bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1254: Small molecule targeting of the kRAS mid-G-quadruplex for potential pancreatic cancer therapeutics
Authors: Morgan Rhianna K. , Brooks Tracy A. 
Published: July 2016

Abstract
Pancreatic cancer is disproportionally lethal (7% of all cancer deaths), as compared to its incidence (3% of cancer incidences) within the United States. One of the most important genetic alterations in pancreatic cancer is within the kRAS oncogene. Over 60% of all pancreatic cancers, and up to 95% of pancreatic ductal adenocarcinomas, harbor mutations in this oncogene. While approaches to therapeutically modulate kRAS activity have not yielded clinical agents, downregulation of expression shows promise in preclinical models. To date, no molecular target has allowed for small molecule mediated downregulation of kRAS expression; however, the promoter region holds promise for a new approach. The kRAS promoter has three distinct guanine-rich regions capable of forming higher order non-B-DNA structures, G-quadruplexes (G4s). In particular the middle (mid) of these three regions forms a stable, inducible, and transcriptionally silencing G4 structures, whereas the more distal (far) region forms no such structure, and the more proximal (near) region has little to no biological function. The structure of this mid-region G4 has been elucidated by electromobility shift assay, DMS footprinting, and circular dichroism (CD). Small molecules capable of stabilizing this structure have been screened from the NCI Diversity Set III by the FRET melt assay, confirmed by CD, and examined for their downregulation of kRAS promoter activity. From the 1600 compounds, the indoloquinolone NSC 317605 is the lead molecule identified. It is particularly interesting as it prefers the mid-, as opposed to the near-, G4 and significantly reduces kRAS promoter activity. This is in contrast to the ellipticine NSC 176327, which favors the near-, over the mid-, G4 and does not decrease kRAS promoter activity. The effect of each compound on cell viability on kRAS transcription is under examination in a panel of pancreatic cancer cells. These works support previous findings that the mid-, and not the near-G4, harbors the potential to transcriptionally downregulate kRAS, and identify a new scaffold for future development.
Brooks Lab startup funds, DoD, Rhianna Morgan GSC Grant, University of Mississippi School of Pharmacy
Citation Format: Rhianna K. Morgan, Tracy A. Brooks. Small molecule targeting of the kRAS mid-G-quadruplex for potential pancreatic cancer therapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1254.
Abstract 1262: Primate-specific estrogen-induced long noncoding RNAs as targets for breast cancer treatment
Authors: Ju Donghong , Xie Daniel , Cai Juan , Goustin Anton Scott , Kosir Mary A. , Lipovich Leonard 
Published: July 2016

Abstract
Purpose: Estrogen is a proliferative hormone that regulates the growth of estrogen receptor positive cells, including breast cancer cells. Although estrogen is a global regulator of protein-coding genes as well as non-coding RNA (ncRNA) genes, its effects on long ncRNA (lncRNA) genes, the most abundant class of human ncRNAs, remain poorly understood. We previously used custom microarrays and Taqman qRTPCR to identify 127 estrogen-responsive lncRNAs, and demonstrated a direct role for 25 of these in breast cancer cell viability and proliferation: estrogen-induced lncRNAs cause cell proliferation (reversed upon siRNA knockdown of these lncRNAs) and estrogen-repressed lncRNAs cause cell death (induced upon overexpression of those lncRNAs).
Furthermore, since over 60% of human lncRNAs, including CR593775, are primate-specific, eight additional primate-specific lncRNAs were used in functional assays to determine whether primate-specific lncRNAs are functional in breast cancer.
Methods/Results: We ablated two new estrogen-induced primate-specific lncRNAs with two independent siRNAs each and validated the knockdowns by qRTPCR. Post-transfection MTT and crystal violet cell proliferation assays revealed that for one lncRNA, both knockdowns reduced cell viability and proliferation. We also used Stellaris RNA fluorescent in situ hybridization (FISH) to determine that the primate-specific estrogen-repressed cell death inducer lncRNA BC041455 is cytoplasmic in MCF7 cells. In addition, CR593775, our top estrogen-induced lncRNA, does not regulate the viability and proliferation of nonmalignant MCF10A breast cells as compared to breast cancer cells that are estrogen receptor positive (T47D, MCF7) and negative (MDA-MB-231).
Conclusion: The primate-specific estrogen-induced lncRNAs are cytoplasmic targets for breast cancer treatment that leads to reduced proliferation and cell viability.
Citation Format: Donghong Ju, Daniel Xie, Juan Cai, Anton Scott Goustin, Mary A. Kosir, Leonard Lipovich. Primate-specific estrogen-induced long noncoding RNAs as targets for breast cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1262.
Abstract 1282: Combination of PI3K targeting with cetuximab and irradiation: a preclinical study on an orthotopic xenograft model of head and neck cancer
Authors: Milano Gérard , Bozec Alexandre , Ebran Nathalie 
Published: July 2016

Abstract
The PI3-kinase (PI3K)/AKT/mTOR signaling pathway is of particular interest in head and neck squamous cell carcinoma (HNSCC). Its activation has been identified as an important mechanism implicated in tumor progression and resistance to epidermal growth factor receptor (EGFR) inhibitors. The anti-EGFR monoclonal antibody cetuximab (Cet), radiotherapy (RT) and their combination are widely used in the therapeutic management of patients with HNSCC. Inhibition of the PI3K/AKT/mTOR signaling pathway has been shown to potentialize the effects of anti-EGFR agents and RT. We conducted a preliminary in vitro study demonstrating synergistic effects of Cet followed by the PI3K inhibitor BKM120 (Buparlisib) in both PI3KCA wild-type and mutated cells. The aim of the present study was to investigate the effects of combining BKM120 with Cet and RT on an orthotopic xenograft model of HNSCC.
In the present study we have used an orthotopic (floor of the mouth) model of human HNSCC to measure the effects of a treatment including BKM120 (40 mg/kg, 5 days/week, p.o.), Cet (2,5 mg/kg/day, 1 day/week, i.p.) and RT (6 Gy/dose, 3 days/week), administered alone or in combination. Investigations were performed using the human PI3KCA-mutated (H1047R) HNSCC cell line, CAL33, injected into the mouth floor of nude mice. The tumor growth was followed by IVIS imagery on days 3, 7 and 12 and tumor size was checked with a caliper ruler on day 13 after animal euthanasia.
As compared with the control, the BKM120-Cet and the BKM120-Cet-RT combinations led to the highest tumor inhibition and induced almost complete tumor growth arrest (p &lt; 0.001). The addition of BKM120 and Cet to RT significantly enhanced the impact of RT alone on tumor growth (p &lt; 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pERK labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the BKM120-Cet association. RT alone (p = 0.10) tended to activate the MAPK pathway but the association of BKM120 and Cet to RT inhibited the RT-induced activation of the MAPK pathway (p = 0.03).
In conclusion, in this orthotopic HNSCC model, the combination of BKM120 with Cet and RT produced synergistic effects on tumor growth. These results could serve as a strong preclinical basis for innovative treatments combining PI3K inhibition with anti-EGFR therapies and RT in patients with HNSCC.
Citation Format: Gérard Milano, Alexandre Bozec, Nathalie Ebran. Combination of PI3K targeting with cetuximab and irradiation: a preclinical study on an orthotopic xenograft model of head and neck cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1282.
Abstract 1286: Cytokine response of stromal cells to prostate cancer chemotherapeutics
Authors: Gales Dominique , Yates Clayton C. , Samuel Temesgen 
Published: July 2016

Abstract
Non-responsiveness to chemotherapeutic drugs presents a significant challenge to the effective treatment of advanced prostate cancer. Exploration of the therapeutic response in prostate cancer has largely focused on the epithelial tumor cells. However, evidence suggests that the tumor microenvironment may modulate response to chemotherapeutics. The tumor microenvironment consists of immune, fibroblastic, and vascular cells, as well as extracellular matrix (ECM) and stromal-derived soluble factors, all of which contribute to interactions within the tumor microenvironment. It has been demonstrated that tumor cells cross-talk with stromal cells, to establish a protective niche at primary and distant sites and to facilitate survival of cancer cells. Such tumor-stroma cell cross-talk often involves secreted factors, such as cytokines. Previous studies have illustrated the importance of cytokines and cytokine receptors as modulators of drug response. In this study, we sought to identify cytokine factors expressed in response to drugs clinically used to control prostate cancer. To obtain the expression profiles, we conducted a human cytokine and chemokine array, which consisted of 84 specific genes. Analysis of the prostate cancer and stromal cells treated with Docetaxel (4nM), Enzalutamide (30μM) and Bicalutamide (30μM) revealed differential expression patterns. The effect of chemotherapeutics on the expression of the cytokine IL-16 and its cognate receptors CD9 and CCR5 in prostate cancer and stromal cell lines was further examined. We found IL-16 expression increased several fold following chemotherapeutic treatment in stromal cell lines compared to prostate cancer cell lines. To validate gene expression, we examined the expression of IL-16 and its receptors by RT-PCR. All experiments were performed in triplicates. Student t- tests were used to determine the statistical significance between groups. IL-16 expression increased following exposure to chemotherapeutics in stromal cell lines. CCR5 expression showed a decrease in PC3 prostate cancer cells but no significant changes were observed in LNCaP cells. CD9 expression showed an increase in both LNCaP and PC3 cell lines. Collectively, these results indicate that chemotherapy of prostate cancer may alter the expression of IL-16 and its receptors. We hypothesize that IL-16 is a soluble stromal factor that is expressed in response to anticancer drugs, and may have paracrine activity on neighboring cells that express the cognate receptors.
Citation Format: Dominique Gales, Clayton C. Yates, Temesgen Samuel. Cytokine response of stromal cells to prostate cancer chemotherapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1286.
Abstract 1288: Targeting the Hippo pathway in NF-2 deficient papillary kidney cancers
Authors: Sourbier Carole , Liao Penny , Ricketts Christopher J. , Wei Darmood , Yang Youfeng , Baranes Sarah M. , Kijima Toshiki , Krane Louis S. , Boufraqech Myriem , Ohanjanian Lernik , Gibbs Ben , Wei Ming-Hui , Neckers Len , Vocke Cathy D. , Linehan. W. Marston 
Published: July 2016

Abstract
About 10% of papillary renal cell carcinomas (PRCC) bear mutations in NF2 or SAV1, two members of the Hippo pathway, which controls cell growth by regulating the transcriptional activity of YES1-Associated Protein YAP1. NF2 or SAV1 mutations lead to aberrant YAP1 activation resulting in cell proliferation and anti-apoptotic signals. The src family kinase YES1 is a known regulator of YAP1 transcriptional activity in the context of β-catenin-dependent tumors. Dasatinib and saracatinib are 2 src inhibitors that have shown to also have potent inhibitory effects on YES1. We hypothesized that inhibition of the Hippo pathway might provide a valuable therapeutic approach for patients with PRCC tumors bearing NF2 mutation, and that inhibiting YES1 might inhibit YAP1 in PRCC. Our data demonstrate that inhibition of the Hippo pathway is lethal to NF2-deficient PRCC cell lines, and that inhibiting YES1 with dasatinib or saracatinib effectively inhibits YAP1 and its downstream targets BIRC5 (survivin), CCND1 (cyclin D1) and CTGF (CTGF). Further, dasatinib proves to have an anti-tumor effect in vivo and was cytotoxic in vivo and in vitro, causing G0-G1 cell cycle arrest in NF2-deficient PRCC cell lines. Thus, inhibiting YES1 and the subsequent transcriptional activity of YAP1 with dasatinib or saracatinib might be a viable therapeutic approach for NF2-deficient PRCC tumors.
Citation Format: Carole Sourbier, Penny Liao, Christopher J. Ricketts, Darmood Wei, Youfeng Yang, Sarah M. Baranes, Toshiki Kijima, Louis S. Krane, Myriem Boufraqech, Lernik Ohanjanian, Ben Gibbs, Ming-Hui Wei, Len Neckers, Cathy D. Vocke, W. Marston Linehan. Targeting the Hippo pathway in NF-2 deficient papillary kidney cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1288.
Abstract 129: Integrated genomic analysis of survival outliers in glioblastoma
Authors: Peng Sen , Dhurv Harshil , Armstrong Brock , Kiefer Jeffrey , Salhia Bodour , Ross Julianna , Legendre Christophe , Virk Selene , Sloan Andrew E. , Ostrom Quinn T. , Barnholtz-Sloan Jill , Tran Nhan L. , Berens Michael E. 
Published: July 2016

Abstract
Despite the general poor prognosis for patients with GBM, a proportion survives well beyond the median survival of 12-14 months following diagnosis. To elucidate molecular features associated with disproportionately protracted survival, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide) wherein “GBM outliers” were identified: patients who responded (long-term survivor, LTS) versus those who failed rapidly (short-term survivor, STS). The datasets enabled interrogation for signatures indicative of tumor vulnerability. Whole genomic, transcriptomic and epigenetic analyses of 18 patients, including 8 LTS with an average 30 months overall survival (OS) and 10 STS with an average of 7 months OS were performed to capture single nucleotide variants (SNVs), indels, translocations, intra-chromosomal rearrangements, copy number variants, along with DNA methylation and mRNA expression. LTS and STS cases showed equal proportion of 7p11.2 (EGFR) amplification and 9p21.3 (CDKN2A) deletion. However, LTS GBM showed frequent chromosomal gains in 4q12 (PDGFRA and KIT) and 12q14.1 (CDK4) and deletion in 19q13.33 (BAX, BCAT2 and CD33), whereas, STS GBM showed frequent deletion in 9p11.2 (FOXD4L2 and AQP7P3) and 22q11.21 (HIC2). In addition, LTS GBM showed a 2-fold increased copy number alteration (specifically deletion) as compared to STS GBM. By gene expression analysis, supervised clustering using the CIN70 signature (prognostic) showed an increased expression in STS GBM. Overall, whole genome methylation analyses showed that STS GBM tumors harbor more hypomethylation in probes situated in -200 bp of transcription start site (TSS) and both exon 1 and 5’UTR region. A methylation signature consist of 89 probes distantly separate LTS from STS GBM tumors. We posit that genomic instability (broadly inclusive) is associated with vulnerability of GBM to standard therapy; conversely, genomic instability coupled with genetic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more-efficacious management.
Supported by a grant from the Ben & Catherine Ivy Foundation.
Citation Format: Sen Peng, Harshil Dhurv, Brock Armstrong, Jeffrey Kiefer, Bodour Salhia, Julianna Ross, Christophe Legendre, Selene Virk, Andrew E. Sloan, Quinn T. Ostrom, Jill Barnholtz-Sloan, Nhan L. Tran, Michael E. Berens. Integrated genomic analysis of survival outliers in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 129.
Abstract 1290: Actinomycin D enhanced immunotoxin RG7787 killing of cancer cells
Authors: Liu Xiu Fen , Xiang Laiman , Prunotto Marco , Niederfellner Gerhard , Pastan Ira 
Published: July 2016

Abstract
Immunotoxins are recombinant fusion proteins that contain an antibody fragment directed against a tumor selective surface antigen attached to a protein toxin. RG7787 is a newly developed, mesothelin-targeted immunotoxin designed to be less immunogenic and better tolerated than the previous clinical candidate SS1P. The targeting moiety of RG7787 consists of a humanized anti-mesothelin Fab, while its effector moiety is a truncated portion of Pseudomonas exotoxin A (PE) consisting essentially only of the catalytic domain III fused via a furin cleavable linker to the Fab fragment. The domain III variant used in RG7787 contains mutations that silence all known human B-cell and some T-cell epitopes. RG7787 targets and kills mesothelin-positive tumor cells, which are prevalent in mesothelioma, ovarian, lung, and pancreatic cancers. Safety and immunogenicity of RG7787 are being assessed in these tumor indications in an ongoing phase I trial. In order to further enhance the anti-tumoral activity of RG7787, we screened for clinically used drugs that can synergize with RG7787 in vitro and/or in vivo. Actinomycin D (Act D) is a potent transcription inhibitor and is used for treating a variety of cancers, including gestational trophoblastic neoplasia, Wilms tumor, rhabdomyosarcoma, and Ewing's sarcoma. In this study we found that the combination of Act D with RG7787 greatly stimulated cell killing of mesothelin positive cell lines, such as KB31, KLM1, and Hay. The combination also produced complete regressions of KLM1 pancreatic tumor xenografts in mice. To investigate the mechanism of killing we used an apoptosis RNA array and found that both Act D and RG7787 stimulate apoptotic stress responsive genes including TNFα, TRAILR2 (DR5), NFκB, GAD45A and TP53. The combination also increased cleavage and activation of the pro-apoptotic proteins caspase-3, -9, and PARP. Taken together our data indicate that combining RG7787 and Act D reduces the threshold for activation of apoptosis in cancer cells.
Citation Format: Xiu Fen Liu, Laiman Xiang, Marco Prunotto, Gerhard Niederfellner, Ira Pastan. Actinomycin D enhanced immunotoxin RG7787 killing of cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1290.
Abstract 1291: Applicability of integrative tumor response assays for recurrent colorectal cancer
Authors: Yoon Yong Sik , Kim Jin Cheon 
Published: July 2016

Abstract
Introduction
Drug response assays use autologous viable tumors to evaluate susceptibility to specific agents in vitro. Histoculture drug reponse assay (HDRA) is a representative methyl thiazolyl-diphenyl-tetrazolium bromide (MTT) assay, which has the advantage of more correctly reflecting the in vivo microenvironment. Many studies showed 66-92% of accuracy rates for clinical correlation of chemotherapy in solid tumors including colorectal cancer (CRC). However, in recurrent cases of metastatic CRC, there is no usable assay to predict second-line chemo-sensitivity. Thus, authors invented novel technique, the integrative tumor response assay (ITRA), can identify drug responses for both first- and second-line chemotherapy simultaneously. We investigated the chemo-sensitivity to clinically used regimens using ITRA of samples from patients with metastatic CRC, and compared their chemo-sensitivity with the observed clinical response.
Methods
A total of 129 patients with metastatic CRC were prospectively enrolled. First-stage HDRAs were performed using 5-fluorouracil with leucovorin and oxaliplatin (FX) or irinotecan (FR). Second-stage HDRAs (ITRA) were done for survived cells after first-stage HDRA, using FX, FR, and their combinations with bevacizumab and cetuximab. The inhibition rate of tumor growth (IR) cut-off value for a positive response was determined to be ≥ 30%. For clinical validation, treatment responses of chemotherapy were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). The primary endpoint of this study was a correlation between the ITRA results and the clinical response in the response rate (RR). This was defined as positive for the effect of chemotherapy for tumor responses between complete response (CR) and partial response (PR).
Results
Among 129 used samples, ITRA failure was 9 (7%), due to deficient volume of samples. Out of 79 evaluated first-line chemotherapeutic regimes, RR was 53% (42/79). The correlation rate of HDRA for first-line chemotherapy was 70.9% (56/79), with a 71.4% (30/42) of sensitivity and 70.3% (26/37) of specificity. For 42 cases completing second-line chemotherapy, RR was 43% (18/42). The accuracy rate of ITRA for second-line chemotherapy was 61.9% (26/42), with a 44.4% (8/18) of sensitivity and 75% (18/24) of specificity.
Conclusions
ITRA might be further developed to be a feasible and useful technique for predicting therapy efficacy and selecting the appropriate anticancer regimen for individual patients despite its relatively low accuracy.
Citation Format: Yong Sik Yoon, Jin Cheon Kim. Applicability of integrative tumor response assays for recurrent colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1291.