bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 465: EVI1 transcriptionally represses SLUG to regulate epithelial-mesenchymal transition (EMT) in human colon cancer
Authors: Nayak Kasturi B. , Chakraborty Soumen 
Published: May 2015

Abstract
Ecotropic viral integration site-1 (EVI1) is an oncogenic transcription factor that is frequently implicated in hematological malignancies and in some solid tumors. Deregulated expression of EVI1 impairs several pathways including proliferation, differentiation, apoptosis and cell cycle through different mechanisms in different cell types. EVI1 was found to be overexpressed in 53% of human colorectal cancer samples, 100% of colon adenocarcinoma samples, 100% of human colon cancer cell lines and its presence might affect disease progression and sensitivity to chemotherapy. To investigate the stage specific expression pattern of EVI1 in colon cancer patient samples, we analyzed two of the publicly available microarray datasets (GEO database) of colon cancer patients and observed that although EVI1 is upregulated in the initial stage of the disease, the expression level decreases with the progression of the disease. In cancer cells loss of epithelial adhesion molecule E-cadherin is considered to be a fundamental event in EMT. To decipher whether EVI1 is involved in EMT, we checked five transcription factors (SLUG, SNAIL, TWIST, ZEB1 and ZEB2) which controls the expression of E-cadherin in cancer cells. Significant negative correlation was observed between the expression levels of EVI1 and all the above transcription factors in colon cancer patient samples. Recently it was shown by using ChIP sequencing that EVI1 target SLUG and SNAIL in SKOV3 cells. To understand whether EVI1 directly binds to both SLUG and SNAIL, we did an in silico analysis and searched for EVI1 binding site(s) in the functional promoter region of both SLUG and SNAIL. Although we did not observe any binding site in SNAIL promoter region; we observed two EVI1 binding sites in the SLUG promoter region. To validate the predicted target sites in vivo, we did a ChIP assay and found that EVI1 binds to one of the site and not both of them. To determine the transcriptional regulation, we cloned the promoter region of SLUG (-1100 bp) in pGL3 vector and did luciferase assay, which revealed that EVI1 significantly represses SLUG activity in EVI1 transfected cells. Analysis of gene expression databases corroborates the above finding and shows that EVI1 negatively regulates SLUG expression in each stage of the disease as well as in colon cancer cell lines. We have worked on the functional aspects of the binding in terms of EMT which will be presented in the poster.
Citation Format: Kasturi B. Nayak, Soumen Chakraborty. EVI1 transcriptionally represses SLUG to regulate epithelial-mesenchymal transition (EMT) in human colon 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 465. doi:10.1158/1538-7445.AM2014-465
Abstract 4652: Cerebrospinal fluid pharmacokinetics and pharmacodynamics following high-dose erlotinib treatment in brain cancer patients
Authors: Pastorino Sandra , Pingle Sandeep C. , Langley Emma , Kim Phillip , Juarez Tiffany , Jiang Pengfei , Tucker Christopher , Yang Txheng , Saria Marlon , Singh Sharat , Kesari Santosh 
Published: May 2015

Abstract
Patients with non-small cell lung cancer (NSCLC) who develop leptomeningeal metastases show significant clinical improvement following high-dose gefitinib therapy. Based on this data, we aimed to explore the effect of high-dose erlotinib on clinical response and CNS penetration in primary or metastatic CNS cancer.
We selected patients who had received prior therapy for either primary glioma or for NSCLC with metastases to the brain and treated them with an alternate dosing regimen of erlotinib. Blood and cerebrospinal fluid (CSF) samples were collected at various time points to assess levels of erlotinib. We found that CSF concentrations of erlotinib were generally 2% that of plasma concentrations. Among the five patients examined, CSF concentrations of erlotinib reached up to 131 nM when high doses were administered at 600 to 1200 mg every four to six days. Additionally, drug clearance was decreased with an increased dosing regimen in one of the patients. In one patient, the area under the curve (AUC) estimations showed a 24% increase in the CSF versus only a 2% increase in the plasma following an increase from 150 mg to 600 mg of erlotinib. Moreover, longitudinal CSF samples were evaluated for expression and activation of EGFR as well as various other receptor tyrosine kinases, such as ErbB2, ErbB3, cMET and IGF1R, using the highly sensitive multiplexed immunoassay CEER© platform. The latter provides insight into the molecular makeup of the CNS cancer throughout the therapeutic regimen.
Our clinical data on patients receiving erlotinib therapy for primary and metastatic CNS disease suggests that increased dosing of erlotinib, administered as a pulse dose every four to six days leads to increased CSF drug concentrations. In spite of the variations seen among different patients, we conclude that higher erlotinib dosing regimens can provide enhanced CNS penetration that may prove to be more effective in primary and metastatic CNS cancers especially when coupled with real-time molecular monitoring of the disease to help guide the clinician during the course of treatment.
Citation Format: Sandra Pastorino, Sandeep C. Pingle, Emma Langley, Phillip Kim, Tiffany Juarez, Pengfei Jiang, Christopher Tucker, Txheng Yang, Marlon Saria, Sharat Singh, Santosh Kesari. Cerebrospinal fluid pharmacokinetics and pharmacodynamics following high-dose erlotinib treatment in brain cancer 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 4652. doi:10.1158/1538-7445.AM2014-4652
Abstract 4654: Plasma, tissue and tumor pharmacokinetics of PM060184 in NSCL xenograft mouse model
Authors: Pernice Tiziana , Bishop Alan , Cataluña Oscar , Palomares Mandy , Lopez Raquel , Núñez Práxedes , Cuevas Carmen , Guillén Maria José , Aviles Pablo M. 
Published: May 2015

Abstract
Background: PM060184 is new marine derived tubulin-binding agent originally isolated from the sponge Lithoplocamia lithistoides. PM060184 has shown potent antitumor activity in vivo against a panel of different tumor xenografted models such as colon, gastric, NSCLC, prostate and renal. Also, PM060184 has demonstrated to have a potent in vitro and in vivo activity in P-gp overexpressing cells. PM060184 is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases.
Material and Methods: Athymic female nu/nu mice were subcutaneously implanted with H460 (NSCLC). Tumor bearing animals were randomly allocated into experimental groups (efficacy or pharmacokinetics -PK-). The animals belonging to the efficacy study received three iv doses in a weekly (q7dx3) schedule of PM060184 at 16 mg/kg or placebo. The antitumor activity was followed by the change in tumor volume for treated and placebo groups. The PK group received a single dose of PM060184 at 16 mg/kg. Then, plasma, tissue (brain, spleen, lung, muscle and heart) and tumor samples (N=3-4/sampling time) were collected at different times and up to 96 h post-administration. Tissue and tumor samples were diluted and homogenized using Precellys®24 bead beating technology. Once homogenized the samples were processed as per plasma. PM060184 was detected in plasma, tissue and tumor extracts by electrospray ionization/tandem mass spectrometry after extraction by supported liquid extraction (SLE).
Results: The mean maximum plasma concentration (Cmax) was 2,452.5 ng/mL. The area under curve (AUC) was 2,963 ng*hr/mL. The plasma clearance was 5,398.5 mL/hr/kg. The volume of distribution at steady state was 880.7 mL/kg. The terminal half-life was 4.7 hr. The AUC0-tlast values for brain, spleen, lung, muscle and heart were 216.2, 7,402.9, 3,857.7, 2,614.6 and 2,929.5 ng*hr/g, respectively; however the AUC value for H460 xenografted tumors was 51,321.4 ng*hr/g (tlast is 96 hours for tumor, 8 hours for brain and 24 hours for the other tissues).
Conclusion: PM060184 showed similar plasma and tissue pharmacokinetics properties as well as preferential tumor distribution until 96 h after an iv administration in mice bearing H460 xenografted tumors.
Citation Format: Tiziana Pernice, Alan Bishop, Oscar Cataluña, Mandy Palomares, Raquel Lopez, Práxedes Núñez, Carmen Cuevas, Maria José Guillén, Pablo M. Aviles. Plasma, tissue and tumor pharmacokinetics of PM060184 in NSCL xenograft mouse model. [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 4654. doi:10.1158/1538-7445.AM2014-4654
Abstract 4664: Single-cell transcriptome analysis on lung squamous cell carcinoma derived from a patient
Authors: Kim Kyu-Tae , Lee Hye-Won , Joo Kyeung Min , Kim Sang-Chul , Lee Jin-Ku , Chang Nakho , Sa Jason K. , Cho Yu Jin , Nam Do-Hyun , Lee Hae-Ock , Park Woong-Yang 
Published: May 2015

Abstract
Distinct genomic signature of a patient's cancer could provide a clue to design and predict accurate therapeutic responses to targeted medicine. Current approaches regarding heterogeneous cancer cells en masse as a pooled population, however, hardly reflect complete genomic landscape of tumor diversity, missing potentially important minor clones' implications regarding metastasis and drug resistance. Here we report a comprehensive analysis to discover different patterns of subclonal behaviors in functional modalities and signaling pathways out of heterogeneous population derived from a patient with lung squamous cell carcinoma, using single-cell mRNA sequencing. As a result of nonnegative matrix factorization as a clustering, we identified discrete 4 subgroups with a major group in accordance with overall expression profile of a pooled population of cells, and the other 3 minor groups that were masked in a pooled sample. Genomic variants were also reliably identified and compared across single cells. We integrated these genomic signatures from single cells to address the different responses in drug screening. Together, our approach provides insights into the more accurate strategy to identify minor but potentially important subclones that are relevant to drug resistance.
Citation Format: Kyu-Tae Kim, Hye-Won Lee, Kyeung Min Joo, Sang-Chul Kim, Jin-Ku Lee, Nakho Chang, Jason K. Sa, Yu Jin Cho, Do-Hyun Nam, Hae-Ock Lee, Woong-Yang Park. Single-cell transcriptome analysis on lung squamous cell carcinoma derived from a patient. [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 4664. doi:10.1158/1538-7445.AM2014-4664
Abstract 4671: Dual mutational changes of ALK gene fusion combined with EGFR or K-ras oncogenes in lung adenocarcinomas
Authors: Lee Jieun , Hong Suk Hee , Jeon Eun Kyung , Kim Jung O. , Kim Seung Joon , Kim Young Kyoon , Park Jae Gil , Sung Sook-Whan , Kim Tae-Jung , Kang Jin Hyoung 
Published: May 2015

Abstract
Purpose
The mutations of the EGFR, K-ras or ALK oncogenes are closely associated with tumorigenesis and progression of lung adenocarcinoma. Their mutational changes are known to be mutually exclusive, but double oncogenic mutations of ALK combined with EGFR or K-ras gene are rarely found. We analyzed the clinical impacts of double oncogenic mutations on clinical characteristics and treatment outcome, according to EGFR, K-ras, ALK mutation or triple negative (EGFR, K-ras, ALK wild) in lung adenocarcinomas.
Patients and Methods
For one hundred ninety six lung cancer patients conformed histologically as adenocarcinoma, we examined activating EGFR (exons 18 and 21) and K-ras (exon 2 and 3) mutations by direct nucleotide sequencing and. ALK gene rearrangements by FISH using break-apart probe. Among 196 patients, 86 patients (43.9%) were triple negative adenocarcinoma, 73 patients (37.2%) presented with activating EGFR mutation, 17 patients (8.7%) with ALK and 13 patients (6.6%) with K-ras mutation. Median age of 17 patients harboring ALK rearrangement was 54 years (range 25∼79), approximately 7 years younger than the patient population harboring EGFR or K-ras mutation (62 and 61 years, respectively). Fifteen patients (88.2%) had stage III or IV and 9 patients (52.9%) were never smoker. Platinum doublet chemotherapy or EGFR TKIs was administered for 14 patients initially presented as stage IV disease or recurred as metastatic disease after local treatment. The median PFS of the patients receiving platinum doublet chemotherapy and EGFR TKIs as first-line treatment was 5.67 months (range 2.97-20.9) and 3.58 months (range 3.53-3.63), respectively. Of 17 ALK-positive patients, dual oncogenic mutations of ALK together with either EGFR or K-ras were identified in 7 patients (3.6%). Six patients (85.7%) receiving platinum-doublet or EGFR TKI as initial treatment. showed partial response, and 1 patient (14.3%) showed stable disease. These seven patients are all alive at present.
Conclusion
Taken together, our data suggest the existence of dual oncogenic mutations in lung adenocarcinomas is not infrequent. We are undergoing the experiment for detection for circulating tumor cells harboring ALK rearrangements, EGFR or K-ras mutation in these patients' peripheral blood.
Citation Format: Jieun Lee, Suk Hee Hong, Eun Kyung Jeon, Jung Oh Kim, Seung Joon Kim, Young Kyoon Kim, Jae Gil Park, Sook-Whan Sung, Tae-Jung Kim, Jin Hyoung Kang. Dual mutational changes of ALK gene fusion combined with EGFR or K-ras oncogenes in lung adenocarcinomas. [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 4671. doi:10.1158/1538-7445.AM2014-4671
Abstract 468: Cancer cells with G/G mdm2 SNP309 have compromised transcriptional elongation of p53 target genes
Authors: Rosso Melissa , Polotskaia Alla , Bargonetti Jill 
Published: May 2015

Abstract
MDM2 protein is often found over-expressed in cancers with wild-type p53. A single nucleotide polymorphism (T to G) near the mdm2 P2 promoter, mdm2 SNP309, leads to MDM2 overexpression. This polymorphism is associated with accelerated tumor formation, decreased sensitivity to DNA damage treatment and compromised p53 transcriptional activity. Two G/G SNP309 cell lines MANCA (Burkitt lymphoma) and A875 (melanoma) express wild-type p53 protein not readily degraded by MDM2. This wild-type p53 does not activate target genes even after DNA damage. During the blocked transcription, MDM2 and p53 co-localize at p53 response elements on chromatin. Therefore, we hypothesized that MDM2 localized with p53 on the chromatin was the contributing factor for the compromised p53 transcriptional activity. We explored the mechanism for compromised p53 transcriptional activity in these G/G SNP309 cancer cell lines. When compared to fully activated wild-type p53 in ML-1 cells treated with etoposide, MANCA and A875 cell lines had comparable recruitment of total and initiated RNA pol II at transcription start sites (TSS) for p21 and puma genes. This indicated that G/G SNP309 cells had functional transcription initiation at p53 target genes after DNA damage treatment. We next assessed epigenetic modifications associated with active transcriptional elongation. Using H3K36 trimethylation (H3K36me3) as a hallmark for active elongation, we observed that ML-1 cells had a substantial increase in H3K36me3 after etoposide treatment at p21 and puma TSS that was not seen in MANCA or A875 cell lines. This lack of H3K36me3 suggested an inhibition in early transcriptional elongation. To address the participation of MDM2 in the elongation block we created a stable MDM2 knockdown MANCA cell line. Interestingly, MDM2 knockdown drastically increased MDMX protein levels and moderately increased activation of p53 target genes implying MDMX played a redundant role for MDM2. We are currently investigating the roles of MDM2 and MDMX in blocking transcriptional elongation. Interestingly, we have found that treatment of MANCA cells with low dose Actinomycin D reactivates the p53 pathway and studies are in progress to determine if this is through activation of transcriptional elongation.
This work was supported by The Breast Cancer Research Foundation and The National Science Foundation (grant MCB-0744316) to J.B. M.R. was supported by the MBRS-RISE Program to Hunter College 3R25-GM060665.
Citation Format: Melissa Rosso, Alla Polotskaia, Jill Bargonetti. Cancer cells with G/G mdm2 SNP309 have compromised transcriptional elongation of p53 target genes. [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 468. doi:10.1158/1538-7445.AM2014-468
Abstract 4682: Recurrence risk factors for advanced gastric cancer after D2 gastrectomy followed by adjuvant chemotherapy
Authors: Hwang Jun-Eul , Kim Min-Jee , Shim Hyun-Jeong , Bae Woo-Kyun , Cho Sang-Hee , Chung Ik-Joo 
Published: May 2015

Abstract
Background
Recent trials demonstrated that the adjuvant chemotherapy for stage II or III gastric cancer after curative D2 gastrectomy is effective for preventing recurrence. The objective of this study was to clarify the risk factors for recurrence in patients who received adjuvant chemotherapy after curative D2 gastrectomy.
Materials and methods
We retrospectively analyzed the factors predicting recurrence in 206 patients with stage II or III gastric cancer who received oral S-1 or 5-FU and cisplatin (FP) chemotherapy following curative D2 gastrectomy between April 2004 and December 2011.
Results
The median follow-up time after surgery was 2.93 years. A total of 136 patients received FP chemotherapy, and 70 patients received S-1. 3 year recurrence-free survival was 66.7%. In univariate analysis, gastroesophageal junction cancer, stage III, T3/T4 tumor, N2/N3 nodal status, and presence of both lymphovascular invasion (LVI) and perineural invasion (PNI) were associated with shorter recurrence-free survival. Moreover, Multivariate analysis showed male (HR 1.909; 95% CI 1.067-3.417; p=0.029), stage III (HR 3.884; 95% CI 1.741-8.662; p=0.001), and presence of both LVI and PNI (HR 2.293; 95% CI 1.367-3.846; p=0.002) were independent risk factors for recurrence.
Conclusion
Presence of both LVI and PNI is a strong recurrence risk factor for patients with stage II and stage III R0 resected gastric cancer who received adjuvant chemotherapy.
Citation Format: Jun-Eul Hwang, Min-Jee Kim, Hyun-Jeong Shim, Woo-Kyun Bae, Sang-Hee Cho, Ik-Joo Chung. Recurrence risk factors for advanced gastric cancer after D2 gastrectomy followed by adjuvant chemotherapy. [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 4682. doi:10.1158/1538-7445.AM2014-4682
Abstract 4687: The PI3K inhibitor GDC-0941 is synergistic with lapatinib, and mediates endocrine sensitivity in uterine papillary serous carcinoma
Authors: Levano Kelly S. , Rodriguez-Gabin Alicia , Goldberg Gary L. , Horwitz Susan B. , Hou June Y. 
Published: May 2015

Abstract
Objectives: Our objective is to determine the effect of PI3K activity in mediating ligand-independent estrogen signaling and endocrine sensitivity in Uterine Papillary Serous Carcinoma (UPSC).
Methods: Drug effect on cell proliferation was calculated via Calcusyn in patient-derived UPSC cell lines ARK 1 and 2. PI3K mutation was analyzed after laser capture microdissection of tumor DNA in 7 consecutive patients with UPSC. Protein expression, via Western Blot, was correlated prospectively with clinical parameters.
Results: Table 1 shows cells line baseline characteristics and IC50 to drugs. Fulvestrant, an ER antagonist, rendered the cells significantly more resistant to taxol in ARK1 and 2(p=0.035, 0.021 respectively). The concomitant decrease in pERS167 and pAKTS473 with Fulvestrant treatment is independent of baseline ER expression and PI3K mutation. In ARK2, a cell line that is ER-, disrupting AKT signaling via the PI3K inhibitor GDC-0941, or with the lapatinib is synergistic with Fulvestrant with Combination Index (CI)50 of 0.441 and 0.229, respectively. Independent of HER2 amplification or PI3K mutation, lapatinib and GDC-0941 exhibited synergistic cytotoxicity in both UPSC cell lines (CI50 of 0.577, ARK 1 and 0.233, ARK2). Finally, PI3K mutation and pAKTS473 expression was analyzed in 7 tumor samples. While none harbored PI3K mutation, patients who are chemotherapy resistant had significantly lower expression of baseline pAKTS473 in their tumor samples than those who are chemosensitive, similar to our cell line data.
Conclusions: PI3K pathway dysregulation, either via upstream erbB amplification, or downstream constitutive activation of AKT, may be important in mediating endocrine and taxol sensitivity in UPSC. pAKTS473 may be an important biomarker of drug sensitivity. The combination of PI3K inhibitor and lapatinib is synergistic and warrant further therapeutic investigation.
Baseline characteristics and drug sensitivities in UPSC cell linesARK1ARK2PI3KCA mutationfExon 9NoERα (WB)YesNopERα167 (WB)YesNopHER (WB)NoYesIC50 nM (mean ± STD)GDC-094193.1±5.9271±116.5LapatinibNo effect135.6±29.2FulvestrantNo effectNo effectTaxol4.6±1.97.8±5.6Cisplatin1103±65.72632.6±1797.9
Citation Format: Kelly S. Levano, Alicia Rodriguez-Gabin, Gary L. Goldberg, Susan B. Horwitz, June Y. Hou. The PI3K inhibitor GDC-0941 is synergistic with lapatinib, and mediates endocrine sensitivity in uterine papillary serous 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 4687. doi:10.1158/1538-7445.AM2014-4687