bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3598: Selective internal radiation (SIRT) is most effective when comparing local treatment to control progressive liver metastases of gastro-intestinal stromal tumors beyond treatment with tyrosine kinase inhibitors
Authors: Hohenberger Peter , Rathmann Nils , Menge Franka , Sadick Maliha , Schönberg Stefan , Diehl Steffen 
Published: August 2015

Abstract
Objective: The liver and the peritoneum are the main area of metastatic spread in gastrointestinal stromal tumors (GIST). Liver surgery plays a minor role for hepatic metastases in comparison to f.e. colorectal cancer. However, once the metastases are resistant to 1st line TKI, surgery, 2nd line therapy, interventional ablation techniques like RFA or selective internal radiation therapy (SIRT) are treatment options. We were interested to analyze the contribution of the different modalities in controlling hepatic progression.
Methods: 731 pts with biopsy proven GIST were followed since 2004 (median follow-up 43.6 months); data were prospectively documented. There were 337 males (46.1%) and 101 (13.8%) pts. presented with M1 disease initially. Of the remaining 630 pts, 358 pts (56.8%) developed tumor recurrence after a median time interval of 22 months. 312/358 pts (87%) developed metastases within the abdomen: liver n = 96, peritoneal n = 97, liver+peritoneal n = 78, locoregional n = 10, locoreg.+hep/per n = 21. Imatinib was the initial treatment in all patients with M1 disease.
Results: Out of 205 patients with liver metastases, 118 remained controlled by drug therapy or showed multi-site progression. In the remaining 87 pts., 26 pts each underwent liver resection or 2nd/3rd line drug therapy (sunitinib, regorafenib), 22 pts had RFA and 13 pts were treated by SIRT. Follow-up was done via dynamic MRI and contrast-enhanced (CE)-CT. The median hepatic-progression free survival (H-PFS) was 15.9 months (4-29) after SIRT (with 3 CR, 6 PR), however, only 5.6 (range, 2 - 13) months after 2nd line drug, 8.2 (3-15) months after surgery, and 7.7 (5-14) months after RFA, p&lt;0.02.
Conclusion: 90Y radiation loaded particles (SIRT) provides the best hepatic progression free survival when compared to 2nd line drugs, RFA or even surgery in imatinib resistant GIST liver metastases. The effect could be mediated by eliminating small (subclinical, micro-) metastases. In patients known to have a GIST resistant to known TKIs, such as wildtype (non-KIT, non-PDGFRA mutated f.e. NF1-associated) lesions, SIRT could be used in earlier treatment lines.
Citation Format: Peter Hohenberger, Nils Rathmann, Franka Menge, Maliha Sadick, Stefan Schönberg, Steffen Diehl. Selective internal radiation (SIRT) is most effective when comparing local treatment to control progressive liver metastases of gastro-intestinal stromal tumors beyond treatment with tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3598. doi:10.1158/1538-7445.AM2015-3598
Abstract 36: Cross-talk of the cytokine pathways in cancer progression
Authors: Bakin Andrei V. , Limoge Michelle , Beattie Amy 
Published: August 2015

Abstract
Anti-inflammatory TGFβ and pro-inflammatory TNFα/IL1β cytokines are among the major cytokines in tumor microenvironment that drive cancer progression and metastasis. Published studies implicate TGFβ-activated protein kinase TAK1 as an important mediator in cytokine-driven tumor invasion and metastasis. TAK1 is an ubiquitin-dependent protein kinase that can activate NFκB and MAPK signaling cascades. This study addressed several foremost questions such as a) what signaling cascade is activated by the cytokine crosstalk and what are major transducers and effectors of this crosstalk; b) whether a crosstalk is associated with a specific genetics or cell type, for example a specific molecular subtype of breast cancer. Molecular profiling study identified a TAK1-dependent molecular signature and revealed a close association of the TAK1 molecular signature with triple-negative breast cancers. The cytokines synergistically stimulated expression of a set of pro-invasive and pro-metastatic molecules including matrix metalloproteinase 9 (MMP9). shRNA screening study identified specific molecular transducers of TAK1 that mediate MMP9 expression and cell motility. In particular, our study found an essential role of RELA but not NFKB2 in regulation of MMP9. Addressing a signaling crosstalk, we found that TGFβ and TNFα robustly activated a significant level of canonical signaling via SMADs and RELA/NFkB, respectively, but neither of these cytokines cross-talked to stimulate canonical transducers for a respective cytokine. Instead, TGFβ and TNFα synergized in activation of MAPK signaling and up-regulation of specific transcription targets of the cytokine pathways. In summary, anti-inflammatory TGFβ and pro-inflammatory TNFα cytokines synergize in stimulation of tumor invasion and metastatic potential by cooperating in TAK1-mediated regulation of MAPK signaling and expression of target genes. A TAK1 molecular signature is associated with triple-negative breast cancers.
Citation Format: Andrei V. Bakin, Michelle Limoge, Amy Beattie. Cross-talk of the cytokine pathways in cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 36. doi:10.1158/1538-7445.AM2015-36
Abstract 360: Senescent hepatocytes secrete CCL2 to accelerate liver cancer growth via accumulation of immunosuppressive myeloid cells
Authors: Eggert Tobias , Ji Juling , Zender Lars , Wang Xin Wei , Greten Tim F. 
Published: August 2015

Abstract
Aim: Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce the immune-mediated clearance of these senescent cells, preventing malignant transformation and tumor initiation; a process termed ‘senescence surveillance’. However, senescent hepatocytes can give rise to hepatocellular carcinomas (HCC), if additional oncogenic mutations, e.g. p53 mutation, abrogate the senescence program. We set out to investigate the effect of senescent cell secreted cytokines on growth of neighboring liver tumor cells.
Experimental procedure: To induce senescence in mouse livers, we hydrodynamically injected a transposon system, which encodes for either oncogenic Nras (NrasG12V) or an effector loop mutant (NrasG12V/D38A) that is incapable of signaling to downstream pathways, into C57BL/6 or CCR2-/- mice. To achieve tumor development in senescent livers, hepatocellular carcinoma cells were intrasplenically injected into mice, which expressed either NrasG12V or NrasG12V/D38A in the liver. Hepatic immune cell infiltrates were analyzed using flow cytometry and immunohistochemistry. Immunosuppressive ability of CD11b+Gr1+ myeloid cells was analyzed in vitro after fluorescence-activated cell sorting. Furthermore, peritumor tissue of 226 HCC patients was hierarchical clustered based on the expression of 35 senescence-associated genes. Senescence-associated gene signature was then compared with CCL2 expression and survival.
Results: Senescent hepatocytes promoted growth of hepatocellular carcinoma cells through accumulation of immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ cells inhibited T cell proliferation via an iNOS-dependent mechanism. Immunosuppressive myeloid cell accumulation as well as tumor growth promotion was abrogated, when senescence was induced in livers of CCR2 knockout mice, indicating a pivotal role for CCL2 in creating a tumor promoting immune environment. Finally, gene expression analysis in patients with hepatocellular carcinoma confirmed the association of senescence-induced CCL2 expression in peritumor tissue and poor prognosis.
Conclusion: Senescent hepatocytes not only induce an inflammatory response that leads to their own clearance, preventing tumor initiation, but surprisingly also induce the accumulation of immunosuppressive myeloid cells that promote growth of neighboring hepatocellular carcinomas.
Citation Format: Tobias Eggert, Juling Ji, Lars Zender, Xin Wei Wang, Tim F. Greten. Senescent hepatocytes secrete CCL2 to accelerate liver cancer growth via accumulation of immunosuppressive myeloid cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 360. doi:10.1158/1538-7445.AM2015-360
Abstract 3608: Prostaglandin E-2 promotes resistance to oxaliplatin in colorectal cancer cells
Authors: Huang Huakang , Rosenberg Daniel W. 
Published: August 2015

Abstract
Oxaliplatin, a platinum-based DNA crosslinking agent, has been used successfully as a first-line chemotherapeutic agent for the treatment of metastatic colorectal cancer (CRC). However, long-term treatment with oxaliplatin results in resistance in nearly all patients, limiting its therapeutic efficacy. Previous studies have shown that treatment of CRC cells with selective inhibitors of the enzyme Cyclooxygenase-2 (COX-2) leads to the development of drug resistance. One of the terminal products of the COX-2 pathway, prostaglandin E-2 (PGE2), is a pro-inflammatory lipid that has been implicated in colorectal tumorigenesis; however, it is unknown whether PGE2 plays a role in the development of drug resistance. In this study, we have begun to investigate the relationship between PGE2 and oxaliplatin resistance using the human CRC cell lines, HT29 and HCT116. Oxaliplatin-resistant HT29 cells (HT29-OXR) were generated by continuous exposure of parental HT29 cells to increasing concentrations of oxaliplatin over a period of 3 months. We have found that HT29-OXR cells produce significantly higher levels of PGE2 (3-fold increase, p&lt;0.05) compared to the parental HT29 cell line. In addition, we have observed concomitantly elevated levels of the terminal PGE2 synthase, microsomal prostaglandin E synthase-1 (mPGES-1). Furthermore, we have demonstrated that the addition of exogenous PGE2 to both parental HT29 and HCT116 cells significantly (p&lt;0.0001) decreased their sensitivity (IC50) to oxaliplatin, measured by the MTT cell viability assay. These findings suggest that PGE2 promotes resistance to oxaliplatin in CRC cells. FACS analysis showed that co-treatment of HT29 cells with exogenous PGE2 for 24 hours leaded to 27% reduction in oxaliplatin-induced Annexin V staining for early apoptosis, while exogenous PGE2 maintained G2/M arrest and simultaneously reduced the proportion of dead sub-G1 cells by approximately 80.4% in parental HCT116 cells. Our findings reveal a role for PGE2 in oxaliplatin resistance, possibly via regulation of apoptosis, and provide new data suggesting that targeting mPGES-1 may be a useful strategy for overcoming oxaliplatin resistance.
Citation Format: Huakang Huang, Daniel W. Rosenberg. Prostaglandin E-2 promotes resistance to oxaliplatin in colorectal cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3608. doi:10.1158/1538-7445.AM2015-3608
Abstract 3612: Study of the functional importance of PPARγ in honokiol-induced apoptosis of hepatoma cells
Authors: Chi Chin-Wen , Hsu Hui-Tzu , Hou Jia-Dong , Lee Chih-Chun , Kuo Ying-Ju , Lee Hsin-Chen , Hsia Cheng-Yuan 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is the leading cause of death in male cancer patients in Asia. PPARγ exhibited an inhibitory role in hepatocarcinogenesis in vitro and in vivo. Recently, it was found that honokiol functions not only as a RXR agonist but also a PPARγ agonist, and is capable of potentiating the activation of PPARγ in the presence of PPARγ agonist rosiglitazone in HLE human hepatoma cells. It also has been reported that honokiol exerts inhibitory effects on the growth and migration in hepatoma cells. However, whether PPARγ overexpression modulates the honokiol-induced growth inhibition in hepatoma cells is not known. Firstly, we examined the expression of PPARγ in tumor samples from 83 HCC patients by immunohistochemical staining. Our results showed that 53 samples had no PPARγ and the clinical parameters including tumor number, stages, and macroscopic vascular invasion (MVI) showed significant negative correlation with PPARγ expression. However, the expression of PPARγ was not associated with disease free survival or overall survival of patients with HCC. Using PPARγ overexpressed SK-Hep1 cells (SK-Hep1-PPARγ) for in vitro analyses, we found that 40 μM honokiol treatment of SK-Hep1-PPARγ cells induced a 20% increase of growth inhibition at 48 hour as compared to vector control cells by MTT assay. This corresponded well with the 15% increase in G0/G1 phase after honokiol treatment at 24 hour compared to vector control cells. In addition, honokiol treatment resulted in decreased cyclin D1, increased p21 and KLF4 expressions in SK-Hep1-PPARγ cells. Moreover, miRNA array analyses showed that increased expression of miR-222, let-7i, miR-628-3p and miR-664 as well as decreased miR-1291, miR184 and miR1249 were observed in SK-Hep1-PPARγ cells. In conclusion, PPARγ is not only a biomarker for prognosis of patients with HCC but also play an important role in the honokiol-induced growth inhibition of hepatoma cells. The functional importance of PPARγ regulated miRNA is currently under further investigation.
Citation Format: Chin-Wen Chi, Hui-Tzu Hsu, Jia-Dong Hou, Chih-Chun Lee, Ying-Ju Kuo, Hsin-Chen Lee, Cheng-Yuan Hsia. Study of the functional importance of PPARγ in honokiol-induced apoptosis of hepatoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2015-3612
Abstract 3629: Balance shift between error-free and error prone DNA double-strand break repair as a novel mechanism of radiosensitization by nucleoside analogs
Authors: Iliakis George , Magin Simon 
Published: August 2015

Abstract
Nucleoside analogs (NAs) represent a large group of anticancer drugs, several members of which have been shown to sensitize cells to ionizing radiation (IR). Among the lesions induced in cells by IR, the DNA double-strand break (DSB) is considered to be the most detrimental. Therefore we focused on interactions between NAs and pathways of DSB repair.
We opted for post-irradiation treatment with NAs to avoid complications arising from redistribution of cells throughout the cycle prior to IR exposure. We compared the effects of 4h treatments post-IR with vidarabine (ara-A), fludarabine (F-ara-A) or gemcitabine (dFdC) on the survival of A549 lung carcinoma cells. We found that post-irradiation treatment with ara-A and F-ara-A, but not dFdC, resulted in cell radiosensitization to killing. Radiosensitization by ara-A was superior to that by F-ara-A. We employed immunofluorescence detection of IR-induced foci and I-SceI-based reporter cell lines to identify the pathways of DSB repair that are inhibited by ara-A and cause the observed radiosensitization. We found that the formation of IR-induced Rad51-foci was compromised by ara-A suggesting inhibition of homologous recombination repair (HRR). Repair of I-SceI-induced DSBs by HRR was also suppressed by ara-A. Furthermore, A549 cells deprived of Rad51 by RNAi could not be efficiently radiosensitized by ara-A. On the other hand, we could not detect impairment by ara-A of non-homologous end-joining (NHEJ), as measured by pulsed-field gel electrophoresis (PFGE) at high doses of IR (20 Gy). Notably, we observed an increase in the frequency of mutagenic NHEJ events in several I-SceI-based repair reporter systems, indicative of processing by error-prone repair pathways such as alternative/backup NHEJ (B-NHEJ). In addition, we could show that treatment with ara-A induces a dramatic increase in B-NHEJ in plateau phase Lig4-/- MEFs. Treatment with F-ara-A also inhibited HRR, but was less proficient in promoting mutagenic NHEJ.
We conclude that inhibition of HRR and promotion of B-NHEJ represent two important mechanisms of radiosensitization by NAs. The strong impact of ara-A on both of these repair pathways underpins its superior radiosensitizing potential. Targeting of both HRR and B-NHEJ may provide a promising new strategy for radiosensitization.
Citation Format: George Iliakis, Simon Magin. Balance shift between error-free and error prone DNA double-strand break repair as a novel mechanism of radiosensitization by nucleoside analogs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3629. doi:10.1158/1538-7445.AM2015-3629
Abstract 3633: Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation
Authors: Wilson Aaron , Yakovlev Vasily A. 
Published: August 2015

Abstract
Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DNA double-strand breaks (DSBs) by the cellular replication and/or transcription machinery. Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair (HRR) of DNA DSB. In BRCA-positive cells, DSBs are repaired by HRR, but they cannot be properly repaired in BRCA-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death.
The role of PARP1 in the DNA damage response promoted the development of PARP inhibitors (PARPi) as chemo- and radio-sensitizers for the treatment of cancers harboring mutations in the BRCA genes. However, inherited BRCA1 or BRCA2 mutations account for 5-10% of breast cancers and 10-15% of ovarian cancers. Hence, a low frequency of BRCA1 loss in non-hereditary tumors can limit the clinical use of this approach.
Our recent work revealed significant down-regulation of BRCA1 gene expression by nitric oxide donors (NO-d) (Yakovlev, 2013). Hence, we assumed that combination of NO-d with PARP inhibitors could be effective in sensitization of the BRCA1-positive tumors to DNA-damaging therapy.
We identified the optimal concentrations of PARPi ABT-888 at 20μM and NO-d SNAP at 200μM, which don't affect cell survival, but effectively block PARP1 activity or BRCA1 expression accordingly. Next, cancer cell lines were pretreated with ABT-888 or SNAP, or with they combination and irradiated. Survival curves were determined by clonogenic assay.
Our preliminary data demonstrates significant radiosensitization when combining an NO-d with a PARPi in BRCA1 positive tumor cell lines (Table 1). We plan to test this drug combination on the additional cancer cell lines and on animal models for sensitization to ionizing radiation and to the different chemotherapeutic agents.
Table 1.Clonogenic assay for A-549 and MDA-MB-231 cell lines: survival fraction.IR (Gy)02468A-549Control1.00±0.0380.55±0.0450.23±0.0360.09±0.0070.0242±0.004ABT-8881.00±0.0650.49±0.0310.18±0.0350.05±0.0040.0076±0.001SNAP0.97±0.0850.43±0.0450.16±0.0330.04±0.0080.0091±0.002ABT-888 + SNAP0.71±0.0750.24±0.0420.05±0.0070.01±0.0020.0014±0.0003MDA-MB-231Control1.00±0.0630.44±0.0380.15±0.0270.039±0.0070.0078±0.0007ABT-8880.85±0.0520.28±0.0170.07±0.0090.012±0.0020.0015±0.0005SNAP1.03±0.0380.3±0.0430.10±0.0080.020±0.0040.0034±0.0007ABT-888 + SNAP0.49±0.0660.12±0.0170.02±0.0070.002±0.00040.00013±0.0001
Citation Format: Aaron Wilson, Vasily A. Yakovlev. Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3633. doi:10.1158/1538-7445.AM2015-3633
Abstract 3643: Targeting the acetyl-lysine binding site of BRD4 with dual nanomolar BET-JAK2 inhibitors: A new anticancer therapeutic strategy
Authors: Gunawan Steven , Muhammad Ayaz , Ember Stuart W. J. , Zhu Jin-Yi , Jacobsen Rebecca A. , Berndt Norbert , Lambert Que T. , Reuther Gary W. , Lawrence Harshani R. , Schonbrunn Ernst , Lawrence Nicholas J. 
Published: August 2015

Abstract
Bromodomain (BRD)-containing proteins are essential for the recognition of acetylated lysine residues of histones during transcriptional activation. The BRD-containing proteins have emerged as promising drug targets for a number of diseases, including many cancers, that are characterized by changes in the epigenetic cell signature. Recent reports have shown that targeting BRD4 with small molecules may represent a new way to treat prostate and breast cancer, acute myeloid leukemia and melanoma. We have identified many type 1 and type 2 kinase inhibitors which also inhibit BRD4 by robotic co-crystallization screening of kinase inhibitor libraries against BRD4. In each case the co-crystal structure unambiguously revealed the inhibitor bound to the acetyl lysine site of BRD4-1. The identified BRD4 ligands were subjected to differential scanning fluorimetry (DSF) and AlphaScreen assay to assess their binding and inhibitory potentials against BRD4. As shown previously for other BRD-inhibitor-protein complexes, the melting temperatures of BRD4-kinase inhibitor complexes were logarithmically proportional to their IC50 values. We now report the design, synthesis, structural analysis and biological evaluation of next-generation nanomolar BET-selective and nanomolar dual-activity BET-JAK2 inhibitors, based on the initial co-crystallization screening hits. Structure activity relationships were developed using both DSF and co-crystallization of the ligands with BRD4, to assess binding potential and binding modes, respectively. We report initial evaluation of the anticancer potential of compounds possessing dual potent BRD4 and JAK2 inhibitory properties. In addition to myeloma cell lines, this includes the evaluation of dual BRD4-JAK2 inhibitor compounds against JAK2-driven myeloproliferative neoplasm cell lines and primary cells from patients.
Citation Format: Steven Gunawan, Ayaz Muhammad, Stuart W. J. Ember, Jin-Yi Zhu, Rebecca A. Jacobsen, Norbert Berndt, Que T. Lambert, Gary W. Reuther, Harshani R. Lawrence, Ernst Schonbrunn, Nicholas J. Lawrence. Targeting the acetyl-lysine binding site of BRD4 with dual nanomolar BET-JAK2 inhibitors: A new anticancer therapeutic strategy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3643. doi:10.1158/1538-7445.AM2015-3643