bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4684: Medical providers perceive a lack of trust in the medical system leads to suboptimal esophageal cancer care for African American patients
Authors: Sarwar Sumaiya , Kemp Michael T. , Revels Sha'Shonda L. , Eilender Benjamin M. , Houtschilt Steven R. , Akateh Clifford , Reddy Rishindra M.
Published: May 2015

Background: Although patient outcomes for esophageal cancer have improved, there remains a reduced survivorship among African Americans compared to Caucasians, possibly due to lower use of surgery in African Americans. While various factors contribute to this disparity, we noted a decreased referral of African American patients to thoracic surgeons in our institution. We hypothesized that interviews with medical providers would provide the reasons behind the barriers that hinder the ability of minority patients to receive optimal care for esophageal cancer.

Methods: Providers (n=20) in the Detroit Metro area that treat African Americans with esophageal cancer participated in 30-minute semi-structured interviews to elicit their perspectives regarding barriers and facilitators in their care for this population. The interview inquired into the challenges faced and techniques employed by providers in establishing trust within this population. Interviewed providers included thoracic surgeons, medical oncologists, gastroenterologists, and radiation oncologists.

Results: Most providers suggested that socioeconomic status, not race, was the primary barrier to accessing adequate cancer care. Within the African American population, 80% of providers reported that mistrust was not an issue in their personal experiences in treating minorities with esophageal cancer, but 95% of providers cited mistrust in the medical system as a contributing factor to unfavorable outcomes. Providers who indicated mistrust in the medical system referred to historical instances that may deter African American patients from trusting the medical system. Many also cited techniques for establishing trust including honesty and patient empowerment. Finally, 3 of 20 respondents referred to direct experiences where patient refusal to participate in clinical trials may have contributed to poorer outcomes.

Conclusions: Medical providers believe that mistrust in the medical system is a key barrier for African American patients with esophageal cancer to receive optimal care. Further investigation to elicit patient perspectives should be explored through direct patient surveys. Particular attention should be directed toward how African Americans' trust of the medical community affects the use of surgical treatment for esophageal cancer.

Citation Format: Sumaiya Sarwar, Michael T. Kemp, Sha'Shonda L. Revels, Benjamin M. Eilender, Steven R. Houtschilt, Clifford Akateh, Rishindra M. Reddy. Medical providers perceive a lack of trust in the medical system leads to suboptimal esophageal cancer care for African American patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4684. doi:10.1158/1538-7445.AM2014-4684
Abstract 4688: Novel prognostic subtype of hepatocellular carcinoma reflecting stem/maturational status of the tumor defined by Gd-EOB-DTPA-enhanced MRI and serum AFP
Authors: Yamashita Taro , Honda Masao , Kaneko Shuichi
Published: May 2015

Survival of patients with hepatocellular carcinoma (HCC) varies on an individually basis, even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (EOB-MRI) has recently been introduced to evaluate hepatic lesions with regard to the activity of the organic anion transporter OATP1B3 as well as vascularity. Here we report that Gd-EOB-DTPA-Enhanced MRI and serum alpha-fetoprotein (AFP) status reflects the stem/maturation status of HCC with distinct biology and prognostic information. Atypical uptake of Gd-EOB-DTPA in the hepatobiliary phase was observed in ∼ 15% of HCCs. This uptake correlated with the low serum alpha-fetoprotein (AFP) levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A, and good prognosis. In contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP presented poor prognosis with the activation of an oncogene FOXM1. Knockdown of HNF4A in cancer cells, obtained from a surgically resected HCC showing atypical uptake of Gd-EOB-DTPA, resulted in the increase of AFP and FOXM1 and the loss of OATP1B3 expression accompanied with the mesenchymal morphological changes, enhanced cell proliferation and tumorigenesis in vivo. HCC classification based on EOB-MRI and serum AFP level (EOB-AFP classification) predicted overall survival in a retrospective cohort (n = 70), and its prognostic utility was validated in a multi-institution cohort of early-stage HCCs (n = 109). This non-invasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging to improve management algorithms, especially in early stage.

Citation Format: Taro Yamashita, Masao Honda, Shuichi Kaneko. Novel prognostic subtype of hepatocellular carcinoma reflecting stem/maturational status of the tumor defined by Gd-EOB-DTPA-enhanced MRI and serum AFP. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4688. doi:10.1158/1538-7445.AM2014-4688
Abstract 4695: Role of KITENIN in malignant gliomas in relation to tumor invasiveness
Authors: Lee Kyung-Hwa , Moon Kyung-Sub , Ahn Eun-Jeong , Oh Se-Jeong , Cho Sang-Hee , Lee Jae-Hyuk , Jung Shin , Kim Kyung Keun
Published: May 2015

Background: KAI1 C-terminal interacting tetraspanin (KITENIN) has been reported to promote tumor invasion and metastasis in various cancers. The aim of this study was to investigate the effect of KITENIN on biological behaviors in human gliomas and in mouse glioma models.

Methods: KITENIN expression was examined using western blot, qRT-PCR and immunohistochemistry on human samples. KITENIN expression rate was compared in each histological grade, and survival rates were analyzed. Tumor invasiveness was investigated both in vitro and in vivo using stable cell lines after KITENIN-overexpression (GL261) and knock down (U251).

Results: Expression of KITENIN tended to be stronger in high-grade gliomas than in low-grade gliomas by western blot & qRT-PCR on frozen human tumor samples and by immunohistochemistry on paraffin-embedded tissues as well. Proportions of strong KITENIN expression were 16.7%, 21.4%, 33.3%, and 56.8%, respectively, from grade I through IV (p=0.001). However, survival analysis using the Kaplan-Meier method did not reveal statistically significant difference between the high KITENIN expression group and the low expression group in terms of overall survival and progression free survival (p=0.55 and 0.807, respectively). In vitro assays revealed that genetic modulation of KITENIN was significantly related with tumor cell invasion & migration. Up-regulated KITENIN expression significantly affected the survival rate possibly due to increased invasiveness in orthotopic mouse glioma models.

Conclusion: Strong KITENIN expression was more likely to be observed in high-grade gliomas and its up-regulation was associated with increased invasiveness supported by shorter survival rates in orthotopic mouse glioma models.

Citation Format: Kyung-Hwa Lee, Kyung-Sub Moon, Eun-Jeong Ahn, Se-Jeong Oh, Sang-Hee Cho, Jae-Hyuk Lee, Shin Jung, Kyung Keun Kim. Role of KITENIN in malignant gliomas in relation to tumor invasiveness. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4695. doi:10.1158/1538-7445.AM2014-4695
Abstract 4701: Acquisition of Oct-4 upregulation transactivates MDR1 and is associated with increased tumor recurrence in bladder cancer
Authors: Lu Chia-Sing , Shiau Ai-Li , Shieh Gia-Shing , Su Bing-Hua , Su Wu-Chou , Yang Wen-Horng , Wu Chao-Liang
Published: May 2015

Platinum-based drug like cisplatin is the standard first-line drug to treat patients with bladder cancer. However, tumors may recur and develop into multiple-drug resistant characteristics. The acquisition of resistance to conventional chemotherapy is a challenge in the treatment of bladder cancer relapse. Cancer stem cell (CSC) hypothesis has been an attractive theory. CSCs can resist therapeutic assaults, giving rise to multiple drug resistance and promotion of tumor relapse and metastasis. It has been shown that the fraction of cancer cells expressing MDR1 that functions as an energy-dependent drug efflux pump may be associated with Oct-4 expression. We have demonstrated that Oct-4 expression in bladder cancer predicts tumor progression. In the present study, we proposed that Oct-4 expression in bladder cancer increases MDR1 gene expression and thereby results in multiple drug resistance. We found a positive correlation between Oct-4 and MDR1 expression levels in clinical samples of bladder cancer. Furthermore, overexpression of Oct-4 increased MDR1 expression, which resulted in poor response to cisplatin in human bladder transitional cell carcinoma cells. Conversely, knockdown of Oct-4 reduced MDR1 expression and rendered cells hypersensitive to cisplatin. We also verified that Oct-4 transactivated the MDR1 gene promoter by binding to the Oct-4 response element (ORE). More importantly, Oct-4 and MDR1 gene expression could be induced by treatment with cisplatin, suggesting that Oct-4 is a member of the MDR1 enhanceosome. Our data can explain, in part, the high recurrence rate and drug resistance of bladder cancer. For clinical implication, we demonstrated that reduction of Oct-4 expression by all-trans retinoic acid, a derivative of vitamin A, improved sensitivity of bladder cancer cells to gemcitabine and cisplatin. In addition, we found that high expression levels of Oct-4 and MDR1 were associated with high tumor recurrence. Taken together, our results provide evidence that Oct-4 plays an important role in cisplatin-acquired resistance in bladder cancer. They also implicate Oct-4 as a therapeutic target.

Note: This abstract was not presented at the meeting.

Citation Format: Chia-Sing Lu, Ai-Li Shiau, Gia-Shing Shieh, Bing-Hua Su, Wu-Chou Su, Wen-Horng Yang, Chao-Liang Wu. Acquisition of Oct-4 upregulation transactivates MDR1 and is associated with increased tumor recurrence in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4701. doi:10.1158/1538-7445.AM2014-4701
Abstract 4702: Caveolin-1 confers a multi-modality therapy resistance phenotype in pancreatic cancer cells
Authors: Chatterjee Moumita , Williams Terence M.
Published: May 2015

Caveolin-1 (Cav-1) is a 21kDa protein found in 50-100nm omega-shaped invaginations of the plasma membrane known as caveolae. It has been implicated in the processes of oncogenic cell transformation, tumorigenesis and metastasis. Cav-1 is upregulated in pancreatic cancer and has been shown to be correlated with poor prognosis. We hypothesized that Cav-1 promotes resistance to chemotherapy and radiation, and that downregulation may lead to sensitization to radiation and/or chemotherapy. We found that radiation and chemotherapy up-regulate Cav-1 expression, and that downregulating Cav-1 in multiple pancreatic cancer cell lines by small interfering RNA induces sensitization to chemotherapeutics such as gemcitabine and 5-fluorouracil. Furthermore, genetic knockdown causes reduction in tumor cell proliferation and colony formation. Knockdown of caveolin-1 also led to radiosensitization of tumor cells and resulted in delayed DNA repair as demonstrated by delayed pH2.AX foci resolution, increased mitotic catastrophe, as well as decreased formation of BRCA1 and DNAPK-cs foci in the nuclei of these cells. Furthermore, Cav-1 loss promoted cleavage of Caspase-9 and PARP after treatment with gemcitabine. These results indicate that knocking down Cav-1 in pancreatic cancer cells sensitizes them to radiation with delayed DNA damage repair and also to chemotherapeutics with the onset of apoptosis. In vivo, stable knockdown of Cav-1 attenuated the rate of tumor growth significantly compared to control tumors in subcutaneous xenograft pancreatic tumors. In summary we conclude that Cav-1 is responsible in promoting resistance to radiation and chemotherapy in pancreatic cancer cells and that downregulation of this protein leads to improved therapeutic response. Thus, it is possible that caveolin-1 may serve as a prognostic predictive biomarker in pancreatic cancer patients for response to radiation and chemotherapy.

Citation Format: Moumita Chatterjee, Terence M. Williams. Caveolin-1 confers a multi-modality therapy resistance phenotype in pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4702. doi:10.1158/1538-7445.AM2014-4702
Abstract 4709: ERK1/2 regulates hepatocellular carcinoma through proinflammatory homeobox gene, ISX
Authors: Wang Shen-Nien , Hsu Shih-Hsien
Published: May 2015

Intestine-specific homeobox (ISX), a newly identified proto-oncogene, regulated cell proliferation and drives hepatocellular carcinoma (HCC) formation but the underlying mechanisms linking gene expression and tumor formation remain obscure. In this study, we compared the expression of MAPK (ERK1/2), E2F1 and homeobox gene ISX in 190 paired specimens of HCC and adjacent normal tissues, and also in paired specimens from 11 non-HCC patients. In pathological analysis, ERK1/2 and E2F1 , as ISX expression, exhibited a tumor-specific expression pattern and a high correlation to patient survival time, tumor size, tumor number and progression stage. Enforced expression of ERK1/2 translocated cytoplasm ISX into nucleus and increased cell proliferation by which increased downstream E2F1 expression in hepatoma cells through ISX induction. In contrast, dominant negative ERK1/2 and shRNA-mediated attenuation of ERK1/2 in hepatoma cells decreased nucleus translocation, cell proliferation and malignant transformation in vitro and in vivo. A high positive correlation existed in human hepatoma tumors between ISX and ERK1/2 expression. Together, our results highlight ERK1/2 as an important regulator of ISX in hepatoma progression with significant potential as a prognostic and therapeutic target in HCC.

Citation Format: Shen-Nien Wang, Shih-Hsien Hsu. ERK1/2 regulates hepatocellular carcinoma through proinflammatory homeobox gene, ISX. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4709. doi:10.1158/1538-7445.AM2014-4709
Abstract 4712: Personalized ovarian cancer surveillance and detection of a therapeutic drug target in circulating tumor DNA
Authors: Martignetti John A. , Camacho-Vanegas Olga , Priedigkeit Nolan , Camacho-Vanegas Catalina , Pereira Elena , Lin Li , Losic Bojan , Shah hardik , Liao Jun , Ma Jian , Lahiri Pratik , Chee Mark , Schadt Eric , Dottino Peter
Published: May 2015

Retrospective studies have demonstrated that nearly 50% of ovarian cancer patients with normal CA125 levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here we demonstrate that for one patient, with the first reported FGFR2 fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125 and it can also inform on a candidate therapeutic. Over a four year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences and multiple chemotherapeutic regimens, blood samples were longitudinally-collected and stored. Whereas post-surgical CA125 levels were elevated only three times over 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by qtRT-PCR in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and other with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhbitor treatment. Using the same overall approach, ctDNA is demonstrated in other patients and the results compared to CA125. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease. To our knowledge, this use of a personalized biomarker represents the first example in ovarian cancer demonstrating the presence of continuous occult disease in the face of negative clinical, radiologic and biochemical examination. Moreover, the recent identification of FGFR fusions in other solid cancers suggests a broader application of this strategy beyond ovarian cancer.

Citation Format: John A. Martignetti, Olga Camacho-Vanegas, Nolan Priedigkeit, Catalina Camacho-Vanegas, Elena Pereira, Li Lin, Bojan Losic, hardik Shah, Jun Liao, Jian Ma, Pratik Lahiri, Mark Chee, Eric Schadt, Peter Dottino. Personalized ovarian cancer surveillance and detection of a therapeutic drug target in circulating tumor DNA. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2014-4712
Abstract 4716: Discovery of biomarkers from highly enriched prostate cancer microparticles for prognostication of prostate cancer
Authors: Biggs Colleen N. , Guo Quiquan , Yang Jun , Chambers Ann F. , Chin Joseph L. , Power Nicholas , Leong Hon S.
Published: May 2015

Prostate cancer microparticles (PCMPs) are essentially fragments of tumor cells that are present in various bodily fluids such as plasma and urine. By using nanoscale flow cytometry, multiple biomarkers can be assessed on PCMPs in patient plasma, a convenient “fluid biopsy” for prostate cancer (PCa). Discovering biomarkers specific for metastatic PCMPs would establish a non-invasive fluid biopsy for detecting the earliest onset of metastatic disease for patients post-prostatectomy. Discovery of biomarkers specific to Gleason score 6 (3+3) and 8 (4+4) lesions that are decorated on the surface of PCMPs would help establish a non-invasvie fluid biopsy for tumor upstaging (i.e., Gleason 6 to 7) of patients placed on active surveillance who have deferred prostatectomy. We hypothesize that biomarkers specific for metastatic PCMPs or Gleason Score-specific PCMPs can only be discovered via proteomics analysis on highly purified PCMPs from plasmas which have minimal levels of non-target microparticles and plasma proteins. To do this, plasmas were incubated with biotinylated anti-PSMA mAb and PSMA+ve microparticles were isolated from plasma by using a magnetic column after several purification runs. Eluted samples were then submitted to nanoscale flow cytometry in which elution fractions that exhibited minimal non-target microparticle concentrations (<1000 events/uL) were submitted to proteomics analysis. PCMPs from plasma samples representing localized (N=7, lymph node negative, PSA>5 ng/mL, Gleason Score 3+3) and metastatic (N=7, confirmed bone metastases, PSA>10 ng/mL, Gleason 4+4) were isolated, evaluated and submitted for iTRAQ labeling, high pH reversed phase fractionation and LC-MS/MS analysis. All data was analyzed using Proteome Discoverer 1.3 and MASCOT v2.3 software. Mass spectometry analysis revealed 8 proteins significantly upregulated and 5 proteins downregulated in the majority of metastatic plasma samples compared to localized plasma samples. Data was normalized to albumin levels by western blot and mass spectrometry. Based on these results, we have identified 8 proteins that may be specific for a subpopulation of PCMPs from metastatic PCa patients. Out of these, 6 may be candidates for flow cytometry because they are membrane-bound or are cytoskeletal elements potentially exposed to the extracellular space (CLIC1, PVR, YWHAE, KRT16, K1C10, KRT2).

Citation Format: Colleen N. Biggs, Quiquan Guo, Jun Yang, Ann F. Chambers, Joseph L. Chin, Nicholas Power, Hon S. Leong. Discovery of biomarkers from highly enriched prostate cancer microparticles for prognostication of prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4716. doi:10.1158/1538-7445.AM2014-4716
Abstract 4723: Prognostic significance of EGFR expression in localized gastric cancer
Authors: Park Ji Soo , Kim Hyo Song , Bae Yoon Sung , Noh Sung Hoon , Kim Hyunki
Published: May 2015

Background: The role of epidermal growth factor receptor (EGFR) expression as predictive or prognostic biomarker in gastric cancer is still in controversy. The aim of this study is to find prognostic role of tumor EGFR expression in gastric cancer patients after curative resection.

Methods: From January 2000 to September 2003, gastric cancer patients who received curative gastrectomy were included in this study. We retrospectively collected clinical characteristics and survival data of the patients, and analyzed EGFR expression on tissue microarrays from formalin-fixed paraffin-embedded specimens of primary tumor tissues by immunochemical staining (IHC). EGFR expression was scored to 0, 1+, 2+ or 3+ based on intensity of reactivity.

Results: Of total 937 patients, 295 (31.5%) patients, 101 (10.8%) patients and 36 (3.8%) patients showed EGFR 1+, 2+, and 3+ expression by IHC, respectively. EGFR overexpression (2+/3+) is more frequently found in intestinal type than diffuse or mixed type (24.2% vs. 5.1%, P<0.001). In stage III disease according to AJCC 7th edition, unlike other stages, the patients with EGFR overexpression (2+/3+) had longer disease free survival (hazard ratio [HR], 0.639; 95% confidence interval [CI], 0.434-0.938; P=0.022) and longer overall survival (HR, 0.630; 95% CI, 0.445-0.890, P=0.009) than other patients in univariate analysis. Additionally, in 279 patients who had stage III gastric cancer with diffuse type histology and received 5-fluorouracil (5-FU) based adjuvant chemotherapy, EGFR overexpression was favorable prognostic marker for overall survival (HR, 0.365; 95% CI, 0.161-0.827; P=0.016) in multivariate analysis, while old age and lymphovascular invasion were poor prognostic factors.

Conclusion: EGFR overexpression was potentially favorable prognostic biomarker for stage III gastric cancer, especially in the patients who received 5-FU based adjuvant chemotherapy.

Citation Format: Ji Soo Park, Hyo Song Kim, Yoon Sung Bae, Sung Hoon Noh, Hyunki Kim. Prognostic significance of EGFR expression in localized gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4723. doi:10.1158/1538-7445.AM2014-4723
Abstract 4726: Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker
Authors: Watanabe Megumi , Kagawa Shunsuke , Ishida Michihiro , Hori Naoto , Kikuchi Satoru , Kuroda Shinji , Kishimoto Hiroyuki , Nishizaki Masahiko , Tazawa Hiroshi , Fujiwara Toshiyoshi
Published: May 2015

Peritoneal dissemination is a common pattern of metastasis in patients with gastric cancer, and associated with worse prognosis. Peritoneal lavage cytology during the operation is an important factor in predicting future development of peritoneal metastasis and determining the treatment strategy, but its sensitivity and specificity are unsatisfactory. TelomeScan is an adenovirus engineered to replicate and express GFP only in telomerase-activating tumor cells, so that we can easily detect viable cancer cells even among numerous normal cells. We hypothesized that TelomeScan might be applicable to detecting free cancer cells in peritoneal wash. Methods: Peritoneal washes were obtained from 42 gastric cancer patients during operation. The number of GFP-positive cells was determined for each sample and compared with cytology results and clinicopathological data Results: Clinical stage was ranged from IA to IV, and thirteen cases were diagnosed as class IV or class V by peritoneal lavage cytology. More than 10 GFP-positive cells were detected in 12 out of 42 cases, and these cases showed a worse prognosis when compared to the other 30 cases. Conclusion: We were able to detect gastric cancer cells as GFP-positive cells in peritoneal wash using TelomeScan. Furthermore, the presence of GFP-positive cells in peritoneal wash was associated with worse prognosis. These results suggest that number of cancer cells detected by TelomeScan in the peritoneal wash may have important clinical implication as prognostic and therapeutic biomarkers in gastric cancer.

Citation Format: Megumi Watanabe, Shunsuke Kagawa, Michihiro Ishida, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Toshiyoshi Fujiwara. Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4726. doi:10.1158/1538-7445.AM2014-4726
Abstract 4732: Vasohibine-1 negative and EZH2 positive may predict the prognosis of cholangiocarcinoma
Authors: Nakagawa Shigeki , Sakamoto Yasuo , Tokunaga Ryuma , Higashi Takaaki , Sakamoto Keita , Chikamoto Akira , Ishiko Takatoshi , Beppu Toru , Baba Hideo
Published: May 2015

Background: Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium, and the status of VASH1 expression has been documented in various cancer prognosis. Some reports shows that VASH1 was negatively regulated by enhancer of zeste homolog 2 (EZH2) epigenetically. The aim of this study was to assess the relationship between EZH2 and VASH1, and the prognostic value of this two molecules in intrahepatic cholangiocarcinoma (ICC) patients.

Method: We examine 47 cases of intrahepatic cholangiocarcinoma to which the R0 liver resection had been performed by our department between 1993 years and 2010. Immunohistochemical staining of VASH1 and EZH2 was performed using paraffin-embedded block, and we examined the relation among the expression of VASH1 and a clinicopathological factor (sex, age, tumor diameter, tumor number, differentiation level, microscopic vascular invasion, and metastasis in lymph node), EZH2 expression, recurrence-free survival (RFS) and overall survival (OS).

Result: VASH1 and EZH2 positivity was observed in 24 (51.1%) and 24 (51.1%) patients respectively, and VASH1 positivity was inversely correlated with EZH2 high expression (R=0.3870, p=0.0018). VASH1 positivity was not significantly correlate with RFS or OS. On the other hands, VASH1 negative and EZH2 positive was observed in 17 (36.2%) patients, and was a significant disadvantage to both RFS (relative risk (RR) 3.39, 95% confidence interval (CI) 1.28-8.67, p=0.0157) and OS (RR 3.69, 95% CI 1.20-11.2, 0.0237) in univariate Cox hazard analysis. In multivariate analysis, VASH1 negative and EZH2 positive group was an independent risk factor for both RFS (RR 4.19, 95% CI 1.33-13.13, p=0.0150), and OS (RR 8.11, 95% CI 2.01-42.1, p=0.0030).

Conclusion: The expression of VASH1 was inversely correlate with EZH2 expression. VASH1 negative and EZH2 positive was an independent risk factor for OS and DFS in ICC patients.

Citation Format: Shigeki Nakagawa, Yasuo Sakamoto, Ryuma Tokunaga, Takaaki Higashi, Keita Sakamoto, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Vasohibine-1 negative and EZH2 positive may predict the prognosis of cholangiocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4732. doi:10.1158/1538-7445.AM2014-4732
Abstract 4733: p62/sequestosome 1, a potent prognostic factor, enhance cell proliferation in human colorectal carcinoma
Authors: Nakayama Shun , Suzuki Takashi , Yabuuchi Shinichi , Takagi Kiyoshi , Onodera Yoshiaki , Nakamura Yasuhiro , Watanabe Mika , Fujishima Fumiyoshi , Yoshida Hiroshi , Morikawa Takanori , Karasawa Hideaki , Sase Tomohiko , Naitoh Takeshi , Katayose Yu , Egawa Shinichi , Unno Michiaki , Sasano Hironobu
Published: May 2015

p62/sequestosome 1 (p62) is a multi-domain protein implicated in the selective degradation of ubiquitinated protein by autophagy, and it also functions as a scaffold protein in cell signaling pathways. p62 was recently reported to be accumulated in several types of human cancer cells, but the clinical significance and biological roles of p62 have remained largely unknown in colorectal carcinoma. p62 immunoreactivity was examined in 118 surgical specimens of human colorectal carcinomas using immunohistochemistry. p62 immunoreactivity was detected in about one third of the carcinoma cases, while it was negligible in the adjacent non-neoplastic epithelium. The immunohistochemical p62 status was significantly associated with synchronous liver metastasis in the carcinoma cases, and multivariate analysis further revealed the p62 status as an independent adverse prognostic factor for overall survival in the patients. We used 4 colon carcinoma cells in the in vitro studies to evaluate the functional roles of p62. The colon carcinoma cells transfected with p62-specific small interfering RNAs showed significantly decreased cell proliferation activities, and the colon carcinoma cells transfected with p62 expression plasmid showed significantly increased the cell proliferation activity. Results of in vitro studies indicated that p62 significantly promoted the cell proliferation of colorectal carcinoma cells, but the autophagic activity was not linked to the p62-mediated cell proliferation. These findings suggest that p62 promotes the proliferation of colon carcinoma cells mainly as a scaffold protein. The p62 status is a potent prognostic factor in human colorectal cancer patients, and could be an important specific therapeutic target of colorectal carcinoma that could improve the clinical outcome in the future.

Citation Format: Shun Nakayama, Takashi Suzuki, Shinichi Yabuuchi, Kiyoshi Takagi, Yoshiaki Onodera, Yasuhiro Nakamura, Mika Watanabe, Fumiyoshi Fujishima, Hiroshi Yoshida, Takanori Morikawa, Hideaki Karasawa, Tomohiko Sase, Takeshi Naitoh, Yu Katayose, Shinichi Egawa, Michiaki Unno, Hironobu Sasano. p62/sequestosome 1, a potent prognostic factor, enhance cell proliferation in human colorectal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4733. doi:10.1158/1538-7445.AM2014-4733
Abstract 4736: Inhibition of STAT3 sensitizes neuroblastoma xenografts cells to Etoposide
Authors: Yan Shuang , Thiele Carol
Published: May 2015

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for more than 7% of malignancies in patients younger than 15 years and causing 10% of all pediatric oncology deaths. Chemoresistance remains a major obstacle to the successful treatment of high-risk NB patients. Since STAT3 is a determinant of chemoresistance and associated with tumor recurrence in several adult tumor model systems, we investigated the biologic consequences of targeting STAT3 in neuroblastoma. Using a Tet-inducible STAT3 shRNA in 3 representative NB cell line models (AS, NGP and IMR32), inhibition of constitutively activated STAT3 (P-STAT3) in NB cells statistically decreased cell proliferation, colony formation and motility as defined by a wound healing assay. NB cell lines with decreased P-STAT3 exhibited increased sensitivity to cisplatin and etoposide-induced cell death (EC50 in each cell line decreased 52% to 80% compared with parental cell lines) which could be partially rescued by caspase inhibitor Z-VAD. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA in AS had little effect on tumor growth and survival in tumor-bearing mice, however the combination of STAT3 inhibition with etoposide significantly decreased tumor growth and increased the survival of tumor-bearing mice (P=0.009). Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional cytotoxic therapy for patients with high-risk NB.

Citation Format: Shuang Yan, Carol Thiele. Inhibition of STAT3 sensitizes neuroblastoma xenografts cells to Etoposide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4736. doi:10.1158/1538-7445.AM2014-4736
Abstract 4741: SerpinA1 promotes gastric cancer progression through regulation of snail
Authors: Kwon Chae Hwa , Park Hye J. , Moon Hyun Jung , Lee Ja-Rang , Park Do Youn
Published: May 2015

In the previous study, we reported that serpin peptidase inhibitor clade A member 1 (serpinA1) were upregulated in snail overexpressing gastric cancer. Although the effect of serpinA1 has been studied in several cancers, there is no report that the expression of serpinA1 correlates with snail. In this study, we examined the relation between serpinA1 and snail, and the role of serpinA1 in gastric cancer. Overexpression of snail resulted in upregulation of serpinA1 in gastric cancer cells, AGS and MKN45 cells. Meanwhile, knockdown of snail inhibited serpinA1 expression. ChIP analysis showed that snail bind to serpinA1 promoter. Overexpression of snail increased snail recruitment to the serpinA1 promoter. Overexpression of serpinA1 increased the invasion and migration of gastric cancer cells, while knockdown of serpinA1 decreased invasion and migration. In addition, we validated the clinicopathological and prognostic significance of serpinA1 expression in 400 gastric cancer patients using immunohistochemistry analysis. SerpinA1 was observed in the cytoplasm of the tumor cells and stroma. Overexpression of serpinA1 was significantly associated with increased tumor size (P = 0.03), tumor progression (advanced T stage; P < 0.0001), perineural invasion (P < 0.0001), lymphovascular invasion (P < 0.0001), lymph node metastases (P < 0.0001) and shorter survival (P = 0.001). In conclusion, serpinA1 induce the invasion and migration of gastric cancer cells and the expression of serpinA1 is associated with the progression of gastric cancer. These results may provide a potential target to prevent gastric cancer invasion and metastasis.

Note: This abstract was not presented at the meeting.

Citation Format: Chae Hwa Kwon, Hye Ji Park, Hyun Jung Moon, Ja-Rang Lee, Do Youn Park. SerpinA1 promotes gastric cancer progression through regulation of snail. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2014-4741
Abstract 4749: New benzazepine BET-inhibitors with improved oral bioavailability
Authors: Schmees Norbert , Haendler Bernard , Lejeune Pascale , Stresemann Antje , Neuhaus Roland , Siegel Stephan , Fernandez-Montalvan Amaury Ernesto , Weinmann Hilmar , Gekeler Volker
Published: May 2015

Bromodomain protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, binds to acetylated histone tails via its two bromodomains BD1 and BD2. It forms a complex with the positive transcription elongation factor b which controls phosphorylation of RNA polymerase II, ultimately leading to stimulation of transcription elongation. An essential role of BRD4 in cell proliferation and cancer growth has been reported in several recent studies.

The benzodiazepine JQ-1 is a strong antagonist of the binding of BRD4 to acetylated histone tails and has been used to elucidate the functions of the BET protein family members. JQ-1 is active in vivo in several therapeutic models but reveals a poor pharmacokinetic profile with high clearance and low oral bioavailability in animal studies. We investigated the benzodiazepine core of JQ-1 with the aim of optimization of oral bioavailability. Several possible core variations were identified that kept overall cellular activity but increased metabolic stability. The benzazepine BAY6356 was selected as a potent BET inhibitor with an improved overall pharmacokinetic profile and oral bioavailability between 60 and 100% in mouse, rat and dog. The strong antiproliferative activity observed in vitro in acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines was confirmed in vivo in the MOLM-13 (AML) and MOLP-8 (MM) tumor models implanted in SCID mice. Daily oral treatment at the Maximal Tolerated Dose of 30 mg/kg led to strong tumor reduction in MOLM-13 (17% T/C on day 13 post tumor implantation) and in MOLP-8 (4% T/C on day 19 post tumor implantation) xenografts (T/C≤ 40% = active, T/C≤10% = highly active, according to NCI criteria). In the MOLM-13 model, c-Myc down-regulation was shown in vivo. Furthermore, for a same total dose, intermittent dosing every other day or twice a week in the MOLP-8 model proved to be as active as daily dosing, demonstrating exposure-driven efficacy. These favorable preclinical data support the evaluation of BAY6356 for further development.

Citation Format: Norbert Schmees, Bernard Haendler, Pascale Lejeune, Antje Stresemann, Roland Neuhaus, Stephan Siegel, Amaury Ernesto Fernandez-Montalvan, Hilmar Weinmann, Volker Gekeler. New benzazepine BET-inhibitors with improved oral bioavailability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4749. doi:10.1158/1538-7445.AM2014-4749
Abstract 4759: Integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor actions of PARP inhibitor in triple-negative breast carcinogenesis
Authors: Leyland-Jones Brian , Carlson Jennifer , Sun Yuliang , Friedman Lori , De Pradip , Dey Nandini
Published: May 2015

Background: The PI3K pathway, in addition to its pro-proliferative and anti-apoptotic effects on tumor cells, is known to contribute to DNA-damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mTOR inhibitor, would potentiate an anti-tumor effect in BRCA-competent TNBC cells when combined with the PARP inhibitor, ABT888 and carboplatin. Methods: Athymic mice bearing BRCA-competent TNBC xenograft tumors were treated with GDC-0980 alone or in combination with ABT888 and carboplatin. Mechanism-based in vitro studies (MTT, CelltiterGLO, flow cytometry-based live/dead cell, cell cycle analyses, anchorage independent soft-agar, anchorage dependent 3D ON-TOP, apoptosis, cell signaling markers assays) using a panel of 5-7 BRCA-wt /mutant TNBC cell lines were performed. Results: GDC-0980 treatment led to DNA damage (increased pgH2AX; WB, IF), gain in PAR and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin in a time-dependent manner. The treatment (1) decreased proliferation signals (pAKT, pP70S6K, p4EBP1, pS6RP), PAR/PARP, PAR/pgH2AX, live/dead cell ratios, cell cycle progression and clonogenic 3D growth, and (2) increased apoptosis markers (cl-caspase3, 9, BIM, cl-PARP, and annexinV positivity). These effects were more pronounced in PTEN-null MDA-MB468 than in RAS/RAF mutated MDA-MB231 cells. Three-dimensional projection movie showed that (1) GDC-0980 alone attenuated nuclear pγH2AXS139 foci in MDA-MB468 cells at 24 hours and (2) cytoplasmic cl-caspase3 increased in GDC-0980+ABT888+carboplatin treated MDA-MB468 cells at 72 hours. Finally, GDC-0980 in combination with ABT888 plus carboplatin blocked the growth of established xenograft tumors by 80-90% with a concomitant decrease in tumor Ki67, cl-caspse3, pVEGFR, CD31, p4EBP1, and pS6RP IHC-levels. Conclusion: This is the first mechanism-based study to demonstrate the inhibition of DDR as another mode of action of GDC-0980. Our data revealed that in a BRCA-competent model, GDC-0980 enhanced the antitumor efficacy of ABT888 in the presence of carboplatin by inhibiting the DDR system in conjunction with inhibition of the PI3K-mTOR pathway mediated pro-proliferative and anti-apoptotic signals.

Citation Format: Brian Leyland-Jones, Jennifer Carlson, Yuliang Sun, Lori Friedman, Pradip De, Nandini Dey. Integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor actions of PARP inhibitor in triple-negative breast carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4759. doi:10.1158/1538-7445.AM2014-4759
Abstract 4760: ER-β/Sp/NFκB/FLIP axis: Potential therapeutic target in prostate cancer
Authors: Yun Huiyoung , Xie Jianping , Batth Izhar Singh , Li Rong , Ghosh Rita , Kumar Addanki Pratap
Published: May 2015

Emergence of hormone-refractory prostate cancer is fatal for lack of effective, durable systemic therapeutic strategies. Therefore, discovery of novel approaches and agents that can prevent development of therapeutically resistant disease and its progression is critical for successful management of prostate cancer (PCA). One of the reasons for the inability to implement such strategies is an incomplete understanding of molecular events associated with the development of therapeutically resistant disease. Previously, we reported the anti-tumorigenic potential of 2-methoxyestradiol (2-ME2) both in vitro and in vivo. We showed that (i) transcription factor Sp1 activates while Sp3 inhibits Sp1-mediated transactivation of anti-apoptotic gene FLIP in androgen independent prostate cancer PC-3 cells, and that (ii) 2-ME2-mediated tumor growth inhibitory effects were accompanied by transcriptional down-regulation of FLIP through 745 bp (-503/+242) sequence elements. In order to fully understand the underlying molecular mechanism of 2-ME2 induced down-regulation of FLIP, we generated exonuclease deletion constructs and performed transient transfection assays. These studies led to identification of -121/+242 sequence containing putative bindings sites for NFκB, CREB and AR in addition to Sp1 with maximal promoter activity in androgen responsive (LNCaP) and androgen independent (PC-3 and DU145) cells. Using ChIP assays, we also observed the enrichment of these factors to the endogenous FLIP promoter. Furthermore, androgen stimulation enhanced promoter activity and recruitment of Sp1, NFκB to the FLIP promoter region in LNCaP cells. Surprisingly, we found DHT but not R1881 decreased FLIP promoter activity in DU145 cells. Further molecular investigations indicated enhanced expression of AKR1C3 (aldo-keto reductase) that catalyzes the conversion of DHT to 3β-Adiol (a potent ligand for ER-β) in response to 2-ME2 treatment in DU145 cells. In addition, not only 3β-Adiol treatment reduced proliferation of prostate cancer cell significantly but co-transfection with ER-β reduced FLIP promoter activity. Taken together, these results implicate an important role for ER-β/Sp/NFκB/FLIP in mediating 2-ME2 induced tumor growth inhibitory effects. Supported by VA-Merit Award and CA 135451 (APK).

Citation Format: Huiyoung Yun, Jianping Xie, Izhar Singh Batth, Rong Li, Rita Ghosh, Addanki Pratap Kumar. ER-β/Sp/NFκB/FLIP axis: Potential therapeutic target in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4760. doi:10.1158/1538-7445.AM2014-4760
Abstract 4779: DNMT3B (a de novo DNA methyltransferase) epigenetically regulates gene expression, independent of its DNA methyltransferase activity
Authors: Mitchell Khadijah A. , Easwaran Hariharan , Baylin Stephen B.
Published: May 2015

DNA methylation is one of several epigenetic mechanisms used by cells to control gene expression. The de novo methyltransferases, DNMT3a and DNMT3b, establish new methylation patterns during early development. DNMT1, the maintenance methyltransferase, ensures propagation of hemi-methylated DNA. Human cancers are characterized by aberrant DNA methylation patterns, including global hypomethylation and hypermethylation of promoters at tumor suppressor genes. This latter change leads to transcriptional silencing. Experimentally, DNMT1 is capable of transcriptional repression without its methyltransferase activity, partially through interactions with histone-modifying enzymes. We hypothesized DNMT3B may also be capable of modulating gene expression independently of its methyltransferase activity, by recruiting repressive epigenetic proteins to the promoters of endogenous DNMT3B targets.

Using an isogenic colorectal cancer cell culture model, we investigated the functional consequences of the removal and re-introduction of DNMT3B on target gene expression, methylation, and chromatin status. A stable genetic knock out cell line, transient shRNA knock down, and pharmacologic inhibition resulted in upregulation of a subset of candidate DNMT3B targets identified by gene expression arrays and validated by quantitative RT-PCR. Interestingly, reintroduction of both wild-type and catalytically dead mutant DNMT3B in the knockout cells transcriptionally repressed the same loci. Infinium 450K arrays were performed to assess DNA methylation status. As expected, the loss of DNMT3B did not result in significant changes in global methylation at TSS, CpG islands, shores, shelves, and UTRs. However, in selected of the above targets, locus-specific demethylation was identified. Overexpression of both wild-type and catalytically dead mutant DNMT3B failed to restore local methylation, in concert with transcriptional repression of these loci, further suggesting an alternative regulatory mechanism to explain transcriptional changes. Interactions of DNMT3B with other repressive proteins could account for the above transcriptional repression. ChIP studies revealed LSD1, a histone demethylase that represses transcription, is lost in the 3B knockout cells but is recruited back to the promoters of repressed DNMT3B target genes with DNMT3B insertion. These data strongly suggest DNMT3B possesses a non-canonical function as a scaffold protein for transcriptional repressors.

Citation Format: Khadijah A. Mitchell, Hariharan Easwaran, Stephen B. Baylin. DNMT3B (a de novo DNA methyltransferase) epigenetically regulates gene expression, independent of its DNA methyltransferase activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4779. doi:10.1158/1538-7445.AM2014-4779