bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 35: Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).
Authors: Lee Jung-Min , Annunziata Christina , Noonan Anne M. , Hays John L. , Minasian Lori , Zujewski Jo Anne , Chen Helen , Wright John , Houston Nicole , Kohn Elise C.
Published: August 2014

Background: Inhibition of the MAPK pathway with sorafenib and neutralization of VEGF with bevacizumab (B) resulted in clinical benefit with interactive toxicity. Dasatinib (D) is a broad spectrum tyrosine kinase inhibitor with high affinity for SRC family kinases. We hypothesized that using this upstream inhibitor of the MAPK pathway with B would maintain activity with less interactive toxicity.

Methods: A 3+3 dose escalation design incorporated with B 5mg/kg q2wk plus daily D 50, 70 and 100 mg in dose levels [DL] 1/2/3, then B 10mg/kg q 2wk plus D 100mg in DL4. DLT was defined during the first 6 weeks of treatment. Safety was assessed each 28d cycle and disease was reassessed every 2 cycles.

Results: 19 pts were treated in the dose escalation portion on 4 DLs. Pts (17F/2M) had a median age of 64 yrs (25-79), ECOG PS 0-1, and normal end-organ function. Most (14/19) pts had metastatic gynecologic cancers (6 endometrial/5 ovarian-peritoneal/2 cervix/1 rectovaginal GIST). Other cancers included breast (2), pancreatic neuroendocrine (1), medullary thyroid (1) and melanoma (1). Median number of prior treatments was 4 (1-11). The highest planned dose combination was examined without exceeding the MTD. No DLT was observed. Grade (g) 3 events included hypertension (2), pleural effusion (2), dyspnea (1) and pulmonary hypertension (1). D-mediated marrow suppression was observed in 12 pts: anemia (g1/2 [12 pts]), lymphopenia (g1/2 [9pts]; g3 [1pt]), thrombocytopenia (g1/2 [5pts]), and neutropenia (g1/2 [4pts]). Confirmed PR was seen in 1/17 evaluable pts, a pt with HER2+ breast cancer (5 mo). Stabilization >/= 4 mo occurred in 9 pts (median 9 mo [4-18+mo]), yielding clinical benefit in 59%.

Conclusions: D 100 mg daily with B 10mg/kg q2wk appears to be active and is well-tolerated in pts with advanced solid tumors. G 3 adverse events were uncommon and g 4 events or severe marrow toxicities were not observed at the doses planned and examined. An expansion cohort is now accruing with functional imaging, tumor biopsies, and blood sampling for measurement of biochemical changes in SRC and VEGF signaling pathways.

Citation Format: Jung-Min Lee, Christina Annunziata, Anne M. Noonan, John L. Hays, Lori Minasian, Jo Anne Zujewski, Helen Chen, John Wright, Nicole Houston, Elise C. Kohn. Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 35. doi:10.1158/1538-7445.AM2013-35
Abstract 3503: A method for quantifying soluble folate receptor 1 in IMGN853 0401 clinical trial patients.
Authors: Testa Nathan , Bartle Laura , Ab Olga , Cheng Judy , Payne Gillian , Lutz Robert J. , Wolf Ben , Carrigan Christina
Published: August 2014

IMGN853, an antibody-“drug” conjugate (ADC), consists of a human folate receptor 1 (FOLR1)-binding monoclonal antibody, M9346A, conjugated to the maytansinoid, DM4, via the cleavable sulfo-SPDB linker. A phase I clinical study has been initiated to identify the maximum tolerated dose, safety, pharmacokinetics (PK), and preliminary efficacy of IMGN853 in patients with FOLR1-positive tumors, including ovarian cancer, non-small cell lung cancer, and other epithelial malignancies. The levels of soluble FOLR1 antigen (sFOLR1) in plasma may vary depending on factors such as tumor antigen expression level, tumor type, and disease stage, and may affect the PK of IMGN853and response to treatment. Previously reported studies describing the detection of sFOLR1 in patient samples are limited and not quantitative.

The aim of this study was to develop a sandwich ELISA to quantify levels of sFOLR1 present in plasma samples from cancer patients for use as a potential biomarker of IMGN853 PK and/or clinical response.

A panel of murine anti-FOLR1 antibodies was generated at ImmunoGen by standard hybridoma technology. Two clones were chosen for use as capture (FR1-9) and detector (FR1-13) antibodies in the ELISA due to their high affinity and ability to bind to FOLR1 even in the presence of IMGN853 or the FOLR1 ligand, folate. The extracellular domain of FOLR1 fused to murine IgG2a Fc region (FOLR1-Fc) was used as a reference standard. A sandwich ELISA was developed using FR1-9 antibody to capture sFOLR1 from patient plasma, and bound sFOLR1 was detected using biotinylated FR1-13 antibody and streptavidin-HRP with TMB as the substrate. The ELISA was used to quantify sFOLR1 in ovarian carcinoma patient plasma using a reference standard curve generated with FOLR1-Fc antigen.

A robust sandwich ELISA was developed to quantify sFOLR1 in patient plasma. The quantitation range of the assay was determined to be 0.2 to 90 nanomolar. Coated plates stored frozen from 0-14 days and protein reagents freeze-thawed over two cycles gave repeatable results. The ELISA was able to detect sFOLR1 in 5 of 10 ovarian cancer patient plasma samples, where the levels of detectable sFOLR1 ranged from 0.7-31 nM. This ELISA is considered suitable to quantify levels of sFOLR1 in patients enrolled in the phase 1 trial over the course of IMGN853 treatment, and resulting data will be assessed for correlations with IMGN853 PK and with clinical response.

Citation Format: Nathan Testa, Laura Bartle, Olga Ab, Judy Cheng, Gillian Payne, Robert J. Lutz, Ben Wolf, Christina Carrigan. A method for quantifying soluble folate receptor 1 in IMGN853 0401 clinical trial patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3503. doi:10.1158/1538-7445.AM2013-3503
Abstract 353: Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc.
Authors: Kim Hongsug
Published: August 2014

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the RB, PI3K and p53 pathways are molecular hallmarks of this disease. Recent work has demonstrated that p53-/-Pten-/- mice form gliomas in a c-Myc dependent manner. To explore the role of the INK4A/ARF locus and Pten deletions in gliomagenesis, we generated Pten-/-Ink4a/Arf-/- mNSCs and such cells were highly proliferative, self- renewing, relatively refractory to differentiation and induced both low and high grade glioma formation in vivo. In contrast to p53-/- Pten-/- mNSCs, however, Pten-/-Ink4a/Arf-/- mNSCs do not express appreciable levels of c-Myc in vitro although glioma stem cells (GSCs) derived from these same cells did. Sequencing of Pten-/-Ink4a/Arf-/-mNSCs- derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten-/-Ink4a/Arf-/- mNSCs, or knockdown of Fbxw7, resulted in re-expression of c-Myc with enhanced Pten-/-Ink4a/Arf- /- mNSCs tumorigenecity. We propose that p53 mutations contribute to gliomagenesis by both allowing the overexpression of c-Myc through downregulation of Fbxw7 and by protecting against c-Myc-induced apoptosis.

Citation Format: Hongsug Kim. Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 353. doi:10.1158/1538-7445.AM2013-353
Abstract 3533: Clinical impact of NF-KB activation in diffuse large B cell lymphoma.
Authors: Odqvist Lina , Montes-Moreno Santiago , Sánchez-Beato Margarita , Sánchez-Verde Lydia , Mollejo Manuela , Young Ken H. , Fresno Manuel F. , Mazorra Francisco , Ruíz-Marcellán Carmen , Piris Miguel A.
Published: August 2014

Deregulated nuclear factor KB (NF-KB) activity has been associated with a number of lymphoproliferative diseases, including diffuse large B cell lymphoma (DLBCL), but the importance and consequence of this activation are still not fully understood. In this study, we describe the extent of NF-KB activation in a range of human lymphoma types and observe a frequent concurrent activation of both classical and alternative pathways in DLBCL. The activation of the classical and alternative NF-KB pathways, was present in 34.8% and 29.3% of DLBCL cases respectively, as assessed by nuclear expression of p50 (classical pathway) and p52 (alternative pathway) by immunohistochemistry in a series of 167 samples. Activation of NF-KB was observed in both germinal centre B-cell like (GC) and activated B-cell like (ABC) subtypes, although with a predominance of classical NF-KB in the ABC subtype (41,8% positive cases versus 21,2% in the GC subtype). In our cohort of samples from 167 R-CHOP treated DLBCL patients, excluding cases positive for Epstein-Barr virus, nuclear expression of NF-KB was significantly associated with a superior overall survival (Log Rank p<0.05), as compared to those without nuclear NF-KB. The 3-year overall survival rate in the NF-KB positive group was 83.6% compared to 68.0% in the NF-KB negative group. While p50 expression alone did not give rise to any significant differences in the survival curves, p52 expression did associate significantly with better clinical outcome (p=0.032). Thus, alternative NF-KB activation is frequently present in DLBCL tumors, is not associated with the ABC subtype, and is characterized by an enhanced overall survival.

Citation Format: Lina Odqvist, Santiago Montes-Moreno, Margarita Sánchez-Beato, Lydia Sánchez-Verde, Manuela Mollejo, Ken H. Young, Manuel F. Fresno, Francisco Mazorra, Carmen Ruíz-Marcellán, Miguel A. Piris. Clinical impact of NF-KB activation in diffuse large B cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3533. doi:10.1158/1538-7445.AM2013-3533
Abstract 354: Conditional inactivation of Pten and overexpression of EGFR in Schwann cells results in early high-grade peripheral nerve sheath tumor development.
Authors: Keng Vincent W. , Watson Adrienne L. , Rahrmann Eric P. , Li Hua , Tschida Barbara R. , Moriarity Branden S. , Choi Kwangmin , Rizvi Tilat A. , Collins Margaret H. , Wallace Margaret R. , Ratner Nancy , Largaespada David A.
Published: August 2014

It is hypothesized that many genetic changes are required for the transformation process of sporadic malignant peripheral nerve sheath tumor (MPNST). Currently, Schwann cells and/or their precursor cells are believed to be the primary pathogenic cell source in peripheral nerve sheath tumor (PNST) formation and malignant progression. Recently, it has been shown that phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) both play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs, because genetically modified mouse models for each gene alone resulted in the formation of low-grade PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, EGFR was expressed under the control of the 2′,3′-cyclic nucleotide 3’ phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Transgenic mice with EGFR overexpression and Pten inactivated have an early postnatal lethality (median survival age of 26-days) and displayed various peripheral nervous system phenotypes. These mice had multiple enlarged dorsal root ganglia, with high incidence of enlarged brachial plexus and trigeminal nerves at various stages of PNST tumorigenesis. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. Taken together, our data suggests that reduced PTEN expression, together with EGFR overexpression, can drive malignant progression of low-grade to high-grade PNSTs. Importantly, our novel mouse model recapitulates sporadic human MPNST and will be useful for testing therapies to prevent or reverse tumor progression.

Citation Format: Vincent W. Keng, Adrienne L. Watson, Eric P. Rahrmann, Hua Li, Barbara R. Tschida, Branden S. Moriarity, Kwangmin Choi, Tilat A. Rizvi, Margaret H. Collins, Margaret R. Wallace, Nancy Ratner, David A. Largaespada. Conditional inactivation of Pten and overexpression of EGFR in Schwann cells results in early high-grade peripheral nerve sheath tumor development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2013-354
Abstract 3543: TOP2A is a therapeutic target for adrenocortical carcinoma .
Authors: Jain Meenu , Zhang Lisa , He Mei , Zhang Ya-Qin , Nilubol Naris , Shen Min , Kebebew Electron
Published: August 2014

Adrenocortical carcinoma (ACC) represents one of the most resistant human cancers to systemic chemotherapy and a major clinical challenge in the field of endocrine oncology. Recent molecular characterizations of ACC suggest new opportunities for targeted therapy. The current study aimed to evaluate expression and function of TOP2A in human adrenocortical neoplasm, and anticancer activity of agents that target TOP2A. TOP2A mRNA and protein expression levels were evaluated in 112 adrenocortical tissue samples. In vitro siRNA knockdown of TOP2A in ACC cell lines (NCI-H295R and SW13) was used to determine its effect on cellular proliferation, cell cycle, anchorage-independent growth and cellular invasion. We screened 14 TOP2A inhibitors for their anticancer activity in ACC cell lines. TOP2A mRNA expression was significantly higher in ACC than in benign and normal adrenocortical tissue samples (p < 0.001); likewise, TOP2A protein expression was significantly higher in ACC (p < 0.05). Knockdown of TOP2A gene expression decreased cell proliferation, anchorage-independent growth and invasion (p < 0.05). Aclarubicin had the most potent antiproliferative activity out of 11 active TOP2A inhibitors, which significantly decreased proliferation and tumor spheroid size in ACC cell lines (p< 0.05). Our data indicate that most TOP2A inhibitors are effective compounds for ACC, with aclarubicin having the best anticancer activity. Thus, TOP2A inhibitors should be tested in future clinical trials for patients with locally advanced and metastatic ACC.

Citation Format: Meenu Jain, Lisa Zhang, Mei He, Ya-Qin Zhang, Naris Nilubol, Min Shen, Electron Kebebew. TOP2A is a therapeutic target for adrenocortical carcinoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3543. doi:10.1158/1538-7445.AM2013-3543
Abstract 3544: The gastric mucosal tissue interleukin-8 mRNA expression level is a promising prognostic marker for prognosis prediction in advanced gastric cancer treatment.
Authors: Chakrabandhu Bandhuphat
Published: August 2014

Background : The Interleukin-8 is one of the potent chemokine that plays the major role in cancer inflammatory and vascular growth pathway. We conduct this experiment to determine how difference of its level between non-cancer and cancer location, and its possibility to predict prognosis and result of advance gastric cancer treatment .

Method : We collected 309 gastric tissue samples from 129 Thai advance gastric cancer patients during January 2007 to March 2012 . Clinical information was prospective collected on electronic data base. The Interleukin-8 expression levels were detected by relative quantitation RT-PCR method with Taqman probe for Interleukin-8 on 7500 series machine, Applied Biosystem . Test of difference of Mean was done with independent and paired t-test by SPSS version 17th. Test of difference was considered significant by p value ≤0.05.

Result : The gastric mucosal tissue IL-8 mRNA expression level was significantly higher in tumor specimen than benign specimen by level of 5469.35 and 565.42 respectively (p =0.13). Its level in diffuse histologic type,metastatic disease and positive lymph node group are higher without significant difference. In subgroup analysis for 50 neo- adjuvant chemotherapy patients, the responder group (partial response and complete response) had a lower IL-8 expression level than non-responder group by the means level of1904.02, 24269.31,respectively (p=0.209).

Conclusion : Gastric mucosal tissue IL-8 mRNA expression level was remarkable increased in advance gastric cancer and signet ring cell type. We found that the higher expression level is directly correlated with more advance of histological grading and prognosis of disease treatment. The chemotherapy response rate was poorer in extremely high expression. High interleukin-8 expression could be considered as poor clinical prognostic factor for gastric cancer treatment, and it may be helpful tool to predict the chemotherapy response in future.

Citation Format: Bandhuphat Chakrabandhu. The gastric mucosal tissue interleukin-8 mRNA expression level is a promising prognostic marker for prognosis prediction in advanced gastric cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3544. doi:10.1158/1538-7445.AM2013-3544
Abstract 3567: Estrogen signaling promotes effective progesterone receptor engagement with DNA in breast cancer cells.
Authors: Swinstead Erin E. , Trotta Andrew P. , Smith Eric , Grover Phulwinder K. , Need Eleanor F. , Buchanan Grant
Published: August 2014

Estrogens and progesterone (PROG) are key mediators of breast cancer aetiology and progression. The predominant actions of these hormones in the breast are mediated via their respective cognate steroid receptors, estrogen receptor alpha (ERα) and progesterone receptor (PGR). As ERα upregulates PGR expression, both are currently measured in clinical breast cancer samples to determine the utility of anti-estrogen therapy. Although the molecular actions of estrogens have been extensively studied, the role of PROG and PGR need further elucidation, particularly in the context of activated ERα signaling. Here, we treated ZR75-1 cells with 17β-estradiol (E2) alone or in combination with PROG and assessed global transcriptional responses by microarray expression profiling and receptor binding profiles by chromatin immunoprecipitation-sequencing (ChIP-seq).

PROG treatment alone significantly altered the regulation of only seven genes, whereas long term E2 treatment increased the PROG transcriptional response altering 785 genes (p value ≤ 0.05), and regulated pathways involved in ErbB signalling and cell proliferation. Consistent with these findings, ChIP-seq identified 10 times more PGR binding sites following long term E2 treatment (4566 at equivalent peak threshold) compared with PROG treatment alone. Candidate PGR ChIP validated these findings at 100% (12/12) sites tested. The long term E2-treated PGR cistrome was highly conserved amongst species, and enriched for progesterone receptor response elements (PREs) and FOXA1 binding sites. E2 enhancement of PGR binding could be abrogated by long term (72h) but not short term (4h) tamoxifen co-treatment. In T-47D cells, long term E2 treatment was not required for efficient interaction of PGR with DNA and FOXA1 silencing resulted in decreased PGR DNA occupancy at several sites. These data suggests that the combination of E2 and PROG regulated a distinct transcriptional response in breast cancer cells, perhaps due to the dependence of PGR on E2 signaling for maintenance of cellular PGR levels, and via the receptors sharing mutual collaborators and coregulators, such as FOXA1. ERα and PGR collectively shape a mitogenic response in breast cancer cells that is dependent on the combined presence of E2 and PROG.

Citation Format: Erin E. Swinstead, Andrew P. Trotta, Eric Smith, Phulwinder K. Grover, Eleanor F. Need, Grant Buchanan. Estrogen signaling promotes effective progesterone receptor engagement with DNA in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3567. doi:10.1158/1538-7445.AM2013-3567
Abstract 3571: Inhibition of Cdk9 blocks ligand induced phosphorylation of Estrogen receptor alpha at Ser294.
Authors: Scott Gary K. , Kaur Ravneet , Rothschild Daniel , Benz C. C.
Published: August 2014

In response to ligand binding, the estrogen receptor (ER, alpha isoform) becomes phosphorylated on several serines including Ser294 and Ser118 to initiate an estrogenic transcriptional program that has been well studied. On the other hand, growth factor stimulation of ER also promotes serine phosphorylation at several sites including Ser305 and Ser118, but not Ser294, to drive a transcriptional program different from that induced by estrogenic ligands. Our previous work demonstrated that following estrogen or tamoxifen stimulation, cyclin dependent kinase (Cdk) mediated phosphorylation of the ER hinge region at Ser294 was essential for full transcriptional activation of ER. Current studies, using a recently developed rabbit monoclonal antibody to phospho-Ser294 ER, show that the Cdk9 inhibitor SCH727956/Dinaciclib, now in phase II clinical trials, completely prevents Ser294 phosphorlyation induced by estrogen stimulation of MCF-7 cells without influencing phospho-Ser118 formation which remains robust. Immunoprecipitation of ER from MCF-7 cells following estrogen treatment results in the co-immunoprecipitaton of cdk9. Further SCH727965/Dinaciclib has no influence upon epidermal growth factor (EGF) induced ER phosphorylation at Ser305, consistent with previous studies linking phospho-Ser305 formation to the activated kinases PKA and PAK. Ongoing studies evaluating siRNA induced knockdown of Cdk9 in MCF-7 cells followed by estrogen and/or EGF stimulation are designed to confirm the specific role of Cdk9 in mediating ligand-induced ER phosphorylation at Ser294. As Cdk9 is essential to promote transcriptional elongation by RNA polymerase II, the Ser294 specific recruitment of Cdk9 to ER following ligand stimulation offers rationale for the clinical use of Cdk9 inhibitors such as SCH727965/Dinaciclib in the treatment of ER-positive breast cancers. In particular, for those ER-positive breast cancers responsive to endocrine therapy the combined use of a Cdk9 inhibitor with antiestrogenic therapy is likely to prove clinically beneficial.

Citation Format: Gary K. Scott, Ravneet Kaur, Daniel Rothschild, C. C. Benz. Inhibition of Cdk9 blocks ligand induced phosphorylation of Estrogen receptor alpha at Ser294. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3571. doi:10.1158/1538-7445.AM2013-3571
Abstract 3582: Licochalcone-A, a natural inhibitor of c-Jun N-terminal kinase 1.
Authors: Yao Ke , Chen Hanyong , Lee Mee-Hyun , Li Haitao , Ma Weiya , Lee Ki Won , Bode Ann M. , Dong Zigang
Published: August 2014

The c-Jun N-terminal kinases (JNKs) pathway plays an important role in many physiological processes induced by a variety of stress signals. Each JNK protein appears to have a distinct function in cancer, asthma, diabetes, or Parkinson's disease. JNK1 is a key contributor for breast cancer and gastric cancer. Herein, we found that licochalcone-A, a major phenolic constituent isolated from licorice root, suppressed JNK1 activity, but had little effect on JNK2 in vitro. Although licochalcone-A binds with JIP1 competitively with either JNK1 or JNK2, a computer simulation model showed that after licochalcone-A binding, the ATP-binding cleft of JNK1 was distorted more substantially than that of JNK2. This could reduce the affinity of JNK1 more than JNK2 for ATP binding. Furthermore, licochalcone-A inhibited JNK1-mediated, but not JNK2-mediated, c-Jun phosphorylation in both ex vivo and in vitro systems. We also observed that in colon and pancreatic cancer cell lines, JNK1 is highly expression compared with normal cell lines. In these cell lines, treatment with licochalcone-A or knocking down JNK1 expression suppressed colon and pancreatic cancer cell proliferation and colony formation. These results demonstrate that licochalcone-A is a selective JNK1 inhibitor. Therefore, we suggest that because of JNK1’s critical role in colon cancer and pancreatic carcinogenesis, licochalcone-A might have therapeutic potential against this devastating disease.

Citation Format: Ke Yao, Hanyong Chen, Mee-Hyun Lee, Haitao Li, Weiya Ma, Ki Won Lee, Ann M. Bode, Zigang Dong. Licochalcone-A, a natural inhibitor of c-Jun N-terminal kinase 1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3582. doi:10.1158/1538-7445.AM2013-3582
Abstract 3591: The role of T-cell protein tyrosine phosphatase (TC-PTP) in UVB-induced epidermal cell proliferation and survival.
Authors: Lee Young S. , Shin Jun W. , Morales Liza D. , Slaga Thomas J. , Kim Dae J.
Published: August 2014

Ultraviolet (UV) radiation is the primary cause of human skin cancer. Signal transducer and activator of transcription 3 (Stat3) is one of the key regulators of epidermal cell survival and proliferation during the development of UV-induced skin cancer. We have previously shown that T-cell protein tyrosine phosphatase (TC-PTP) contributes to the rapid dephosphorylation /deactivation of Stat3 in response to UVB irradiation in keratinocytes. In the current work, we investigated the functional role of TC-PTP in keratinocyte survival and proliferation following UVB exposure. Knockdown of TC-PTP in mouse keratinocytes using siRNA significantly reduced apoptosis following UVB irradiation in comparison with control keratinocytes as evidenced by the decreased levels of activated caspase-3 and PARP cleavage. This reduction corresponded with an increased level of phososphorylated Stat3 in TC-PTP-deficient keratinocytes. Knockdown of TC-PTP in keratinocytes also significantly increased cell proliferation following UVB irradiation compared with control keratinocytes. Similar with these results, overexpression of TC-PTP in keratinocytes significantly increased apoptosis and decreased cell proliferation in response to UVB irradiation compared with control keratinocytes, which corresponded with a decreased level of phosphorylated Stat3. Further studies using TC-PTP-deficient keratinocyte cell lines showed that cell viability was increased in TC-PTP-deficient cells following UVB irradiation. Treatment of TC-PTP-deficient keratinocytes with specific Stat3 inhibitor, STA21 significantly reduced cell viability, upon UVB exposure in comparison with untreated TC-PTP-deficient keratinocytes, which suggests that the effect of TC-PTP on cell viability is mediated by Stat3 dephosphorylation. Combined, our results indicated that TC-PTP plays an important role in the regulation of keratinocyte proliferation and survival after UVB exposure via modulation of Stat3 signaling. Furthermore, these results suggest that TC-PTP may be a novel potential target for the prevention of UVB-induced skin cancer.

Citation Format: Young S. Lee, Jun W. Shin, Liza D. Morales, Thomas J. Slaga, Dae J. Kim. The role of T-cell protein tyrosine phosphatase (TC-PTP) in UVB-induced epidermal cell proliferation and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3591. doi:10.1158/1538-7445.AM2013-3591
Abstract 3593: GABA counteracts ethanol induced stimulation of pancreatic cancer cells and normal pancreatic duct epithelia .
Authors: Al-Wadei Mohammed H. , Al-Wadei Hussein A.N. , Schuller Hildegard M.
Published: August 2014

Pancreatic cancer has a high mortality rate and alcoholism is a risk factor independent of smoking. We have shown that nicotinic acetylcholine receptors (nAChRs) regulate pancreatic ductal epithelia and pancreatic ductal adenocarcinoma (PDAC) cells in an autocrine fashion by stimulating their production of the stress neurotransmitters noradrenaline and adrenaline that signal through beta-adrenergic receptors (β-ARs). Our current study has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by γ-amino butyric acid (GABA).

Treatment for seven days with ethanol at a concentration equivalent to the legal blood alcohol limit in the United States induced protein expression and sensitivity of nAChRs α3, α5 and α7 resulting in increased production of noradrenaline and adrenaline which drive proliferation and migration via cAMP-dependent signaling downstream of β-ARs. Treatment with GABA prevented all of these responses to chronic ethanol, reducing cell proliferation and migration below base levels in untreated cells.

Our findings suggest that alcoholism induces multiple cAMP-dependent PDAC stimulating signaling pathways by up-regulating the protein expression and sensitivity of nAChRs that regulate stress neurotransmitters production. Moreover, our data identify GABA as a promising agent for the prevention of PDAC in individuals at risk due to chronic alcohol consumption.

Supported by R01CA042829 and R01CA130888 with the National Cancer Institute

Citation Format: Mohammed H. Al-Wadei, Hussein A.N. Al-Wadei, Hildegard M. Schuller. GABA counteracts ethanol induced stimulation of pancreatic cancer cells and normal pancreatic duct epithelia . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3593. doi:10.1158/1538-7445.AM2013-3593
Abstract 3597: Further studies on cadmium-adapted lung epithelial cells: evidence for the attenuation of general stress response, enhancement of metallothionein-induction response, and loss of p53 expression.
Authors: Xu Yan-Ming , Zhou Yuan , Huang Dong-Yang , Zhang Jian , Chiu Jen-Fu , Lau Andy T. Y.
Published: August 2014

Adaptation is a cellular process in which cells are progressed from the starting sensitive state to the later adapted state to the exposing agent. Acute exposure of cells to cadmium (Cd) can cause cell death; however, chronic exposure of Cd can develop acquired tolerance where cell death is suppressed. We previously reported that during Cd adaptation in lung epithelial cells, cells develop tolerance to cell death, generally due to perturbation of the c-Jun N-terminal kinase (JNK) signaling pathway and the nonresponsiveness of JNK phosphorylation is critical for the Cd-tolerance in these cells (1, 2). In this study, we further studied the properties of these Cd-adapted cells. Our results indicate that Cd-adapted cells, when compared with Cd-treated parental Cd-sensitive cells, show negligible general stress response to the same dosage of cadmium exposure. Moreover, although metallothionein (MT) is induced in both Cd-sensitive and Cd-adapted cells, Cd-adapted cells show enhanced MT-induction response and this was not due to MT gene amplification. Lastly, we showed that the tumor suppressor p53 protein level is severely abrogated in these Cd-adapted cells, suggesting that the normal p53 function is lost and may account for the death tolerance, genome instability, as well as the progression of carcinogenesis.

Citation Format: Yan-Ming Xu, Yuan Zhou, Dong-Yang Huang, Jian Zhang, Jen-Fu Chiu, Andy T. Y. Lau. Further studies on cadmium-adapted lung epithelial cells: evidence for the attenuation of general stress response, enhancement of metallothionein-induction response, and loss of p53 expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3597. doi:10.1158/1538-7445.AM2013-3597
Abstract 3615: Does selenium supplementation increase serum glucose levels in men at high risk for prostate cancer.
Authors: Algotar Amit M. , Hsu C H. , Stratton Steven P.
Published: August 2014

Background: Current literature regarding the effect of selenium supplementation on risk of diabetes is inconclusive. Hence a longitudinal study was conducted to investigate the effect of selenium supplementation on serum glucose levels in elderly men.

Methods: Data were obtained from 699 men participating in a randomized, double-blind, placebo-controlled Phase 3 clinical trial investigating the effect of two doses of selenium (200 and 400 μg/day) compared to placebo on incidence of prostate cancer. Subjects were followed every six months for up to five years. Serum glucose levels were obtained every six months. Mixed effects regression models were used to assess if rate of change of serum glucose levels was significantly different in the selenium supplemented groups as compared to placebo. Sensitivity analyses were performed to assess the robustness of findings and to minimize the possibility of residual bias due to fasting status.

Results: Of the total 2893 glucose measurements, 734 were carried out when the subject had been fasting for ≥ 8 hours. The changes in serum glucose levels during the course of the trial were not statistically significantly different as compared to placebo for the selenium 200 μg/day (p = 0.88) or selenium 400 μg/day (p = 0.45) treatment groups. Sensitivity analyses demonstrated comparable results for models using the total population and models restricted to subjects with only fasting glucose data.

Conclusion: These results do not support a relationship between selenium supplementation and risk of diabetes. Hence recommendations regarding selenium supplementation based on increased risk of diabetes seem premature.

Citation Format: Amit M. Algotar, C H. Hsu, Steven P. Stratton. Does selenium supplementation increase serum glucose levels in men at high risk for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3615. doi:10.1158/1538-7445.AM2013-3615
Abstract 3617: Fat intake after prostate cancer diagnosis and risk of lethal prostate cancer and total mortality.
Authors: Kenfield Stacey A. , Richman Erin L. , Sesso Howard D. , Ma Jing , Stampfer Meir J. , Chavarro Jorge E.
Published: August 2014

Context and Objective: Although prostate cancer is the 2nd leading cause of cancer death in the US, few studies have evaluated the effect of diet after diagnosis on prostate cancer progression and all-cause mortality. We examined fat intake after prostate cancer diagnosis in relation to risk of lethal prostate cancer and all-cause mortality. Methods: This was a prospective study of 1,019 men diagnosed with prostate cancer between 1982 and 2000 in the Physicians’ Health Study. Men completed a dietary food frequency questionnaire a median of 5.1 years after diagnosis. We examined post-diagnostic intake of saturated, monounsaturated, polyunsaturated, and trans fats, as well as animal and vegetable fats. Cases were confirmed by medical record review. The main outcomes were lethal prostate cancer, defined as prostate cancer-specific death or metastasis to bone, and all-cause mortality. Multivariate Cox proportional hazards regression was used to estimate the relative risk of lethal prostate cancer and all-cause mortality. Models were adjusted for age at diagnosis, time since diagnosis, clinical T-stage, Gleason Score, prostate cancer treatment, BMI, smoking status, intake of alcohol and protein, total calories, and other fats. Results: We observed 87 lethal prostate cancer events and 395 total deaths over a median follow-up after diagnosis of 13.9 years. There was a suggestion of a positive relation between saturated fat intake and lethal prostate cancer that failed to reach statistical significance. The hazard ratio (HR) for lethal prostate cancer associated with a 5% increase in energy from saturated fat was 1.97 (0.89, 4.36; p=0.10). In addition, saturated fat intake after diagnosis was associated with increased risk of all-cause mortality (HR per 5% energy: 1.49; 95%CI: 1.02, 2.16; p=0.04) while vegetable fat was associated with reduced risk of all-cause mortality (HR per 10% energy: 0.63; 95%CI; 0.46, 0.88; p=0.007). Conclusions: Among men diagnosed with prostate cancer, replacing calories from carbohydrates with saturated fat after diagnosis may increase risk of all-cause mortality, while replacing calories from carbohydrates with vegetable fat may reduce risk of all-cause mortality.

Citation Format: Stacey A. Kenfield, Erin L. Richman, Howard D. Sesso, Jing Ma, Meir J. Stampfer, Jorge E. Chavarro. Fat intake after prostate cancer diagnosis and risk of lethal prostate cancer and total mortality. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3617. doi:10.1158/1538-7445.AM2013-3617
Abstract 3623: Association between helicobacter pylori infection and lung cancer: a meta-analysis.
Authors: Wu Na , Xu Bin , Li Yafei
Published: August 2014

Lung cancer is still the leading death cause of cancers. Helicobacter pylori (Hp) is one of the most common bacteria infecting human. In the past decade, some investigators endeavored to clarify the possible association of lung carcinoma risk with Hp infection, with conflicting results. Whether Hp infection is a risk factor for lung cancer remains largely uncertain. We performed a meta-analysis on the association between Hp infection and lung cancer. Medline, OVID, EMBASE and Chinese Biomedical Literature database (CBM) database were comprehensively searched for the relevant literatures until September 2012. Meta-analysis was performed using the program Review Manager 6.2. Heterogeneity was also explored. Seven case-control studies with a total of 1011 cases and 1040 controls met the inclusion criteria and were included in the meta-analysis. Hp infection was detected seropositivity for antibodies against Hp using ELISA in all 7 studies. Our meta-analysis showed that patients with lung cancer have a significantly higher rate of seropositivity for antibodies against Hp than controls, with an odds ratio of 3.15 (95% CI, 1.49-6.67). This meta-analysis suggests there may be a potential effect of Hp infection on the risk of lung cancer. This warrants further large and well-designed studies for thorough investigation.

Citation Format: Na Wu, Bin Xu, Yafei Li. Association between helicobacter pylori infection and lung cancer: a meta-analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2013-3623
Abstract 3624: Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.
Authors: Leng Shuguang , Picchi Maria A. , Liu Yushi , Lin Yong , Stidley Christine A. , Gilliland Frank D. , Jacobson Marty R. , Belinsky Steven A.
Published: August 2014

Epidemiological studies of underground miners suggest that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks (DSBs) induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P=0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (Odds Ratio = 1.69, P = 8.2×10−5) and greater survival in SCC cases (Hazard Ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggested that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.

Citation Format: Shuguang Leng, Maria A. Picchi, Yushi Liu, Yong Lin, Christine A. Stidley, Frank D. Gilliland, Marty R. Jacobson, Steven A. Belinsky. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3624. doi:10.1158/1538-7445.AM2013-3624
Abstract 3636: Systems biology approach links genetic, epigenetic, and transcriptomic features to tamoxifen sensitivity.
Authors: Gamazon Eric R. , Weng Liming , Im Hae Kyung , Zhang Xiaotong , Ziliak Dana M. , Huang R. Stephanie
Published: August 2014

Utilizing existing genome-wide genotype, transcriptome and microRNA (miRNA) datasets, we developed an integrative approach to evaluate the role of genetic-epigenetic regulatory networks in human complex traits. In this study, we focused on cellular sensitivity to tamoxifen, a commonly prescribed breast cancer medication as a phenotype of interest. A sequential multi-dimensional model was constructed to first identify genes/miRNAs whose expression levels are correlated with tamoxifen sensitivity. This in turn facilitated the identification of SNPs associated with potential functionally relevant genomic features. Finally, associations between these selected SNPs and cellular sensitivity to tamoxifen were evaluated. A permutation-based false discovery rate (FDR) procedure showed that association findings from our approach have much lower FDRs when compared to those obtained through a traditional single-step genome-wide association study (GWAS) between SNP and drug sensitivity. Our model identified 50 unique SNPs associated with 30 miRNAs and 34 gene expression levels, all of which associated with cellular sensitivity to tamoxifen phenotypes in HapMap YRI samples. Among them, several miRNAs and genes have been previously implicated to play a role in tamoxifen sensitivity; most are novel. Functional studies on select miRNAs/genes are currently underway in both the HapMap samples and breast cancer cell lines.

Citation Format: Eric R. Gamazon, Liming Weng, Hae Kyung Im, Xiaotong Zhang, Dana M. Ziliak, R. Stephanie Huang. Systems biology approach links genetic, epigenetic, and transcriptomic features to tamoxifen sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2013-3636