bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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