bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 637: MEHD7945A, an EGFR/ErbB3 dual specific antibody, overcomes acquired resistance to EGFR inhibitors in head and neck and lung tumors
Authors: Huang Shyhmin , Li Chunrong , Sliwkowski Mark X. , Harari Paul M. 
Published: June 2012

Abstract
The development of acquired resistance to EGFR inhibitors is emerging as a potential treatment barrier for EGFR targeted therapies. Efforts to better understand underlying mechanisms of acquired resistance to EGFR inhibitors, and strategies to overcome this resistance are highly desired. We have previously identified that acquired resistance to EGFR inhibitors may result from the trans-activation of ErbB3 by EGFR. We therefore examined the capacity of the EGFR/ErbB3 dual specific antibody, MEHD7945A to overcome acquired resistance to EGFR inhibitors.
We first examined the antiproliferative effects of MEHD7945A across a panel of human head and neck (HNSCC) and non-small cell lung (NSCLC) tumor cell lines. MEHD7945A significantly inhibited the proliferation in tumors cells that express EGFR and ErbB3. We then applied MEHD7945A to EGFR inhibitor-resistant clones from HNSCC (SCC-1 and SCC-6) and NSCLC lines (H226) that have been chronically exposed to cetuximab or erlotinib and show EGFR inhibitor-resistant phenotypes. Using identical doses of MEHD7945A and cetuximab, we found that MEHD7945A inhibited the growth of tumor cells that exhibit resistance to cetuximab. Similar results were observed in our erlotinib-resistant clones. MEHD7945A also significantly inhibited EGFR and ErbB3-dependent downstream signaling. Additional studies to confirm the antitumor activity of MEHD7945A in xenograft models using EGFR inhibitor-resistant clones are in progress. In addition, studies to investigate the impact of MEHD7945A on radiation response profiles in a panel of HNSCC, NSCLC and EGFR-inhibitor resistant cell lines are underway. These data not only support an important role of ErbB3 in acquired resistance to EGFR inhibitors but also suggest MEHD7945A may provide a valuable treatment strategy for patients who develop acquired resistance to EGFR targeting agents.
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 637. doi:10.1158/1538-7445.AM2011-637
Abstract 645: Preclinical efficacy of AZD8055, an ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitor, in vitro in clear cell renal cell carcinoma (RCC)
Authors: Gupta Gopal N. , Lin Kelly Y. , Sourbier Carole , Baba Masaya , Guichard Sylvie , Linehan W. Marston , Srinivasan Ramaprasad 
Published: June 2012

Abstract
Inhibitors of the mTORC1 complex such as the rapamycin analogues temsirolimus and everolimus are approved by the FDA for treatment of advanced renal cell carcinoma. However, objective responses with these agents are infrequent and clinical benefits transient, with the majority of patients eventually developing progressive disease and dying from metastatic disease. Dual mTORC1/2 inhibitors may overcome some of the limitations of rapamycin analogues by suppressing the feedback activation of AKT induced by mTORC1 inhibition. In this study, we investigated the in vitro efficacy of AZD8055, a potent inhibitor of both mTORC1 and mTORC2, in clear cell RCC utilizing 2 von Hippel Lindau (VHL) null clear cell kidney cancer cell lines, UOK139 and UOK140. AZD8055 strongly suppressed mTORC2 signaling in RCC and at concentrations ranging from 50nM-250nM, downregulated pAKTs473 and pmTORs2481 in a concentration-dependent fashion. Phosphorylation of AKTt308 was also diminished in both cell lines at these concentrations. In contrast, rapamycin did not significantly inhibit either mTORC2 signaling or AKTt308 phosphorylation. Both AZD8055 and rapamycin were able to downregulate the mTORC1 substrate pS6; however, only AZD8055 was effective in downregulating p4E-BP1, a critical component of cap-dependent translation that is regulated by mTORC1. The vast majority of clear cell renal tumors are characterized by inactivation of the VHL tumor suppressor gene due to mutation or promoter hypermethylation. One well characterized consequence of VHL inactivation is upregulation of hypoxia inducible factor-2α (HIF-2α), an important mediator of both tumorigenesis and neo-angiogenesis in clear cell RCC. While HIF expression is dependent on mTOR activity, it has been reported that mTORC1 inhibition does not reliably suppress HIF-2α expression; we show that treatment with AZD8055 resulted in significant downregulation of HIF-2α levels in both UOK139 and UOK140, an effect that may be mediated by mTORC2 inhibition. AZD8055 exhibited potent in vitro antitumor activity against clear cell RCC, with an IC50 of 100-150nM in the MTT assay; rapamycin had minimal antitumor activity at these concentrations (IC50 not reached at 10uM). These data demonstrate that AZD8055 is a potent inhibitor of mTORC2 and a more effective inhibitor of downstream mTORC1 targets than rapamycin. Simultaneous mTORC1/2 kinase inhibition may be superior to selective mTORC1 inhibition, and is worthy of clinical evaluation in clear cell RCC.
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 645. doi:10.1158/1538-7445.AM2011-645
Abstract 65: Regulation of KEAP1 expression by promoter methylation in malignant gliomas and association with patient's outcome
Authors: Barbano Raffaela , Muscarella Lucia Anna , D'Angelo Vincenzo , Copetti Massimiliano , Coco Michelina , Balsamo Teresa , la Torre Annamaria , Notarangelo Angelo , Troiano Michele , Parisi Salvatore , Icolaro Nadia , Catapano Domenico , Valori Vanna Maria , Pellegrini Fabio , Merla Giuseppe , Carella Massimo , Fazio Vito Michele , Parrella Paola 
Published: June 2012

Abstract
The Keap1 (Kelch-like ECH-associated protein 1) protein tightly regulates the functions of Nrf2 (nuclear factor-erythroid 2-related factor 2) which plays a pivotal role in the cellular response to oxidative stress. Initial reports uncovered mutations in the KEAP1 gene in non-small cell lung cancer (NSCLC) leading to a permanent nrf2 activation. Mutations were often associated with loss of heterozigosity at the KEAP1 gene locus and promoter hypermethylation suggesting that biallelic inactivation is a common event in NSCLC.
In this study, we sought to determine whether KEAP1 gene is epigenetically regulated in malignant gliomas and if promoter aberrant methylation may impact patient's outcome.
We developed a Quantitative Methylation Specific PCR (QMSP) assay to analyze 86 malignant gliomas and 20 normal brain tissues. The discriminatory power of the assay was assessed by Receiving Operating Curve Characteristics (ROC) analysis. The AUC value of the curve was 0.823 (95%CI: 0.764-0.883) with an optimal cut off value of 0.133 yielding a 74% sensitivity (95%CI: 63%-82%) and an 85% specificity (95%CI: 64%-95%). Bisulfite sequencing analysis confirmed QMSP results and demonstrated a direct correlation between percentage of methylated CpGs and methylation levels (Spearman's Rho 0.929, P=0.003). Remarkably, a strong inverse correlation was observed between methylation levels and KEAP1 mRNA transcript in tumour tissue (Spearman's Rho -0.656 P=0.0001) and in a cell line before and after treatment with 2-deoxy-5 Azacytidine (P=0.003). RECPAM multivariate statistical analysis studying the interaction between MGMT and KEAP1 methylation in subjects treated with radiotherapy and temozolomide (n=70), identified three prognostic classes of glioma patients at different risk to progress. While simultaneous methylation of MGMT and KEAP1 promoters was associated with the lowest risk to progress, patients showing only MGMT methylation were the subgroup at the higher risk (HR 5.54, 95% CI 1.35-22.74). Our results indicate that that KEAP1 expression is frequently methylated in malignant gliomas and may represent a novel predictor of patient's outcome.
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 65. doi:10.1158/1538-7445.AM2011-65
Abstract 653: Combination of TORC1/2 and MEK kinase inhibitors in colorectal cancer models
Authors: Garcia-Garcia Celina , Serra Violeta , Scaltriti Maurizio , Ibrahim Yasir , Guzman Marta , Jessen Katti , Liu Yi , Rommel Christian , Tabernero Josep , Baselga Jose 
Published: June 2012

Abstract
MAPK pathway mutations are frequent in colorectal cancer (CRC) and associated with resistance to standard therapies. This provides a rationale for the use of targeted therapies against the MAPK pathway. However, the response of CRC cells to MEK inhibitors varies depending on coexisting mutations in both MAPK and PI3K pathways. As a matter of fact, dual inhibition of MEK and PI3K or AKT in mouse models of CRC has proven effective due to aberrations in both pathways. Inhibition of TORC1, a shared downstream effector of the MAPK and PI3K pathways, was described to be partly responsible for the efficacy of the dual blockade.
In order to explore additional mechanisms involved in the superior antitumor activity of combined MAPK and PI3K pathway suppression we directly targeted TORC1/2 by active-site kinase inhibitor of mTOR, in addition to MEK, in our cell models. We tested the antiproliferative activity of INK128, a selective and potent TORC1/2 inhibitor, in combination with a MEK inhibitor, PD-0325901, in a panel of colon cancer cell lines with diverse alterations of the MAPK and PI3K pathways. PD-0325901 treatment effectively inhibited ERK phosphorylation, which resulted in decreased phosphorylation of Rb and reduced expression of E2F in all the cell lines tested. In CRC cell lines harboring sole mutations in the MAPK pathway, we observed sensitivity to PD-0325901 that was not further enhanced when combining with INK-128. In contrast, CRC cell lines harboring concurrent mutations of both pathways exhibited a striking sensitivity to dual ERK and TORC1/2 blockade associated with an enhanced arrest in cell cycle and, above all, a concomitant increase in apoptosis. Inhibition of TORC1 and TORC2 by INK128 could not be further enhanced by MEK inhibition in any of the cell lines tested. These data suggest that, besides complete suppression of both pathways, additional mechanisms must be at work to explain the observed enhanced cell death following dual suppression of PI3K and MEK. Interestingly, we observed differential regulation of key components of the cell cycle in response to dual blockade. We are currently investigating whether this specific biochemical behaviour plays a causative role in the observed phenotype.
In summary, dual inhibition of TORC1/2 and MEK has potential for effective antitumor activity in CRCs with dysregulation of both signaling cascades. A better understanding of the molecular mechanisms responsible for the enhanced efficacy of this therapeutic combination will help defining the best biomarkers that need to be assessed in phase I combination trials.
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 653. doi:10.1158/1538-7445.AM2011-653
Abstract 655: Combination of MM-111, an ErbB2/ErbB3 bispecific antibody, with endocrine therapies as an effective strategy for treatment of ER+/HER2+ breast cancer
Authors: Zhang Bo , Huhalov Alexandra , Burenkova Olga , Adams Sharlene , Nguyen Stephanie , Overland Ryan , Kudla Arthur J. , Nielsen Ulrik B. , Niyikiza Clet , McDonagh Charlotte F. , MacBeath Gavin 
Published: June 2012

Abstract
Approximately 75% of breast cancers are estrogen receptor (ER) positive. Although endocrine therapies such as tamoxifen, fulvestrant, and letrozole have demonstrated significant efficacy in treating ER+ breast cancer patients, intrinsic or acquired resistance has limited their success. Recent studies suggest that crosstalk between ErbB receptor signaling and ER signaling may contribute to resistance to endocrine therapy. Overexpression of human epidermal growth factor receptor 2 (HER2, synonymous with ErbB2) and upregulation of the ErbB3 ligand heregulin are associated with poor prognosis and reduced overall survival.
MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and blocks heregulin binding to ErbB3. MM-111 inhibits ligand-induced ErbB3 phosphorylation, tumor cell cycle progression, and tumor growth when ErbB2 is overexpressed. We hypothesized that combination of endocrine therapies with MM-111 may improve anti-tumor efficacy. In an estrogen-stimulated BT474-M3 ER-positive breast cancer cell three-dimensional spheroid assay, MM-111, when used as a single agent, showed growth inhibitory effects similar to the anti-estrogen drugs tamoxifen and fulvestrant. Combination of MM-111 with anti-estrogen therapy showed superior activity to either drug alone. In the presence of heregulin, MM-111 maintained its growth inhibitory activity, whereas the inhibitory effect of tamoxifen and fulvestrant was diminished. This suggests that activation of ErbB3 confers tumor cell resistance to anti-estrogen therapies. When both estrogen and heregulin were present, the combination of MM-111 and the anti-estrogen drugs demonstrated a significantly greater inhibitory effect than either drug alone. Western blot analysis showed that treatment of BT-474-M3 cells with the combination of MM-111 and the anti-estrogen drugs significantly increased apoptosis markers such as cytochrome C and BAX. Furthermore, an in vivo BT474-M3 xenograft model showed resistance to tamoxifen treatment (5 mg/pellet, 60-day release). In this xenograft model MM-111 sensitized tumor response to tamoxifen and the combination treatment dramatically inhibited tumor growth. In conclusion, the combination of MM-111 and endocrine therapies may provide a potent regimen that overcomes acquired resistance to endocrine therapies in ER+, ErbB2-overexpressing breast cancer patients.
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 655. doi:10.1158/1538-7445.AM2011-655
Abstract 658: CBS9106 is a novel low toxic reversible oral CRM1 inhibitor with CRM1 degrading activity
Authors: Sakakibara Keiichi , Saito Naoya , Sato Takuji , Suzuki Atsushi , Hasegawa Yoko , Friedman Jonathan M. , Suganuma Masashi , Kufe Donald W. , VanHoff Daniel D. , Iwami Tadahiko , Kawabe Takumi 
Published: June 2012

Abstract
CRM1 plays an important role in the nuclear export of cargo proteins bearing Nuclear Exporting Signal sequences. Leptomycin B (LMB), a well-known irreversible inhibitor of CRM1, possesses strong anti-tumor properties, however, its toxicity prevents it from being clinically useful. In this study, we show that a novel compound, CBS9106, inhibits CRM1-dependent nuclear export and induces G1-arrest and apoptosis in time- and dose-dependent manner in a broad-spectrum of cancer cells including multiple myeloma cells. IC50s of growth inhibition by CBS9106 (48h) are in the range from 46.7 to 366 nM in multiple myeloma cell lines (MM.1R, MM.1S, ARH-77 and RPMI-8226). In contrast with LMB, CBS9106 acts reversibly and reduces CRM1 protein without affecting the mRNA expression level. CBS9106-dependent reduction of CRM1 is abolished by MG132, a proteasome inhibitor. Pretreatment of cells with LMB suppresses CBS9106-induced CRM1 degradation. Moreover, CBS9106-biotin captured CRM1 in a pull down analysis and the amount of CRM1 captured by CBS9106-biotin was reduced by LMB treatment and vice versa. These results suggest that CBS9106 acts on the domain of CRM1 that includes LMB's covalent binding site at Cys-528, leading to proteasome-dependent CRM1 degradation. Oral administration of CBS9106 significantly suppressed tumor growth and prolonged survival duration in xenograft model mice. It caused prolonged reduction of CRM1 protein in tumor xenografts without showing significant body weight loss. Taken together, the results indicate that CBS9106 is a novel CRM1 inhibitor and a promising clinical candidate.
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 658. doi:10.1158/1538-7445.AM2011-658
Abstract 661: Efficiency of the multivalent pseudopeptide nucant 6L in castration- and chemo-resistant prostate cancers
Authors: Destouches Damien , Gostoli Julie , Terry Stéphane , Briand Jean-Paul , Zimmer Robert , Courty José , de la Taille Alexandre , Vacherot Francis 
Published: June 2012

Abstract
Introduction: Targeted therapies on advanced prostate cancer, resistant to castration and chemotherapy, offer significant hope for future treatments. NucAnt 6L (N6L) is a ligand of surface nucleolin. This protein is overexpressed at the cell surface of tumoral and endothelial cells, and is involved in tumor growth and associated angiogenesis. It has been demonstrated that N6L displays, in vitro and in vivo, a double anti-tumoral activity. It inhibits growth of various human tumor cell lines derived from mammary and colorectal carcinoma, melanoma, glioblastoma and lymphoma. In addition, it can compromise associated angiogenesis. In this context, N6L might be of value for therapeutic intervention. Previous studies have demonstrated drug's efficacy of this agent in prostate cancer cell lines. However, its effect on therapeutic resistant lines has yet to be documented. Using in vivo and in vitro models, the aim of this work is to evaluate N6L activity on castration and chemo-resistant prostate cancers.
Methods: When maintained in medium deprived of androgens, androgen-responsive LNCaP cells undergo a “transdifferentiation” process giving rise to neuroendocrine (NE) like LNCaP cells which are resistant to androgen deprivation and chemotherapeutic agents such as docetaxel. Here, the anti-tumoral activity of N6L has been evaluated, in vitro, on human LNCaP-NE cells. Cell viability, as assessed by MTT test, and soft agar assays were performed at 72 hours after treatment with N6L (range of 0.1 to 100 µM). In vivo, anti-tumoral activity was then confirmed using VCaP ectopic xenografts into athymic nude mice, a condition that mimics clinical evolution of advanced prostate cancers in human. Mice bearing tumors of about 600 mm3 were castrated. Mice were treated with either vehicle or N6L at 10 mg/kg by the intraperitoneal route at different times of tumor growth. Tumors volumes were monitored at different time points using the caliper method.
Results: N6L induces death of LNCaP-NE cells with a IC50 of 16.2 µM. These findings were supported by soft agar assays in which LNCaP-NE cells were found to be sensitive to N6L treatment whereas they were resistant to docetaxel. In vivo, N6L inhibits VCaP tumor growth at different stages of tumor progression, the castration-sensitive state and also the castration resistant state.
Conclusions: N6L, which is currently in I/IIb phase of clinical trials, might represent a new targeted approach to treat advanced prostate cancers resistant to castration and chemotherapy.
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 661. doi:10.1158/1538-7445.AM2011-661
Abstract 677: Effects of the vascular disrupting agent ASA404 on tumor growth of gastric cancer in an experimental model
Authors: Moser Christian , Lang Sven A. , Jung Ernst M. , Pfister Karin , Geissler Edward K. , Schlitt Hans J. 
Published: June 2012

Abstract
Background: A functional vascular system is essential for growth of solid malignancies including gastric cancer. For establishment and maintenance of such a vascular system endothelial cells (ECs) and pericytes (e.g. vascular smooth muscle cells, VSMC) are required. We hypothesized that targeting tumor vasculature with the vascular disrupting agent (VDA) ASA404 reduces tumor growth in a model of gastric cancer. Methods: Gastric cancer (GC) cell lines, ECs and VSMCs were used for experiments. Effects of ASA404 on growth of GC, EC and VSMC were assessed by MTT assays. Impact of ASA404 (20 mg/kg on day 1, 5, 9) in combination with paclitaxel (10 mg/kg on day 1 and 7) on tumor growth was assessed in a subcutaneous tumor model. Treatment was started when tumors reached a size of approximately 200 mm3. Tumors were measured and harvested on day 23 for IHC analyses. Effect of ASA404 on blood perfusion of tumors during therapy was monitored by contrast-enhanced ultrasound (CEUS). Results: In vitro ASA404 impaired growth of ECs and VSMCs upon stimulation with condition media from gastric cancer cells. No direct effect on tumor cells was observed. In vivo, treatment with ASA404 led to marked decrease of tumor perfusion and an increase of necrosis as determined by CEUS. Furthermore, combination of ASA404 with paclitaxel showed significant reduction of tumor growth compared to controls (P&lt;0.05). In addition, tumor vascularisation and tumor cell proliferation were significantly reduced as determined by CD31-positive vessel area and BrdU-positive cells (P&lt;0.05). Conclusion: Combination of the VDA ASA404 with paclitaxel impairs tumor growth and perfusion of gastric cancer in an experimental model. Hence, targeting tumor vasculature with ASA404 appears to be a promising strategy for therapy of gastric cancer.
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 677. doi:10.1158/1538-7445.AM2011-677