bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1752: Nonclinical safety and pharmacokinetics of Sym004: A synergistic anti-EGF receptor antibody mixture
Authors: Skartved Niels Jørgen , Pedersen Mikkel W. , Jacobsen Helle , Jørgensen Thomas K. , Kragh Michael 
Published: August 2014

Abstract
Epidermal growth factor receptor (EGFR) is a well validated oncology target for monoclonal antibodies (mAb's). Symphogen is developing a novel and more efficacious anti-EGFR therapy to treat cancer patients with EGFR-dependent tumors. Sym004 is a recombinant antibody product consisting of a 1:1 mixture of two chimeric IgG1 mAb's targeting non-overlapping epitopes of EGFR. Preclinical proof-of-concept studies have shown that the Sym004 mixture is superior to existing anti-EGFR mAb's currently in clinical use (1).
The nonclinical safety data of Sym004 are presented. The studies were designed to evaluate toxicity and pharmacokinetics of Sym004 as well as the individual antibodies comprising Sym004. No apparent accumulation was observed upon weekly dosing of Sym004 to non-human primates for eight consecutive weeks, whereas, a prolonged half life and accumulation were noted for both of the individual antibodies if these were administered alone. Weekly administration of Sym004 to non-human primates was well tolerated although dose limiting toxicity was observed in a dose-range-finding toxicology study. In a head-to-head comparison with the licensed anti-EGFR mAb, cetuximab (Erbitux®), weekly administration of Sym004 did not induce any distinct or novel adverse findings in the animals. However, and in accordance with the enhanced pharmacological profile of Sym004, an accelerated onset of anticipated anti-EGFR-mediated effects (skin rash and liquid faeces) was observed compared to cetuximab. None or only minor effects were observed in the animals treated with the individual antibodies comprising Sym004. All experimental observations, except a single case of rash, showed reversibility during the 4-week treatment free recovery period. In tissue cross reactivity studies, Sym004 had a staining pattern similar to cetuximab in a full tissue panel from both human and non human primates.
In conclusion, Sym004 is considered to be safe, and the nonclinical safety data supported the initiation of the currently ongoing Phase I/II trial.
1. Pedersen MW et al. Cancer Res; 70(2) January 15, 2010
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 1752. doi:10.1158/1538-7445.AM2011-1752
Abstract 1757: MEDI-573, an IGF-I/II neutralizing human antibody inhibits both IGF-1R and IR-A signaling pathways
Authors: Gao Jin , Chesebrough Jon W. , Incognito Leonard , Coats Steven , Bosslet Klaus , Jallal Bahija , Chang Yong S. 
Published: August 2014

Abstract
Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). Overexpression of IGF-II and IR-A has been reported in multiple types of cancer, and has also been proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R targeting therapy. MEDI-573 is a dual targeting human antibody that neutralizes both IGF-I and IGF-II. We have shown previously that this antibody inhibits IGF-1R activation by IGF and demonstrated potent in vivo tumor growth inhibition activity in IGF driven xenograft models. Here we show that MEDI-573 inhibits IGF-II activated IR-A signal pathways without cross reactivity to insulin, and therefore has minimum impact on glucose metabolism, which is mediated mainly by insulin/IR interaction. MEDI-573 blocks the binding of IGF-II to, and inhibits the subsequent phosphorylation of IR-A and IRS-1. MEDI-573 inhibited IGF-II-induced in vitro growth of IR-A overexpressing cells with or without the presence of up to 10uIU of insulin in the medium. In addition, MEDI-573 inhibited IGF-II-induced proliferation of IR-A-overexpressing cells as effectively as it inhibited the IGF-1R-overexpressing cells. The anti-proliferative activity of MEDI-573 is not changed across heterogeneous mixed cell populations with various ratios of IR-A- versus IGF-1R-expressing cells. In contrast, an IGF-1R specific antibody was most active at inhibiting the proliferation of a pure IGF-1R expressing homogenous population, but lost activity when the heterogeneous cell population contained increasing percentages (25-50%) of IR-A-expressing cells. We also examined the relative abundance of IR-A versus IR-B (insulin receptor isoform B) mRNA in multiple cancer cell lines using a previously published quantitative RT-PCR method. The results show that IR-A is frequently the dominant isoform overexpressed in these cancer cells. Taken together, these results demonstrate that by neutralizing IGF-I and IGF-II ligands, MEDI-573 is a dual targeting antibody that offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways and potentially overcome IGF-1R targeting resistance.
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 1757. doi:10.1158/1538-7445.AM2011-1757
Abstract 1764: DOTA-conjugated antibodies for scintigraphic evaluation of new anti cancer treatments
Authors: Raguin Olivier , Moreau Mathieu , Collin Bertrand , Brunotte François , Tizon Xavier , Duchamp Olivier , Boschetti Frederic , Denat Franck 
Published: August 2014

Abstract
Introduction: The treatment of cancer is being revolutionized by the development of targeted therapeutic biologics. Translational pharmaco-imaging represents a key step in the evaluation of these new targeted anti cancer therapies. In this respect, we have implemented and validated an antibody radiolabeling process for scintigraphic SPECT imaging.
Methods: A new macrocyclic reagent (DOTAGA, bearing an anhydride function able to react with primary amines) was used for DOTA conjugation of Trastuzumab®. DOTA Trastuzumab was synthesized by directly reacting DOTAGA with Trastuzumab®. The number of DOTA per antibody was determined using mass spectrometry.
The DOTA-conjugated antibodies were metallated with Indium-111. The functionality of DOTA Trastuzumab analogs was evaluated by in vitro saturation assays using two human breast cancer cell lines (SK BR 3 and HCC1954).
Results: Two DOTA- Trastuzumab analogs were synthesized. The first analog was bearing one DOTA per antibody while the second was bearing 4 DOTA per antibody. The labeling yield reached 90% for both conjugates and high specific activities were obtained (400 MBq/mg). The affinity of the DOTA Trastuzumab analogs, determined on Her2 expressing SK BR 3 and HCC1954 cell lines, was 1 nM and was similar to that of Trastuzumab®. SPECT imaging experiments in tumor bearing rodents are in progress for in vivo validation of the two analogs.
Conclusion: Together, these results demonstrate the efficiency of our new DOTA-synthesis and conjugation processes for biologics radiolabeling to assess biodistribution, anti-cancer efficacy and related toxicity of anti-cancer drugs by in vivo non invasive imaging.
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 1764. doi:10.1158/1538-7445.AM2011-1764
Abstract 1767: Targeting prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature
Authors: Mohamedali Khalid A. , Li Zhi Gang , Starbuck Michael W. , Wan Xinhai , Yang Jun , Kim Sehoon , Zhang Weihe , Navone Nora M. , Rosenblum Michael G. 
Published: August 2014

Abstract
Purpose: A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF121/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting non-tumor cells expressing the receptors for VEGF121, namely VEGFR-1 and VEGFR-2, can inhibit tumor progression in a clinically relevant model of osteoblastic PCa.
Experimental Design: We examined the effect of VEGF121/rGel on osteoblast precursors and several PCa cell lines in vitro; on osteoid formation in a mouse calvaria culture assay ex vivo; and on PCa osteoblastic progression in the femurs of mice injected with MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa.
Results: VEGF121/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF121/rGel internalization into osteoblasts was VEGF121 receptor driven. Furthermore, VEGF121/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, systemic administration of VEGF121/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomography analysis revealed that VEGF121/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non-tumor bearing) femurs. VEGF121/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF121/rGel-treated mice had significantly less tumor burden than control mice did. Our results thus indicate that VEGF121/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation.
Conclusions: Targeting VEGFR-1- or VEGFR-2-expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. We believe that VEGF121/rGel in combination with tumor cell-targeting therapies (e.g., chemotherapy) constitutes a novel strategy for advanced PCa. Research conducted, in part, by the Clayton Foundation for Research.
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 1767. doi:10.1158/1538-7445.AM2011-1767
Abstract 1778: Anticancer activities and regulatory effects on apoptotic gene expression of Bufalin in the orthotopic transplantation model of human colorectal cancer in nude mice
Authors: Wang Jie , Feng Dian-Xu , Chen Chao , Ni Zhen-Hua , Zhao Ronghua , Zuo Qing-Song , Chen Ya-Feng , Wang Xu , Zhang Yong , Casson Alan G. , Chen Teng 
Published: August 2014

Abstract
Background: Bufalin, a natural small-molecule compound from the Traditional Chinese Medicine “Chansu”, shows inhibitory effects on many human cancer cells. However, whether or not Bufalin has anticancer activity in human colorectal cancer (CRC), and its possible underlying mechanism, remains unclear.
Objectives: 1) To investigate anticancer activities of Bufalin in human CRC using an orthotopic transplantation model in nude mice and 2) to study possible underlying mechanisms related to apoptosis.
Materials and methods: An orthotopic transplantation tumor model was established by implanting human CRC HCT-116 cells into the colon of nude mice. Sixty mice were randomly divided into five treatment groups (12 mice in each group): normal saline group, 5-FU group, and 3 Bufalin groups with low (BL), medium (BM), and high (BH) doses. After cell transplantation, 0.2 ml normal saline, 25 mg/kg 5-Fu, or 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg Bufalin was injected intraperitoneally in mice in each corresponding group, daily for 7 days (days 15 to 21). Six mice in each group were sacrificed on day 24. Tumor size, growth inhibition rate, and morphological changes of tumor cell under microscopy were recorded. Apoptosis was determined by TUNEL staining, mRNA and protein expressions of Bcl-xl and Bax were evaluated with real-time RT-PCR and immunohistochemical staining, respectively. The overall survival (OS) was determined in the remaining 6 mice in each group.
Results: The tumor size in mice treated with 5-Fu, BL, BM, or BH was significantly smaller than that in mice treated with normal saline (p&lt;0.05), with the tumor inhibitor rates of 64.3%, 51.4%, 48.7%, and 36.3%, respectively. Under microscopy, increased tumor necrosis was observed in the 5-Fu, BM and BH groups. The tumor apoptotic rate in each of 3 Bufalin treated groups was significantly higher than that in the normal saline group (p&lt;0.05). Real time RT-PCR and immunohistochemical staining showed both mRNA and protein expressions of Bcl-xl were decreased, whereas the expression of Bax increased, in tumor treated with Bufalin. The OS was prolonged in groups of BL and BM (p&lt;0.05).
Conclusion: Bufalin has significant anticancer activity in a human CRC orthotopic transplantation model in nude mice, and induces tumor cell apoptosis, which may be associated with the down-regulation of Bcl-xl and up-regulation of Bax in tumor cells.
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 1778. doi:10.1158/1538-7445.AM2011-1778
Abstract 1779: Selective oncolysis of multiple myeloma cells by reovirus is mediated through apoptosis
Authors: Thirukkumaran Chandini M. , Shi Zhong-Qiao , Luider Joanne , Kopciuk Karen , Morris Don 
Published: August 2014

Abstract
Introduction: Multiple myeloma (MM) is an incurable hematologic malignancy that accounts for 10% of hematopoietic neoplasms. Recently we have demonstrated the potential of reovirus as novel therapeutic agent for MM, however, the oncolytic mechanism has not been elucidated yet. Reovirus is known to utilize multiple signalling pathways for cancer cell destruction depending on histological origin. It is currently unknown if the apoptotic signalling pathways are involved in reovirus mediated cell death of multiple myeloma.
Methods: The MM cell lines RPMI 8226, U266, NCIH929, HUNS-1, MC/CAR, and OPM2 were incubated with live or UV-inactivated reovirus at a multiplicity of infection of 40 for 24, 48, and 72 hours respectively. Apoptosis was assayed by Annexin V/7-AAD expression and DNA fragmentation using flow cytometry. RPMI 8226 was further investigated at 2, 6 12, 24 and 48 hours for the presence of Phospho -Akt and activated caspase 3 post reovirus infection.
Results: RPMI 8226, U266, and NCIH929 demonstrated an apoptotic response to reovirus infection within 24 hours. All 3 cell lines showed statistically significant (all F tests, p&lt;0.00001) increases in DNA fragmentation in response to reovirus and this increase was more pronounced as time progressed. Similarly expression of Annexin V was significantly higher (all F tests, p&lt;0.00001) in all 3 cell lines with live reovirus treatment but the kinetics were cell line dependent where a significant (p&lt; 0.05) time effect was seen for U266 but not for RPMI 8226 and NCIH929. In contrast, the MM cell lines HUNS-1, MC/CAR, and OPM2 appeared resistant to reovirus infection and showed no evidence of apoptosis at 72 h. Supporting the apoptotic mechanism of cell death, RPMI 8226 showed down regulation of the anti-apoptotic signalling protein, Phospho-Akt, at 24 hours of incubation with reovirus. This was accompanied by a simultaneous expression of activated caspase 3.
Conclusion: Not all MM cell lines are amenable to reovirus mediated cell death. This has important implications for the future use of reovirus as a therapeutic agent for cancer and highlights the importance of understanding cell signalling mechanisms as Phase 3 clinical trials of solid tumours with reovirus are currently underway. Ongoing research utilizing pharmacologic and molecular inhibitors of Akt and caspase3 will enable us to confirm the importance of these molecules in reovirus oncolysis of haematological malignancies. Understanding these signalling pathways will help develop a more personalized approach of reovirus therapy for cancer patients in the 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 1779. doi:10.1158/1538-7445.AM2011-1779
Abstract 178: Pre-treatment with histone deacetylase inhibitor HDACI) synergizes the anti-cancer effect of sorafenib in renal cell carcinoma cells
Authors: Kim Dong Eun , Kim Mi Joung , Jang Sejin , Lee Je-Hwan , Choi Jene , Ro Seonggu , Kim Choung-Soo , Hwang Jung Jin 
Published: August 2014

Abstract
Background: Renal cell carcinoma (RCC), account for 3% of all adult malignances and 75% of RCCs are clear cell renal cell carcinoma (ccRCC), which are highly vascularised tumors. Although a multi-kinase inhibitor, sorafenib has been used for treatment of advanced renal cell carcinoma, it has limitation such as toxicity and long term resistance. Recently, it was reported that histone deacetylase (HDAC) activity is increased in cancer, which leads to suppression of the genes that are related to tumor suppressor and differentiation. Therefore, histone deacetylase inhibitors (HDACIs) are considered as a new anti-cancer drug. In this study, we evaluated the effect of HDACI on anti-tumor effect of sorafenib in ccRCC cells.
Materials and Methods: We used various types of RCC cells including Caki-1(VHL+/+), ACHN (VHL+/+), 786-O (VHL−/−), A498 (VHL−/−), SN12C, TK-10, RXF393, and MDR-over-expressing UO31 cells. We calculated the viability of RCC cells treated with HDACIs (belinostat or vorinostat) alone or in combination with sorafenib using MTS Assay. Combination indexes were determined by CalcuSyn software. We analyzed activation of caspases, and the levels of Mcl-1, Bcl-xl, p-Erk by Western Bolt. Levels of secreted vascular endothelial growth factor (VEGF) were measured by ELISA kit.
Results: Mono-treatment with HDACI (belinostat or vorinostat) induced apoptosis via activation of intrinsic and extrinsic pathways in all RCC cells. Moreover, pre-treatment with belinostat or vorinostat synergistically potentiated cell death induced by sorafenib in Caki-1 and 786-O ccRCC cells. The combination treatment activated caspase-8, -3 and -9 and down-regulated Mcl-1, Bcl-xl, phosphorylation of Erk (p-Erk) and secretion of VEGF in Caki-1 and 786-O cells.
Conclusions: HDACI alone induced apoptotic cell death in various RCC cells. In addition, combination treatment with HDACIs and sorafenib represented synergistic anti-cancer effect in ccRCC cells, indicating that this combination may be a new therapeutic modality for 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 178. doi:10.1158/1538-7445.AM2011-178
Abstract 1780: Potentiating chronic myeloid leukaemia treatment using oligomeric disruption and RNAi
Authors: Woessner David W. , Dixon Andrew S. , Lim Carol S. 
Published: August 2014

Abstract
Exploiting multiple pathways to treat Chronic Myelogenous Leukemia (CML) may improve therapeutic efficacy. CML is caused by expression of the tyrosine kinase oncoprotein, Bcr-Abl, in hematopoietic stem cells resulting in an overproliferative granulocyte cell lineage. Increased circulation of granulocytes or granulocyte progenitors floods the circulatory system resulting in organ failure, infection, hemorrhage and eventually death. Imatinib (Gleevec®) therapy is initially effective in about two-thirds of patients; however resistance to this drug may develop over the course of the disease. Recent reports in the literature have combined imatinib therapy with RNA interference (RNAi) technology in vitro resulting in a more effective induction of apoptosis. An engineered peptide which binds the coiled-coil domain of Bcr-Abl prevents oligomerization and transactivation of the oncogene in K562 cells. This disruption of Bcr-Abl reduces proliferation and blocks downstream oncogenic signaling. To enhance therapeutic efficacy we have integrated short hairpin-mediated RNAi against known disease progression or anti-apoptotic proteins. RNAi targets include autophagy promoting factor ATG7, the aberrant oncoprotein MUC-1, and a leukemic stem cell factor Alox5. Experimental constructs were tested in Bcr-Abl containing K562 cells, a CML blast phase model. Colony forming assays, microscopy and flow cytometry were used to asses proliferation, transformative ability, and apoptosis. When combined with a plasmid encoding the peptide which disrupts Bcr-Abl function, an additive or synergistic enhancement of apoptosis is possible. Targeting CML-causing cells simultaneously through disparate cellular pathways promotes a more complete apoptosis in CML than with currently available TKI therapies.
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 1780. doi:10.1158/1538-7445.AM2011-1780