum was measured with Enzyme-linked immunosorvent assay (ELISA) before treatment in 51 patients with esophageal carcinoma, 54 patients with colorectal carcinoma, and 84 patients with breast carcinoma. clinical and pathological features of these cancers

The association between clinicopathological factors of these cancers and the level of p53-Ab in serum was evaluated.

Results: Twenty-one(41%) of 51 patients with esophageal cancer, 23 (42%) of 54 with colorectal cancer, and 26 (30%) of 84 with breast cancer were diagnosed as p53-Ab positive according to the Manufacture's cut-off value. p53-Abs in serum were observed in all these cancer patients with earlier stage. Positive p53-Ab cases in esophageal, colorectal, and breast cancer in stage I were 33%, 25%, and 35%, respectively. There was no correlation between the positive cases and the age, sex, lymph node metastases, distant metastases, or tumor stage.

Conclusion: This study showed that p53-Ab in serum was frequently detected in patients with esophageal, colorectal, and breast cancer. p53-Ab can be a promising tumor marker for the early detection of these cancers.

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 3187. doi:10.1158/1538-7445.AM2011-3187
Abstract 3191: Immune cell bound MUC16 (CA125): A novel diagnostic marker for ovarian cancer
Authors: Belisle Jennifer A. , Felder Mildred , Kapur Arvinder , Tyler Chanel T. , Connor Joseph P. , Patankar Manish S.
Published: June 2012

MUC16 is a cell surface mucin expressed at high levels by epithelial ovarian cancer cells. Following proteolytic cleavage, cell surface MUC16 (csMUC16) is shed (sMUC16) in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. csMUC16 acts as an adhesion molecule and facilitates peritoneal metastasis of ovarian tumors. Both sMUC16 and csMUC16 also protect cancer cells from cytotoxic responses of natural killer (NK) cells. In a previous study, we demonstrated that sMUC16 binds to a specific subset of NK cells. Here, we demonstrate that in addition to NK cells, sMUC16 also binds to B cells and monocytes isolated from the peripheral circulation and the peritoneal fluid. I-type lectin, Siglec-9, is identified as the sMUC16 receptor on these immune cells. The inhibitory receptor Siglec-9 is expressed on approximately 30-40% of CD16pos/CD56dim NK cells, 20-30% of B cells and >95% of monocytes. sMUC16 binds to the majority of the Siglec-9pos NK cells, B cells and monocytes. sMUC16 is released from the immune cells following neuraminidase treatment. While sMUC16 binds to Siglec-9, it has no affinity for another I-type lectin, Siglec-7. Experiments with Siglec-9 transfected Jurkat cells and monocytes isolated from healthy donors demonstrate that immune cells can bind to ovarian tumor cells via Siglec-9-csMUC16 interaction. sMUC16-Siglec-9 binding is a high affinity and event and the mucin is detected on the surface of the patient-derived immune cells even after the cells have been cultured in vitro in media that does not contain any sMUC16. The MUC16 mucin is also expressed by the human decidua and higher circulating levels of this molecule (measured as CA125) are detected in peripheral circulation of pregnant women. Flow cytometry analysis of immune cells from pregnant women indicates that MUC16 can be detected on the surface of specific subsets of immune cells even when the serum CA125 levels are very low or undetectable. Furthermore, we have observed that sMUC16 is detected on distinct subsets of NK cells of women with preeclampsia as compared to healthy pregnant women and patients with ovarian tumors. Our on-going studies are focused on monitoring sMUC16 binding to specific subsets of immune cells to determine if this information can be used to devise a novel assay for the diagnosis and monitoring of ovarian tumors.

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 3191. doi:10.1158/1538-7445.AM2011-3191
Abstract 3200: HPV status influences the survival of HNSCC patients: A consideration for the TNM staging system
Authors: Ruiz-Fullana Francisco J. , Velez-Reyes German , Garcia Aurian , Trinidad-Pinedo Juan , Báez Adriana
Published: June 2012

Objective: Head and neck cancers are a heterogeneous group of malignancies, affecting various sites with differing prognoses. Accurate and reliable stratification of head and neck squamous cell carcinomas (HNSCC) for prediction of outcomes continues to be very challenging. The TNM staging system for HNSCCs is an important tool for reporting and defining treatment. However, there is increasing evidence for the role of human papillomavirus type 16 (HPV) in the pathogenesis of oropharyngeal SCC and predictive of a better prognoses. We have shown that Puerto Ricans have a high percentage of HPV-positive HNSCC particularly in the larynx. The goal of this study is to evaluate the relevance of HPV-positivity in the prediction of HNSCC patient's outcome together with the TNM staging system.

Methods: Patients presenting to our department with HNSCC until 2005 and whose treatment was surgical were in included in this study. Survival trends (Kaplan-Meier survival curves) were used to evaluate survival differences according to anatomic subsite, HPV status, risk factors and clinicopathological characteristics.

Results: One hundred eight -four patients were included in the study with a median follow-up of 59 months. Distribution according to specific tumor sites was 86 (46.7%) in the larynx; 70 (38%) in the oral cavity, 16 (8.7%) in the oropharynx, and 12 (6.5%) in the hypopharynx. The highest incidence of HPV – positive was in the oropharynx (67%). Multivariate analysis showed that HPV had an independent prognostic effect on the overall survival after adjusting other confounding factors such as histological grade, TNM stage and tobacco usage. The patient of HPV-positive laryngeal SCC showed a statistically longer absolute (p<0.05) and relapse-free (p=0.001) 5-year survival time than the HPV-negative group. However, the difference between HPV- positive and HPV-negative oral cavity tumors was less prominent. Patients younger than 30 years of age presented with advanced tumor stages. Failure pattern in younger age SCC patient may be attributable to biologic behavior.

Conclusion: HPV status on HNSCC patients is a determinant factor in the survival of such patients dependent on tumor site and should be considered in addition to the actual TNM staging system.

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 3200. doi:10.1158/1538-7445.AM2011-3200
Abstract 3214: Identification of a new marker of hepatocellular carcinoma with HBV in female
Authors: Chen-Shiou Wu , Chia-Jui Yen , Chung-Yi Wu , Yung-Luen Yu
Published: June 2012

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Early prognostic markers are needed to allow effective treatments and prevent HCC from developing. Serum alpha-fetoprotein, the currently used clinical marker, is elevated in only approximately 60% of HCC patients; therefore, the identification of additional markers is expected to have significant public health impact. The objective of our study was to discover and validate serum glycoprotein biomarkers in HCC using glycan microarray. We used glycan microarray for quantitative comparison of 188 in serum samples (155 HCC cases, and 33 normal). To explored the diagnostic possibilities of antibody changes as a marker for HCC. In addition, we compared the accuracy of using this serum patterns with the conventional AFP biomarkers for HCC patients. we have shown that the new biomarker with glycan microarray can be useful in the screening of serum biomarkers for HCC. The serum concentration of anti-disialogangliosides in HCC patients was significantly higher than in normal. Besides, in female the anti-gangliosides antibody in HCC patients was significantly higher than in normal. The marker candidates have good prediction sensitivity than AFP in this population. The glycan microarray thus provides a new platform for use to monitor the immune response to carbohydrate epitopes during the course of cancer progression. Additional study of its utility for diagnosis and follow-up is recommended.

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 3214. doi:10.1158/1538-7445.AM2011-3214
Abstract 3217: Influence of PIK3CA mutation and methylation of BNIP3, p16 and Dkk1 on outcome in colorectal cancer
Authors: Iida Satoru , Kato Shunsuke , Ishiguro Megumi , Ishikawa Toshiaki , Kobayashi Hirotoshi , Higuchi Tetsuro , Enomoto Masayuki , Uetake Hiroyuki , Sugihara Kenichi
Published: June 2012

Many studies have exhibited that EGFR pathway triggers a complex program of intracellular signals ant is activated in various human cancers. Among the oncogenic abnormalities that affect this pathway, mutation of PIK3CA and K-Ras mutation are reported to appear most frequently in colorectal cancer (CRC). Epigenetic alteration such as promoter hypermethylation of gene, as well as genetic abnormality such as gene mutation, occurs frequently during the pathogenesis of human cancers. Recent studies exhibit the increasing observations that both epigenetic and genetic changes combine to determine the phenotype of cancer. However, the relationship between PIK3CA and KRAS mutations and methylation status remains uncertain in CRC. Therefore, we examined the mutation of PIK3CA and KRAS and the methylation status of BNIP3, p16 and hMLH1 in CRC and analyzed the influence of the combination of mutation and methylation on prognosis in CRC patients. Tissue samples from 166 CRC patients who underwent surgical resection were examined. The sequences of exons 9 and 20 of PIK3CA and exon 1 of K-Ras were determined by direct sequencing, and the methylation status by MethyLight, using genomic DNA extracted from paraffin-embedded blocks. Correlation between these factors and clinicopathological findings/patients survival were examined. As a result, mutations of PIK3CA and KRAS were found in 12% and 31% of the specimens respectively, and methylations of BNIP3, p16 and hMLH1 in 58%, 33% and 21% respectively. Mutation and methylation of each gene had no correlation with any clinicopathological factor. Patients with PIK3CA mutation and/or two or three methylations had significantly shorter disease-specific survival than those without both mutation and methylation (p=0.0082, Log-rank test). Classifying CRC based on PIK3CA mutation and BNIP3, p16 and hMLH1 methylation status may be a clinically powerful predictor of patient outcome.

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 3217. doi:10.1158/1538-7445.AM2011-3217
Abstract 3218: High pathological CR rate and low recurrence rate was observed in liver metastasis of colorectal cancer after preoperative bevacizumab plus FOLFOX therapy
Authors: Uetake Hiroyuki , Ishikawa Toshiaki , Mitsunori Yusuke , Tanaka Shinji , Arii Shigeki , Sugihara Kenichi
Published: June 2012

[Background] We reported the effectiveness of intraoperative contrast-enhanced ultrasonography using perflubutane (SONAZOIDTM) for complete resection of liver metastasis from colorectal cancer (CRC) after Bevacizumab (Bmab)+FOLFOX therapy (Annual meeting of AACR, 2010). In this study, we report pathological CR (pCR) rate of resected liver tumors and recurrence rate of disappeared lesions that were not resected. [Material and methods] Sixteen patients of advanced CRC with liver metastasis only (no extrahepatic lesion) were treated with Bmab+FOLFOX therapy. Response rate of chemotherapy was 81%. Among the 16 patients, 8 (50%) were underwent liver resection after chemotherapy. We study 6 of the 8 patients, who were followed up longer than a year (20-33 months). [Result] By CT angiography, 47 liver metastases were detected before chemotherapy. By intraoperative contrast-enhanced ultrasonography, 26 liver tumors were detected and resected. In histological examination, 11 (42%) were without viable cancer cell (pCR). Among 21 lesions that were not detected by intraoperative ultrasound and not resected, only 2 lesions were re-detected in follow up period and both lesion were resected. [Conclusion] High pCR rate and low recurrence rate was observed in liver metastasis of colorectal cancer after preoperative Bmab + FOLFOX therapy. Contrast-enhanced ultrasonography was effective for complete resection of liver metastases, as well as low recurrence rate of disappeared lesion after 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 3218. doi:10.1158/1538-7445.AM2011-3218
Abstract 3222: Pre-clinical toxicology and pharmacology of 4-hydroperoxyifosfamide (4-HOOI) and L-lysine salt
Authors: Morgan Lee R. , Rodgers Andrew H. , Struck Robert F. , Jursic Branko S. , Bastian Gerard , Waud William R. , Papiagiannis Chris , Papiagiannis Chris
Published: June 2012

HOOI is a hydroperoxy-derivative of ifosfamide (IFOS) and a pro-drug of isophosphoramide mustard (IPM) [the active metabolite of IFOS] – a bi-functional alkylator that cross-links with G/C DNA base sequences resulting in irreparable inter-strand DNA cross-linking and cell death. HOOI has been an unstable laboratory curiosity for years; however, HOOI.L-lysine is a stable salt complex that has allowed the development of HOOI for clinical trials. HOOI spontaneously releases acrolein and chloroacetaldehyde in situ in cancer cells not extracellular in the general circulation (as does IFOS) and has not been associated with cystitis, renal tubular necrosis and/or CNS toxicity.

HOOI has been screened in 20+ human xenograft tumor and murine tumor models and has significantly improved %ILS in intracranially implanted human xenografts – MX-1, U251; ZR-75-1 and in P399/CPA leukemia vs. IFOS and IPM. The U251 data (%ILS – 84+) is impressive considering – BCNU produced a 72% ILS. The ZR-75-1 breast cancer had a %ILS – 83.

Bone marrow failure was the DLT in mice – LD10 100 mg/kg (for M/F). Dogs (M/F) were treated with 10, 15, 20 and 30 mg/kg. For both sexes, the LD10 was calculated to be 17.2, while the LD50 was calculated to be 17.3 mg/kg. PK values in dogs revealed the following profile for groups dosed with 30 mg/kg: AUC0- t = 1.53 (mg h/L), T1/2α = 0.93 (h), T1/2β = 6.1 (h) & CL = 19.5 (L/ h) [a two compartment model]. The AUC was linear for the 10 and 30 mg/kg doses. HOOI did not generate any detectable plasma chloroacetaldehyde vs. IFOS (2.12 µg/mL from 400 mg/kg) and 25% of the acrolein generated by the MTD of CPA & IFOS. No convulsions, neuropathies or renal dysfunction were observed in either specie.

Unlike IFOS/IPM, HOOI is lipophilic, activated intracellular (with < extracellular acrolein and no chloroacetaldehyde released); no IFOS/IPM-associated CNS or GU toxicity was noted. HOOI may increase the safety and efficacy margins of this class of alkylators in advanced CPA- and IFOS-resistant cancers and broaden the target-range (CNS-gliomas). The L-lysine salt stability supports developing HOOI for clinical trials. Supported by grant R44 CA094566 from the NCI/SBIR program.

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 3222. doi:10.1158/1538-7445.AM2011-3222
Abstract 3229: Thermo-responsive double packaged system for localized drug delivery for cancer treatment
Authors: Williams Eva Christabel , Wiranowska Marzenna , Toomey Ryan , Alcantar Norma
Published: June 2012

This research aims at developing a drug delivery system that will provide a plethora of benefits including cost effectiveness, reduction of toxicity and a control over the release of chemotherapeutics in Ovarian Cancer and Brain Tumor patients. We have designed a drug delivery system consisting of non-ionic surfactant vesicles (niosomes) packaged within a biodegradable, temperature and pH sensitive hydrogel (chitosan) network. Optimization of the release rates were accomplished by altering the molecular weight and cross-link density of the chitosan network and the size of the niosomes. Two chemotherapeutics Paclitaxel and Carboplatin were used for encapsulation. The interaction between niosome and chitosan were observed using Attenuated Total Reflectance- Fourier Transform Infrared (ATR-FTIR) spectroscopy. The drug delivery system was further investigated in human ovarian (OV2008) and human glioma (U373) cell lines. The concentration of the therapeutics used ranged from 0.04-0.4 µg/ml. Confocal imaging of the cells verified that the activity of the drugs remained intact within the niosome-chitosan drug delivery system and cell's toxicity was observed within two hours confirming cellular delivery of the drug. The effect of the niosome-chitosan without the chemotherapeutic drugs on normal cells was also examined indicating that this system is non-toxic. Our results showed that this route of drug delivery to the cancer cells was effective since microtubule stabilization, fragmentation of the nucleus, and condense morphology were noted. Moreover, the time release of the drugs can be finely controlled by varying the crosslinking ratio in the chitosan network from 3:1 (loose network which translates into high release) to 5:1 (tight network which translates into low release). In addition, this system is a liquid solution at room temperature and undergoes a change of phase to a soft, self-containing gel at physiological conditions. The system therefore, can be injected into a tumor site. The materials used to construct this system are low cost and biocompatible and provides a flexible method for drug delivery with applications to intracavitary ovarian cancer and glioma treatment.

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 3229. doi:10.1158/1538-7445.AM2011-3229
Abstract 3234: Fiber optic-guided photosensitizer drug delivery
Authors: Zamadar Matibur , Ghosh Goutam , Mahendran Adaickapillai , Minnis Mihaela , Kruft Bonnie I. , Kruft Bonnie I. , Ghogare Ashwini , Aebisher David , Greer Alexander
Published: June 2012

A fiber optic device has been developed with a maneuverable probe tip that sparges oxygen gas and photo-detaches pheophorbide (sensitizer) molecules. Singlet oxygen is produced at the probe tip surface which reacts with an alkene bridge causing the release of sensitizer upon fragmentation of a dioxetane intermediate. For optimal sensitizer release the probe tip was loaded with 0.3% sensitizer resulting, where crowding of pheophorbide molecules and self-quenching were kept to a minimum. The fiber optic device delivers pheophorbide molecules and singlet oxygen to discrete locations. Site-selective release of pheophorbide occurred in lipophilic media, it was quantitative in petrolatum (petroleum jelly, 100%), and was inefficient in toluene (5%) and water (<1%) due to poor the solvation. The results open the door to applications in tumor eradication in lipophilic and hypoxic structures requiring cytotoxic control.

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 3234. doi:10.1158/1538-7445.AM2011-3234
Abstract 3245: Novel anticancer agents – lead discovery and optimization
Authors: Meng Liping , Wang Don-Hong , Wu Chun-Yi , Lam Kit S.
Published: June 2012

Though cancer chemotherapy helps in successful treating some types of solid tumors, lymphomas, and leukemias, cancer is still responsible for about one in every four deaths in the United States nowadays. Thus, it is urgent to develop novel anticancer agents to overcome the problems of toxicity and resistance of existing cancer chemotherapeutic agents, and eventually to cure cancer. Recently we have found some lead compounds possessing anticancer effects through a novel ultra-high-throughput multiplex screening of OBOC (one-bead-one-compound) small molecule combinatorial library against a M13 phage display cDNA expression proteome library derived from T-lymphoma Jurkat cell. These compounds were able to kill both Jurkat cells and HepG2 hepatocarcinoma cells with IC50s ranging from 15 µM to 80 µM. Further biopanning and pull down results showed that some compounds bounded to EIF5B – a eukaryotic translation imitation factor, which might inhibit the cellular translation initiation and result in apoptosis and eventually cause cell death. The lead optimization was carried out by using the method of “methyl walking” and “deletion studies”. A series of novel derivatives have been synthesized and structure-activity relationship will be investigated.

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 3245. doi:10.1158/1538-7445.AM2011-3245
Abstract 3251: Characterization of a novel Rac inhibitor as an anti cancer metastasis compound
Authors: Ortiz Brendaliz Montalvo , Ofarrill Eliud Hernandez , Hernandez Jonibeth , Vlaar Cornelis , Flanagan Surangani Dharmawardhane
Published: June 2012

The objective of this project is to design novel therapeutics targeting cancer metastasis, the most deadly aspect of epithelial cancers. Our previous studies have shown that Rac, a key signaling intermediate that regulates actin cytoskeletal changes during cell migration/invasion and cancer metastasis, is associated with high cancer metastatic efficiency. Since Rac proteins are activated by GDP/GTP exchange, inhibition of the interaction of Rac with its guanine nucleotide exchange factors (GEF) is expected to inhibit Rac activity. Since the known Rac inhibitor NSC-23766 is not effective at therapeutically useful concentrations, we synthesized novel NSC-23766 derivatives. Results show that the new inhibitor EHop-016 is 100-fold more efficient than the parent compound at inhibiting Rac activity of metastatic cancer cells without affecting the activity of the related GTPase, Rho. EHop-016 inhibited Rac activity of metastatic cancer cells with an IC50 of 0.78 microM. Cell viability assays, performed to test for the toxicity of this compound, demonstrated that at concentrations below 5 microM, EHop-016 did not affect mammary epithelial cell (MCF-10A) viability and decreased proliferation of metastatic cancer cells (MDA-MB-435) by only 20%. We conclude that EHop-16 is a potent Rac inhibitor with promise of further development as a small molecule inhibitor of cancer cell invasion, and thus, metastasis.

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 3251. doi:10.1158/1538-7445.AM2011-3251