bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive Value of XRCC1 Gene Polymorphisms on Platinum-Based Chemotherapy in Advanced Non–Small Cell Lung Cancer Patients: A Systematic Review and Meta-analysis
Authors: Wu Junjie , Liu Jie , Zhou Yuhao , Ying Jun , Zou Houdong , Guo Shicheng , Wang Lei , Zhao Naiqing , Hu Jianjun , Lu Daru , Jin Li , Li Qiang , Wang Jiu-Cun
Published: June 2012

Purpose: Published data have shown conflicting results about the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms (Arg399Gln and Arg194Trp) and clinical outcome of platinum-based chemotherapy in patients with advanced non–small cell lung cancer (NSCLC). A meta-analysis is needed to provide a systematic review of the published findings.

Experimental Design: We conducted a systematic review and meta-analysis to evaluate the predictive value of XRCC1 gene polymorphisms on clinical outcome up to October 1, 2010. The quality of each study was scored on the basis of predefined criteria.

Results: A total of 13 eligible follow-up studies met all the inclusion criteria. The XRCC1194Trp allele was found to be significantly associated with a favorable response rate relative to 194Arg [Trp vs. Arg: OR, 1.88; 95% confidence interval (CI), 1.48–2.38]. XRCC1399Gln was less favorably associated with both response rate (Gln vs. Arg: OR, 0.67; 95% CI, 0.52–0.87) and overall survival (Gln vs. Arg: HR, 1.30; 95% CI, 1.04–1.63) than 399Arg in analyses using all available studies; but these associations became insignificant when only high-quality studies were used.

Conclusion: These findings suggest a predictive role for XRCC1 gene polymorphisms in clinical outcome. However, the role of 399Gln could be considered controversial because its impact on clinical outcome was insignificant in high-quality studies. These findings show the importance of establishing suitable criteria, including genetic epidemiologic, phenotypic, and clinical criteria, to improve quality control of study design and methods in pharmacogenomic studies related to XRCC1 gene polymorphism. Clin Cancer Res; 18(14); 3972–81. ©2012 AACR.
Abstract A105: Phase 2 trials of linifanib (ABT-869) in advanced hepatocellular, renal cell and non-small cell lung cancer: Associations of response by CT or DCE-MRI with patient outcome
Authors: Toh Han Chong , Yong Wei Peng , Wong Yu-Ning , tan Eng-Huat , Kollmannsberger Christian K. , Devanarayan Viswanath , Zhang Ke , Luo Yanping , Chen Daniel , Ashton Edward , Ricker Justin L. , Carlson Dawn , Chen Pei-Jer
Published: June 2012

Background: Linifanib is a novel orally active and selective inhibitor of VEGF and PDGF families of receptor tyrosine kinases. Linifanib has demonstrated antitumor activity in a variety of advanced solid tumors in phase 1 and 2 trials. The objective of this analysis was to assess associations between pt outcome (PFS or OS) and response by CT (per RECIST or tumor volume change), or DCE-MRI (per Ktrans), in patients (pts) enrolled in ongoing phase 2 linifanib monotherapy trials.

Methods: Three open-label, phase 2 monotherapy studies were conducted internationally in advanced/metastatic solid tumor pts with hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Interim efficacy and safety results have been previously reported. A retrospective exploratory analysis of associations between pt outcome and CT or DCE-MRI response was conducted. An independent centralized review of tumor response assessment by CT (baseline, and Q8 wks) and DCE-MRI (baseline, and 2 wks) was performed using a uniform charter. CT assessed tumor volume and best percent change from baseline and pts were classified as PR, SD, or PD by RECIST. Baseline Ktrans and percent change in Ktrans were derived from DCE-MRI. Statistical analysis was performed using the Cox proportional hazard model and logrank test, and significance considered at the level of P≥0.05. Threshold estimates were determined by the Bootstrapping & Aggregating Thresholds from Trees (BATTing).

Results: Across the 3 phase 2 trials, 236 pts were enrolled from 08/07 to 10/08 at 34 centers: 44 pts with HCC, 53 pts with RCC, and 139 pts with NSCLC. Based on the BATTing methodology, 79/191 evaluable pts had a maximum CT tumor volume decrease of >32%. This was associated with improved OS (log-rank p<0.001) and PFS (log-rank p<0.001). Pts with confirmed or unconfirmed PR (n=27) per RECIST had better OS (p=0.021) and PFS (p=0.017) than those who did not achieve a PR (n=181). Among the 236 pts, 117 had DCE-MRI scans at baseline and Day 15. Of these, 68/117 pts (58%) had baseline Ktrans above the BATTing cutoff of 0.055 and this was associated with improved OS (log-rank, p=0.011), but not PFS (log-rank, p=0.835). DCE-MRI response (Ktrans decrease) at 2 wks was not associated with significant improvement in PFS or OS.

Conclusions: CT tumor volume reduction and CT response were associated with improved OS and PFS. Greater baseline Ktrans was associated with improved OS but not PFS. Ktrans changes at 2 wks were not associated with improvement in pt outcome.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A105.
Abstract A155: Activation of PI3K/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells
Authors: Chen Kuen-Feng , Feng Wen-Chi , Hsu Chih-Hung , Chen Pei-Jer , Cheng Ann-Lii
Published: June 2012

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal human malignancies. Sorafenib, a tyrosine kinase inhibitor, was recently approved by FDA for HCC.

Material and Methods: We established two sorafenib-resistant HCC cell lines (Huh7-R1 and Huh7-R2) from Huh7, a human HCC cell line, by chronic exposure of cells to sorafenib. The mechanisms of resistance were investigated.

Results: Sorafenib induced significant apoptosis in Huh7 cells. However, Huh7-R1 and Huh7-R2 showed significant resistance to sorafenib-induced apoptosis at the clinical relevant concentrations (up to 10 M). Thorough comparisons of the molecular changes between Huh7 and resistant cells, we found PI3K/Akt signaling pathways played a significant role in mediating acquired resistance to sorafenib in Huh7-R1 and Huh7-R2 cells. Our data showed that phospho-Akt and p85 (a regulatory subunit of PI3K) were up-regulated, while PTEN was down-regulated in these resistant cells. In addition, ectopic expression of constitutive Akt in Huh7 demonstrated similar resistance to sorafenib. Knocking down Akt by RNA-interference reversed the resistance to sorafenib in Huh7-R1, indicating the importance of Akt in drug sensitivity. Furthermore, the combination of MK-2206, a novel allosteric Akt inhibitor, and sorafenib restored the sensitivity of resistant cells to sorafenib-induced apoptosis.

Conclusions: Activation of PI3K/Akt signaling pathway medicates acquired resistance to sorafenib in HCC cells. The combination of sorafenib with MK-2206, an Akt inhibitor, overcomes the resistance at clinical achievable concentrations. This study is supported by NTUH 98P03, NSC 98-3112-B-002-037, DOH (94–98)-TD-B-111-001 and MK-2206 was kindly provided by Merck & Co., Inc. (Whitehouse Station, NJ, USA).

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A155.
Abstract C10: A novel combination of a small molecule IAP inhibitor and a TRAIL-R1 monoclonal antibody synergize to induce apoptosis in pancreatic tumor cell lines
Authors: Humphreys Robin C. , Poortman Carol , McCormick Kathy , Carrell Jeff , Shepard Lindsey
Published: June 2012

X-linked inhibitor of apoptosis protein (XIAP) is a critical inhibitory protein regulating the activation of apoptosis. A small molecule IAP inhibitor, HGS1029, that inhibits the anti-apoptotic activity of multiple IAPs including; XIAP, leading to tumor cell apoptosis, is currently in phase 1 trials. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) death receptors, TRAIL-R1 and TRAIL-R2, are expressed on the cell surface of many human tumor cells and activation of these receptors induces programmed cell death in a wide of variety human tumor cell lines. Mapatumumab is a fully human agonistic monoclonal antibody that targets and activates cell death via TRAIL-R1 and has demonstrated robust preclinical activity against many tumor types. Mapatumumab is currently being evaluated in phase 2 clinical trials. Because mapatumumab and HGS1029 target the apoptotic pathway at different points we hypothesized that combining two pro-apoptotic agents would have synergistic anti-tumor activity.

We assessed the in vitro cytotoxic activity of mapatumumab in combination with the IAP inhibitor, HGS1029, in human pancreatic cell lines. All 8 pancreatic cell lines expressed low to moderate levels of both TRAIL-R1 and TRAIL-R2 on the cell surface. Three pancreatic cell lines were resistant (3/8) and 5 were moderately sensitive (5/8) to treatment with mapatumumab alone in an in vitro cytotoxicity assay. Four cell lines showed a very modest response to HGS1029 single agent treatment. When combined, mapatumumab and HGS1029 significantly increased cytotoxicity in these 4 weakly sensitive cell lines. Two of these cell lines were resistant to mapatumumab alone and two were sensitive. EC50 values shifted substantially in the combination treatments when compared to either agent alone. Isobologram analysis revealed this increased cytotoxicity to be synergistic in all cell lines sensitive to the combination. Investigation into the in vivo anti-tumor activity of this combination is on-going in murine xenograft models of pancreatic cancer.

These results demonstrate the combination of two pro-apoptotic agents; HGS1029 and mapatumumab, that directly target and activate the apoptotic pathway, can synergize and overcome single agent resistance in pancreatic tumor cell lines. The significant anti-tumor activity of this novel combination is a potential therapeutic strategy for the treatment of human cancer. These preclinical data support the evaluation of IAP inhibitors in combination with TRAIL-R mAbs in future clinical studies.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C10.
Abstract C197: A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors
Authors: Faulkner Neil , LoRusso Patricia M. , Guthrie Tina , Soria Jean-Charles , Bahleda Ratislav , Bendell Johanna C. , Infante Jeffrey R. , Massard Christophe , Van Leeuwen Barbara , Martini Jean-Francois , Scheffold Christian , Burris Howard A.
Published: June 2012

Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mediator of resistance to EGFR inhibitors. In preclinical xenograft models, the oral selective Class I PI3K inhibitor XL147 augments the anti-tumor efficacy of EGFR inhibitors, including erlotinib.

Methods: Patients (pts) with advanced solid tumors are enrolled in successive cohorts of 3 to receive escalating doses of XL147 in combination with erlotinib. Erlotinib is dosed qd, and XL147 is dosed once daily on Days 1–21 of each 28-day cycle. Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated every 8 weeks.

Results: As of 01 Aug2009, 18 pts with advanced solid tumors have been enrolled: NSCLC (7), CRC (5), HCC, HNSCC, biliary tract, carcinoid, ethmoid, and esophageal cancer (1 each). Pts have been treated at 6 dose levels up to 400 mg XL147/150 mg erlotinib. No DLTs or study treatment-related SAEs have been reported. The MTD has not yet been established. The most frequently reported related AEs were rash (40%), fatigue (30%), diarrhea, nausea, and vomiting (each 20%). Two events of Grade 3 thrombosis (both unrelated) were reported. Based on preliminary data, the PK of XL147 in combination with erlotinib is consistent with that observed for XL147 given alone (Exelixis Study XL147-001). Likewise, XL147 does not appear to alter the PK of erlotinib as the PK parameters of erlotinib are similar to published single agent values. Modulation of PI3K pathway and EGFR signaling by XL147/erlotinib has been demonstrated in PBMCs by reductions in phosphorylation of AKT, the AKT substrates PRAS40 and GSK3 , and ERK. In skin and tumor biopsies, robust post-dose reductions were evident in phosphorylation of AKT, the mTOR substrate 4EBP1, ERK, and EGFR. For example, in tumor biopsies from a subject with an ethmoid tumor (400 mg XL147/150 mg erlotinib), reductions in pAKT-T308 (43%), p4EBP1 (44%), pERK (43%), and pEGFR (40%) were evident at Day 15 post-dose, with a corresponding reduction in Ki67 (47%) and induction of apoptosis (2.7-fold). One EGFR inhibitor-naïve NSCLC pt (no EGFR mutations detected in archival tumor sample, 200 mg XL147/150 mg erlotinib) had a confirmed PR with a 59% reduction in the sum of target lesions. Nine pts continued on study ≥ 12 weeks, including 2 pts who remained on study ≥ 24 weeks.

Conclusions: The combination of XL147 and erlotinib is generally well tolerated at doses up to 400 mg XL147/150 mg erlotinib, with no apparent drug-drug PK interaction or emergent toxicities, and results in robust simultaneous inhibition of PI3K and EGFR signaling.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C197.
Abstract B232: Activity of a potent and selective phase I ALK inhibitor LDK378 in naive and crizotinib-resistant preclinical tumor models.
Authors: Li Nanxin , Michellys Pierre-Yves , Kim Sungjoon , Pferdekamper AnneMarie Culazzo , Li Jie , Kasibhatla Shailaja , Tompkins Celin S. , Steffy Auzon , Li Allen , Sun Frank , Sun Xiuying , Hua Su , Tiedt Ralph , Sarkisova Yelena , Marsilje Thomas H. , McNamara Peter , Harris Jennifer
Published: June 2012

A c-MET/ALK kinase inhibitor crizotinib has demonstrated significant activity in lung cancer patients with EML4-ALK in clinical studies. However relapse (or acquired resistance) has also been reported. We have developed crizotinib resistant tumor models and used the models to evaluate the ALK inhibitor LDK378. LDK378 is a potent and selective ALK inhibitor that does not cross react with c-MET. In a mouse xenograft tumor model derived from the EML4-ALK+ lung cancer cell line NCI-H2228, LDK378 caused complete tumor regression when dosed orally at 25 mg/kg/day. After tumor bearing animals had been treated with LDK378 at 50 mg/kg/day for 14 days, remission was maintained for more than 4 months. In several NCI-H2228 tumor models that were induced to become resistant to crizotinib, LDK378 demonstrated efficacy at 50 mg/kg/day. Based on 4-wk GLP toxicology studies the drug exposure associated with this dose is predicted to be below the exposure at the MTD in humans. ALK resistance mutations reported in crizotinib relapsed patients were also found in the crizotinib resistant NCI-H2228 tumor models. The results from these preclinical studies suggest that LDK378 may be active in crizotinib-relapsed patients. A phase I clinical study of LDK378 has recently begun in both crizotinib-relapsed and crizotinib-naïve patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B232.
Abstract 1: Mcl-1 downregulation plays a crucial role in the synergistic anticancer activities between PI-3 kinase inhibitors and histone deacetylase inhibitors in primary NSCLC tumors in vitro and in vivo
Authors: Zhang Hao , Tang Haikou , Shao Huanjie , Gao Chun , Hylander Bonnie L. , Repasky Elizabeth A. , Dy Grace K , Ma Wen Wee , Yu Chunrong , Adjei Alex A.
Published: June 2012

Interactions between the PI-3 kinase inhibitors and histone deacetylase inhibitors (HDACi) were examined in vivo using SCID mice bearing patient-derived primary NSCLC xenografts which contain the “hot spot” mutation PIK3CA [E545K (G1633A)] (K-Ras and EGFR wild-type), and in vitro using the primary cell cultures derived directly from the in vivo xenografts. Co-treatment of primary cell cultures to marginally toxic concentrations of GDC-0941 (1.0 uM) and HDACi LBH589 (2.5 nM) induced a striking increase of apoptosis, as evidenced by Annex V positive staining, cytochrome c release and caspase 3 cleavage. Similar effects were observed using other HDACis (e.g. SAHA or MS275). The combination was associated with profound Akt inactivation, GSK-3β activation and Mcl-1 attenuation without affecting other Bcl-2 family members. Although LBH589 induced p21CIP1/WAF1 expression, GDC-0941 blocked LBH589-mediated p21CIP1/WAF1 accumulation. Ectopic expression of the constitutively active (myristolated) Akt, dominant negative GSK-3β (K85A), Mcl-1, or p21CIP1/WAF1 significantly blocked apoptosis induced by this combination. Inactivation of GSK-3β by either shRNA knockdown or its pharmacological inhibitor markedly diminished GDC-0941/LBH589-induced cell death, and abrogated the Mcl-1 and p21CIP1/WAF1 downregulation seen with the combination, indicating that GSK-3β modulation is the process upstream of Mcl-1 and p21. However, overexpression of either Mcl-1 or p21CIP1/WAF1 did not demonstrate an interaction with each other under the co-treatment, suggesting an independent functional cascade for each Mcl-1 and p21CIP1/WAF1. The downregulation of Mcl-1 and p21CIP1/WAF1 was reversed by proteasome inhibitor, indicating a proteasome-dependent degradation of Mcl-1 and p21CIP1/WAF1. Lastly, the combination of GDC-0941/LBH589 in vivo inhibited the growth of primary tumor xenografts more efficiently than either agent alone. In vivo downregulation of Mcl-1 and p21CIP1/WAF1 was also observed, consistent with the modulation of molecular events presented in vitro. Taken together, our results demonstrate that GDC-0941 potentiates HDACi-mediated apoptosis through PI3K/Akt/GSK-3β pathway, and subsequently attenuates Mcl-1 and abrogates p21CIP1/WAF1 induction in primary NSCLC xenografts in vivo and the primary cell cultures in vitro, thereby suggesting a novel therapeutic approach for NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1. doi:10.1158/1538-7445.AM2011-1
Abstract 1415: The Notch ligand Jag 2 promotes growth and invasion in uveal melanoma cells
Authors: Asnaghi Laura , Coonfield Michael L. , Schreck Karisa C. , Bar Eli E. , Handa James , Merbs Shannath , Ebrahimi Katayoon B. , Harbour J William , Eberhart Charles G.
Published: June 2012

Uveal melanoma is the most common primary intraocular cancer in the adults, and up to 50% of patients die from hematogenous visceral metastases which are extremely resistant to chemotherapy. Using oligonucleotide expression array analysis of mRNA from primary uveal melanomas, we found that the Jag 2 ligand was 1.9 fold more expressed in tumors which metastasized than those which did not. Other Notch pathway members were also significantly induced in the metastatic cohort. We then used quantitative RT PCR to analyze mRNA extracted from a second cohort of 30 snap-frozen primary tumors, and confirmed that elevated Jag 2 mRNA levels were significantly associated (p = 0.048) with the metastatic Class 2 signature as compared to non-metastatic Class 1 uveal melanoma. To directly examine the importance of Jag 2 in driving cellular growth and invasion, we introduced the ligand into a uveal melanoma cell line, Mel 290, which has low baseline levels of Notch activity as measured by expression of the pathway targets Hes1, Hey1 and Hey2. The Jag 2-GFP-MSCV-infected cells showed a 2.5 to 6 fold induction of Notch targets Hey 1 and Hes1, indicating that pathway activity had been induced. While overall growth of the Jag 2-GFP-MSCV infected cultures as measured by MTT increased only slightly, overexpression of Jag 2 induced an approximately 3 fold increase in clonogenic growth in soft agar. Finally, we assayed the migratory properties of the cells using a wound-healing (“scratch”) assay, as well as their ability to invade Matrigel. Jag 2 expressing cells showed increased motility in both of these tests, with a significant (p = 0.0003) approximately 2 fold induction of transwell invasion capacity. Our data suggest that expression of the Notch ligand Jag 2 may play an important role in uveal melanoma growth and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1415. doi:10.1158/1538-7445.AM2011-1415
Abstract 1674: Significant reduction of primary growth and metastases through combined CXCR4 and HER-2 inhibition in an esophageal carcinoma orthotopic model
Authors: Gros Stephanie J. , Kurschat Nina , Dohrmann Thorsten , Drenckhan Astrid , Reichelt Uta , Schultze Alexander , Effenberger-Harms Katharina , Rawnaq Tamina , Peldschus Kersten , Eicke-Kohlmorgen Ute , Hoffman Robert M. , Adam Gerhard , Izbicki Jakob R. , Kaifi Jussuf T.
Published: June 2012

Metastatic disease is the main cause of morbidity and mortality in esophageal carcinoma and the leading cause of death. While in the early stages surgical resection is the best therapeutic option, in late stages the conventional therapies surgery, chemotherapy, and radiation are limited. The expression of the chemokine receptor CXCR4 is known to be involved in metastatic homing and is associated with a poor prognosis in esophageal cancer patients. Trastuzumab treatment leads to significant tumor growth reduction in a model of HER-2 positive esophageal carcinoma. In the present report, we show the effects of the humanized monoclonal antibody trastuzumab, the CXCR4 inhibitor AMD3100 and their combined use in a metastastic orthotopic nude mouse model of esophageal cancer. Although both single therapies lead to tumor growth reduction the effect is further enhanced by their combination and leads to significant reduction of metastases. Tumor progression was monitored by non invasive MR imaging. High correlation between HER-2 and CXCR4 expression in primary tumor and metastatic organs was observed and might suggest a link between the chemokine receptor CXCR4 and receptor tyrosine kinase HER-2 in tumor progression and metastases. The results of this study suggest an effective treatment of metastatic prostate cancer by the combined use of drugs that target HER-2 and CXCR4.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2011-1674
Abstract 2557: Preclinical synergy of Plk1 inhibitors and HDACIs
Authors: Paller Channing J. , Wissing Michel D. , Rosmus Nadine S. , Hammers Hans , Rudin Charles M. , Carducci Michael A. , Kachhap Sushant K.
Published: June 2012

Our laboratory is interested in the synergy between spindle check point inhibitors and histone deacetylase inhibitors (HDACIs). Previous work investigated two polo-like kinase inhibitors in prostate cancer and in non-small cell lung cancer (NSCLC). In preliminary studies we have investigated two polo-like kinase inhibitors, BI2536 and BI6727, in NSCLC cell lines H358 and H1838. In MTS proliferation assays, we found a significant inhibition of proliferation (For H358 the IC50 = 100nM for BI2536and BI672; and for H1838 the IC50 = 25nM for BI2536 and 50nM for BI6727). In clonogenic assays both polo-like kinase inhibitors caused a dose dependent inhibition of proliferation and survival in NSCLC. We explored these findings further with western blot analysis and found that both compounds arrested both cell lines in G2/M transition with elevated phosphorylated histone H3 and elevated cyclin B1. These findings show that polo-like kinase can be effectively targeted in NSCLC by these compounds. Given other studies in lung and prostate demonstrating down regulation of mitotic spindle proteins upon treatment with HDACIs, we plan to combine polo-like kinase inhibitors and HDACIs to investigate for additive or synergistic effects in NSCLC cell lines as has been seen in prostate cancer cell lines.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2557. doi:10.1158/1538-7445.AM2011-2557
Abstract 2821: Anti-tumor activity of ASP3026, – A novel and selective ALK inhibitor -
Authors: Kuromitsu Sadao , Mori Masamichi , Shimada Itsuro , Kondoh Yutaka , Shindoh Nobuaki , Soga Takatoshi , Furutani Takashi , Konagai Satoshi , Sakagami Hideki , Nakata Mari , Ueno Yoko , Saito Rika , Sasamata Masao , Mano Hiroyuki , Kudou Masafumi
Published: June 2012

EML4-ALK is an oncogenic fusion kinase which was first identified in non-small cell lung cancer (NSCLC), and is regarded as an attractive therapeutic target for treating a subpopulation of NSCLC patients.

We synthesized and screened chemical compounds utilizing an ALK kinase inhibition assay aimed at the EML4-ALK target for drug discovery, and found ASP3026, a novel and selective inhibitor for the ALK kinase. ASP3026 inhibited ALK kinase activity at an IC50 value of 3.5 nmol/L, and showed more selective ALK inhibition in a Tyr-kinase panel than PF02341066. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3, with an IC50 value of 64.8 nmol/L. This growth inhibition was accompanied with the decrease in phosphorylation of EML4-ALK protein, indicating that ASP3026 exerts its anti-proliferative activity through ALK kinase inhibition.

The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor after a 5-day repeated oral dosing of ASP3026 (10 mg/kg once daily) were determined using high-performance liquid chromatography-tandem mass spectrometry. Tmax values were 4 h in plasma and tumors. Cmax values at the corresponding doses were, respectively, 875 nmol/mL and 15500 nmol/g. A decrease of phophorylated EML4-ALK was confirmed 4 hours after a single administration of ASP3026 at 10 mg/kg by Western-blot analysis.

The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts. ASP3026, administered as twice daily oral dosing for 14 days, induced dose dependent anti-tumor effects starting at 1 mg/kg with strong regression at 10, 30 and 100 mg/kg. No influence on body weights was observed in all dose range of ASP3026 treated-mice. In contrast, PF02341066 at twice daily oral dosing resulted in growth inhibition of NCI-H2228 xenografted tumors at 10 mg/kg, and tumor regression at 30 mg/kg. In addition, 100 mg/kg of PF02341066 was intolerable in this model.

These results suggest that ASP3026 is a novel and selective ALK inhibitor, which is orally active, and will possibly target NSCLC patients possessing the EML4-ALK fusion. We are starting phase I clinical trials of ASP3026 in the near future.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2011-2821
Abstract 3523: Biochanin A enhances anticancer activity of temozolomide in glioblastoma multiforme
Authors: Jain Aditi , Lai James C.K. , Bhushan Alok
Published: June 2012

Glioblastoma multiforme (GBM) is the most common and most lethal form of primary brain tumor, classified as a Grade IV astrocytoma by World Health Organization (WHO). The poor prognosis of patients is a result of an extremely invasive and aggressive nature of this tumor. Temozolomide, an anticancer agent currently approved for the treatment of glioblastoma is only modestly effective as a single agent in enhancing patient survival. Therefore, it is imperative to design therapies which are safe and can more effectively target the progression of glioblastoma. Our laboratory has been investigating the anticancer properties of biochanin A, a bioactive isoflavone found in red clover and soy products. This compound shows anticancer potential against breast, oral, pancreatic and brain cancers. Previous studies from our laboratory show that biochanin A inhibits invasion in GBM cells. In this study we investigated the anticancer potential of combination of biochanin A and temozolomide on U-87 MG cells (human glioblastoma cell line). We hypothesized that this combination will enhance the efficacy of temozolomide towards inhibiting invasion and proliferation of glioblastoma cells. We performed colony formation assay to assess the cytotoxicity of treatment(s). Biochanin A (20μM and 70μM) enhances the effect of temozolomide in decreasing the number of colonies formed as determined by the colony formation assay. Further, we determined the effect of temozolomide (100μM) alone and in combination with biochanin A (20μM and 70μM) on cell signaling, invasive processes and transcription factors. Western blot analysis shows a decrease in the protein expression of p-EGFR, p-ERK, uPAR, MMP-2. Our results implicate that combining biochanin A with temozolomide can improve the anticancer effect of temozolomide on glioblastoma cells. These findings help us better understand how biochanin A can be used to seek new and more effective combination therapy. Further studies are aimed to elucidate the mechanism(s) by which this combination inhibits invasion of U-87 MG cells.

This study was supported by in parts from NIH INBRE GRANT P20RR016454.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3523. doi:10.1158/1538-7445.AM2011-3523
Abstract 5057: HuGAL-F2, a humanized monoclonal antibody to Fibroblast Growth Factor 2, effectively inhibits the growth of hepatocellular carcinoma xenografts
Authors: Wang Lihong , Hangil Park , Chhim Sophea , Ding Yi , Kim Jin
Published: June 2012

FGF2 (also known as basic FGF; bFGF) is a potent mitogenic and angiogenic growth factor believed to play a role in various tumors, especially hepatocellular carcinoma (HCC). In this study, we explored the therapeutic potential of the HuGAL-F2 humanized monoclonal antibody (mAb) derived from our neutralizing anti-FGF2 mAb, GAL-F2.

The GAL-F2 mAb was previously shown to recognize a unique epitope on human FGF2 in a competitive binding assay with various other anti-FGF2 mAbs. By testing several FGF2-FGF1 chimeric proteins followed by alanine scanning mutagenesis of FGF2, we demonstrated that FGF2 residues F40 and M151 are critical for GAL-F2 binding and that residues R31, Y33, K55 and S152 are also part of the epitope. Using well-established humanization techniques, GAL-F2 was humanized to create HuGAL-F2, which binds FGF2 with at least as high affinity as GAL-F2. HuGAL-F2 also had similar activity to GAL-F2 in various bioassays such as inhibition of FGF2-induced proliferation of Mv 1 Lu epithelial cells and HUVEC cells.

Hepatomas are characterized by neovascularization, and angiogenesis plays a key role in their growth. Thus, we determined the levels of two angiogenic factors, FGF2 and VEGF, secreted from several HCC cell lines (HEP-G2, HLE, HLF, SK-HEP-1, and SMMC-7721) using ELISA. All these cell lines secreted significant levels of FGF2 and VEGF. To demonstrate that FGF2 indeed plays an important role in HCC tumor growth and to investigate the therapeutic potential of HuGAL-F2, we tested the efficacy of HuGAL-F2 in xenograft tumor models of the HCC lines, SMMC-7721 and HEP-G2. HuGAL-F2, administered i.p. at 5 mg/kg twice per week, significantly inhibited the growth of established xenografts of both these cell lines. Moreover, in the HEP-G2 model, GAL-F2 and HuGAL-F2 were equally effective as sorafenib (Nexavar) and the A4.6.1 anti-VEGF mouse precursor mAb of bevacizumab (Avastin) and had strong additive activity with each of these agents. We conclude that FGF2 is a promising molecular target, and that HuGAL-F2 is a viable clinical candidate for the treatment of HCC and possibly other cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5057. doi:10.1158/1538-7445.AM2011-5057
Abstract 5217: MMP9 is a prognostic biomarker for metastatic colorectal cancer
Authors: Goos Jeroen A.C.M , Fijneman Remond J.A. , Geldof Albert A. , Group DeCoDe PET , Meijer Gerrit A. , Hoekstra Otto S.
Published: June 2012

Background: Worldwide almost 700000 patients are diagnosed with colorectal cancer (CRC) each year. Of these patients more than 45% die as a consequence of metastases, of which the majority is located in the liver. Although patient selection for hepatectomy by 18FDG PET has significantly reduced futile surgery (Ruers, J Nucl Med 2009), 70% of all operated patients still die of metastases within 5 years after hepatic resection. To improve prediction of patient outcome, novel PET tracers with better prognostic value are needed. Matrix metalloproteinases, frequently associated with reduced survival in several types of cancer, might serve as prognostic biomarkers that can be used in PET imaging.

Aim: To investigate the prognostic value of MMP9 expression in colon cancer liver metastases.

Methods: Formalin-fixed paraffin-embedded colon cancer liver metastases, collected from 85 patients having had curative hepatectomy between 1990 and 2009, were incorporated into tissue microarrays (TMAs). MMP9 expression in both epithelial and stromal cells was assessed by immunohistochemistry and expression was correlated to patient survival data. Survival analysis was performed using a log rank test.

Results: Mean age of the colon cancer patients (62.1% males, 37.9% females) was 62.0 (standard deviation 10.5). Chemotherapy was received by 45.9% (15.3% neoadjuvant, 14.1% adjuvant, 16.5% palliative) and radiofrequency ablation (RFA) was performed in 10.8%. Median overall survival was 35.0 months (standard deviation 5.7). High expression of MMP9 by epithelial colon cancer cells within the liver metastases was associated with increased survival rates (p=0.007 for disease-free survival and p=0.056 for overall survival). MMP9 expression in stromal cells was not associated with patient survival.

Discussion and conclusion: Our results suggest that elevated levels of MMP9 in metastatic epithelial colon cancer cells are indicative of a good prognosis. Whether MMP9 qualifies as a target with prognostic relevance for imaging of lesions in patients with metastatic colorectal cancer remains to be determined. This research was supported by the Center for Translational Molecular Medicine (DeCoDe project).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5217. doi:10.1158/1538-7445.AM2011-5217
Abstract 5381: A novel strategy to eliminate chemoresistant colon cancer cells
Authors: Kanwar Shailender S. , Yu Yingjie , Nautiyal Jyoti , Patel Bhaumik B. , Padhye Subhash , Sarkar Fazlul H. , Majumdar Adhip P.N.
Published: June 2012

Recurrence of colon cancer, which affects nearly 50% of patients treated by conventional therapeutics, is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs) Therefore, development of therapeutic strategies for targeted elimination of CSCs would be a novel treatment strategy for colon cancer. The current study examines whether diflourinated-curcumin (CDF), a novel analog of the dietary ingredient of curcumin, in combination with 5-fluorouracil and oxaliplatin (5-FU+Ox), the mainstay of colon cancer chemotherapeutic, would be an effective strategy to eliminate colon CSCs. Multiple molecular techniques that include real-time RT-PCR, Western blot analysis, MTT assay, caspase-3 activity, colonosphere formation in stem cell media, Hoechst-33342 dye exclusion and NF-κB-ELISA, were used. We observed that CDF together with 5-FU+Ox to be more potent than curcumin in reducing CD44 and CD166 expression. This was accompanied by inhibition of cell growth, induction of apoptosis and disintegration of colonospheres. These changes were associated with down-regulation of the membrane transporter protein ABCG2, and attenuation of EGFR, IGF-1R, and NF-κB signaling consistent with inactivation of β-catenin, COX-2, c-Myc and Bcl-xL and activation of the pro-apoptotic Bax. Our results suggest that CDF together with the conventional chemotherapeutics could be an effective treatment strategy for preventing the emergence of chemo-resistant colon cancer cells by eliminating CSCs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5381. doi:10.1158/1538-7445.AM2011-5381
Expression of N-Cadherin in Salivary Gland Tumors
Authors: Kehagias N. , Epivatianos A. , Sakas L. , Andreadis D. , Markopoulos A. , Antoniades K.
Published: June 2012

Objective: To detect immunohistochemically the N-cadherin expression in different types of benign and malignant salivary gland tumors in an attempt to note any possible correlation to their development, stage and invasive properties. Materials and Methods: N-cadherin expression was examined in tissue specimens from 49 salivary gland tumors including: pleomorphic adenomas (4), Warthin’s tumors (10), and myoepitheliomas (4) (benign tumors), as well as adenoid cystic carcinomas (14), mucoepidermoid carcinomas (4), polymorphous low-grade adenocarcinomas (6), and adenocarcinomas not otherwise specified (5) (malignant tumors). Twelve specimens of normal salivary glands were used as control. The perineural invasion and stage of malignant salivary gland tumors were evaluated. Immunohistochemical procedure was performed automatically using the Bond Polymer Refine Detection Kit. Results: N-cadherin expression was not found in normal salivary glands. In benign salivary gland tumors, N-cadherin along membranes of neoplastic cells as well as in centrocytes of lymphoid germinal centers was seen in 1 and 4 cases of Warthin’s tumors, respectively. Varied degree of N-cadherin expression was found in 13 (45%) cases of malignant salivary gland tumors. N-cadherin expression was significantly correlated with perineural invasion (χ2 = 11.7, p < 0.0001), but not with stage of malignant salivary gland tumors. Conclusion: N-cadherin expression was observed in malignant salivary gland tumors and could be an indicator of potentially aggressive behavior. N-cadherin expression by tumor cells could be attributed to perineural invasion.
Auditory System Dysfunction due to Infantile Thiamine Deficiency: Long-Term Auditory Sequelae
Authors: Attias J. , Raveh E. , Aizer-Dannon A. , Bloch-Mimouni A. , Fattal-Valevski A.
Published: June 2012

Eleven infants who were fed a thiamine-deficient formula for a mean of 3 months were evaluated for immediate and long-term auditory abnormalities. At presentation, 8 infants had auditory neuropathy spectrum disorder (ANSD), which resolved with supplementary thiamine in 5 children, was permanent in 2 children, and deteriorated in 1 patient who died at the age of 7 years. An additional patient had an auditory pattern corresponding to that of auditory neuropathy of brain stem origin. The 2 remaining patients had unilateral cochlear hearing loss. Six to 8 years later, all patients with transient ANSD had normal audiograms, 2 patients had unilateral cochlear hearing loss, and the rest had neural hearing loss. All survivors had a language developmental delay and impaired speech intelligibility of varying degrees, especially in the presence of background noise. Thiamine is crucial for normal auditory development and function, and its deficiency may be considered an acquired metabolic cause of ANSD in infants.
Interleukin-10 Treatment Attenuates Pressure Overload–Induced Hypertrophic Remodeling and Improves Heart Function via Signal Transducers and Activators of Transcription 3–Dependent Inhibition of Nuclear Factor-κB
Authors: Verma Suresh Kumar , Krishnamurthy Prasanna , Barefield David , Singh Neha , Gupta Rajesh , Lambers Erin , Thal Melissa , Mackie Alexander , Hoxha Eneda , Ramirez Veronica , Qin Gangjian , Sadayappan Sakthivel , Ghosh Asish K. , Kishore Raj
Published: June 2012

Background—

Inflammation plays a critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared toward inhibiting inflammation may provide therapeutic benefits. We tested the hypotheses that genetic deletion of interleukin-10 (IL-10), a potent antiinflammatory cytokine, exacerbates pressure overload–induced adverse cardiac remodeling and hypertrophy and that IL-10 therapy inhibits this pathology.

Methods and Results—

Cardiac hypertrophy was induced in wild-type and IL-10 knockout mice by isoproterenol (ISO) infusion. ISO-induced left ventricular dysfunction and hypertrophic remodeling, including fibrosis and fetal gene expression, were further exaggerated in knockout mice compared with wild-type mice. Systemic recombinant mouse IL-10 administration markedly improved left ventricular function and not only inhibited but also reversed ISO-induced cardiac remodeling. Intriguingly, a very similar cardioprotective response of IL-10 was found in transverse aortic constriction–induced hypertrophy and heart failure models. In neonatal rat ventricular myocytes and H9c2 myoblasts, ISO activated nuclear factor-κB and inhibited signal transducers and activators of transcription 3 (STAT3) phosphorylation. Interestingly, IL-10 suppressed ISO-induced nuclear factor-κB activation and attenuated STAT3 inhibition. Moreover, pharmacological and genetic inhibition of STAT3 reversed the protective effects of IL-10, whereas ectopic expression of constitutively active STAT3 mimicked the IL-10 responses on the ISO effects, confirming that the IL-10–mediated inhibition of nuclear factor-κB is STAT3 dependent.

Conclusion—

Taken together, our results suggest IL-10 treatment as a potential therapeutic approach to limit the progression of pressure overload–induced adverse cardiac remodeling.
The Formation Mechanism of a Spring Sea Fog Event over the Yellow Sea Associated with a Low-Level Jet
Authors: Li Pengyuan , Fu Gang , Lu Chungu , Fu Dan , Wang Shuai
Published: June 2012

In this paper, a dense sea fog event that occurred over the Yellow Sea (YS) on 9 March 2005 is investigated using the Weather Research and Forecasting Model version 3.1.1 (WRF v3.1.1). It is shown that the WRF can reasonably reproduce the main features of this fog case with a newly implemented planetary boundary layer (PBL) scheme developed by Mellor–Yamada–Nakanishi–Niino (MYNN). The low-level jet (LLJ) associated with this fog episode played an important role in triggering the turbulence. During the fog formation, sea fog extended vertically with the aid of turbulence. The mechanical production term resulting from wind shear contributed to the generation of the turbulence. WRF simulation results showed that the fog layer was thicker in the northeastern part of the YS than that in the southwestern part due to the intensity of the inversion layer and the LLJ. The topography test in which the mountain region in Fujian Province was removed showed that the roles of topography were to prevent the moisture from extending to land, to intensify the inversion layer, and to enhance the intensity of LLJ, as well as to elevate its altitude.
Religious Conversion and Treatment Outcome
Authors: Chu Doris C. , Sung Hung-En , Hsiao Gail Y.
Published: June 2012

Religious conversion has been the core of religion-based treatment models (e.g., Teen Challenge programs in the United States and Operation Dawn in Taiwan). This study aims to assess the impact of religious conversion on treatment retention and completion and to identify correlates of treatment retention and completion. In-take data and administrative records from 708 substance abusers who participated in an Evangelical faith-based recovery program in Taiwan between January 2001 and March 2009 were used to analyze the effect of religious conversion on treatment retention and completion. It was found that religious conversion is a strong predictor of length of stay in treatment and completion of treatment. Findings shed light on the empirical adequacy of the religious model of recovery and the profile of substance abusers likely to respond to faith-based interventions.
Thermal and water vapor resistance of the elastic and conventional cotton fabrics
Authors: Gorjanc Dunja Šajn , Dimitrovski Krste , Bizjak Mateja
Published: June 2012

The research focuses on the influence of elastane (Spandex) incorporation in the weft direction of cotton fabrics, and the structural properties (fabric density, type of weave) on the thermal and water vapor resistance level.

For that purpose, woven fabrics, in plain and twill weave with two different densities (17 and 20 yarns/cm) in the weft direction, were made from 100% cotton (conventional) and from a mixture cotton/elastane in the ratio 93.8%/6.2% (elastic fabric) intended for men’s shirts for the summer season.

Thermal and water vapor resistance were determined with two novel methods, which were compared with the well-known Permetest method. The thermal resistance was calculated according to the thermal conductivity method which was established by the faculty research laboratory and with the Permetest, while the water vapor resistance was measured with the water cup method (developed by Professor D. Jaksic) and with the Permetest.

The research results indicate that cotton fabrics in twill weave with elastane in the weft direction have higher thermal and water vapor resistance compared to conventional cotton fabrics. The reason lies in the higher yarn density of fabrics with elastane in the weft direction in twill weave (from 24 to 29–31 yarns/cm in the warp direction) compared to the plain weave (from 24 to 28 yarns/cm in the warp direction).
Photocatalytic self-detoxification by coaxially electrospun fiber containing titanium dioxide nanoparticles
Authors: Woo Dong Jin , Hansen Nathaniel S , Joo Yong Lak , Obendorf S Kay
Published: June 2012

Electrospun nanofibers containing titanium dioxide (TiO2) were investigated as a self-detoxifying system consisting of polyacrylonitrile (PAN) and anatase TiO2 nanoparticles. Fibers were prepared by uniaxial and coaxial electrospinning to study the effect of nanoparticle placement on the detoxification activities of the photocatalyst. Coaxially spun fibers had the particles selectively placed in the sheath layer by electrospinning pure PAN solution and PAN/TiO2 solution as the core and sheath layer, respectively. Using scanning electron microscopy, X-ray microanalysis and X-ray photoelectron spectroscopy, it was confirmed that the coaxial approach resulted in the location of nanoparticles near the surface of the fibers compared to the uniform distribution obtained for uniaxial fibers. Photocatalytic activity of the fibers under ultraviolet irradiation was demonstrated by the degradation of aldicarb, as measured by high-performance liquid chromatography. In terms of degradation kinetics, the distribution density of TiO2 nanoparticles in the fiber surface region significantly affected the initial degradation rate, while the final decomposition amounts after 3 h did not differ significantly.