bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2730: Anti-Her2/neu immunotoxins: Impact of monovalent and bivalent designs on in vitro and in vivo antitumor efficacy
Authors: Cao Yu , Marks John W. , Liu Zhigang , Chueng Lawrence H. , Hittelman Walter N. , Rosenblum Michael G. 
Published: August 2012

Abstract
Immunotoxins and designed fusion constructs have significant potential for improved cancer therapy and reduced toxic side effects. We compared the efficacy of anti-Her2/neu immunotoxins containing recombinant gelonin (rGel) in either monovalent or bivalent formats. The bivalent conjugate was Herceptin/rGel chemical conjugate and the monovalent constructs were Herceptin-derived scFv (4D5) fused to rGel in two orientations: 4D5/rGel and rGel/4D5. All three immunotoxins retained the affinity and specificity of the original antibody as well as the biological activity of rGel toxin. Cytotoxicity studies against a panel of Her2/neu expressing tumor cell lines revealed significant differences among these constructs. Both Herceptin/rGel conjugate and rGel/4D5 displayed the best cytotoxicity and specificity whereas 4D5/rGel was the least potent. IC50 values ranged from 0.1-1nM for Herceptin/rGel conjugate and rGel/4D5, but were 10-1000 fold higher for 4D5/rGel. BT474 M1 HR cells with acquired resistance to Herceptin, either by constitutive Akt activation or external factor stimulation, remained sensitive to these constructs compared to the parental cells. The cytotoxicity of all constructs was generally restricted to cells expressing high levels of Her2/neu indicating that Herceptin-based immunotoxins may not be toxic to normal tissues with endogenous (low or medium) levels of Her2/neu. Treatment of nude mice bearing well-developed SKOV3 tumor xenografts with either Herceptin/rGel or rGel/4D5 resulted in impressive tumor inhibition compared to either Herceptin or 4D5/rGel. These studies demonstrate that engineered fusion constructs are competitively effective compared with chemically-generated immunotoxins with longer plasma circulation times. Further characterization of the constructs on Her2/neu overexpressing tumor cells with MDR/MRP resistance is currently ongoing. In conclusion, our studies suggested that smaller, engineered monovalent fusion constructs have excellent, comparable activity compared to intact bivalent antibody conjugates. In addition, the orientation of rGel/scFv vs scFv/rGel can significantly impact the in vitro and in vivo therapeutic activity and should be a consideration in design optimization. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2730. doi:1538-7445.AM2012-2730
Abstract 2733: LJM716: an anti-HER3 antibody that inhibits both HER2 and NRG driven tumor growth by trapping HER3 in the inactive conformation.
Authors: Garner Andrew , Sheng Qing , Bialucha Uli , Chen Dongshu , Chen Yan , Das Rita , Elis Winfried , Heidt Analeah , Kunz Christian , Li Sharon , Liang Jinsheng , Murtie Joshua , Saxena Parmita , Schuller Alwin , Sineshchekova Olga , Sprague Elizabeth , Wang Hui Qin , Huang Alan , Ettenberg Seth 
Published: August 2012

Abstract
HER3 (ErbB3) is a member of the ErbB family of receptor tyrosine kinases (RTK). Inappropriate HER2/ HER3 dimerization as a result of HER2 or neuregulin (NRG) over-expression in cancer results in HER3 mediated activation of PI3K signaling. Consequently, HER3 is a mediator of oncogenic transformation. Although, ligand blocking HER3 antibodies inhibit growth of neuregulin driven xenograft models they are ineffective in models of HER2 amplified cancer as HER2 mediated activation of HER3 occurs in a ligand- independent manner. LJM716 is a high affinity HER3- targeted antibody selected from a Human Combinatorial Antibody Library (HuCAL) specifically for its ability to neutralize multiple modes of HER3 activation. LJM716 is a potent inhibitor of HER3/ AKT phosphorylation and proliferation in a range of HER2 amplified and NRG expressing cell lines in vitro. LJM716 induced tumor regression in Fadu (NRG expressing, HNSCC) tumor xenografts and significant tumor growth inhibition (&gt;80%) in a variety of xenograft models including BT474 (HER2 amplified breast). Furthermore, the combination of LJM716 with trastuzumab, cetuximab or PI3K- targeted agents was synergistic in a panel of in vitro cell lines while the in vivo combination of LJM716 with trastuzumab or erlotinib was efficacious in BT474 and L3.3 (pancreatic) tumor xenografts respectively. To further understand the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to the HER3 extra-cellular domain. This data revealed that LJM716 binds to a novel conformational epitope contained within domains 2 and 4 and appears to trap HER3 in the inactive conformation. Interestingly, LJM716 does not block NRG binding to HER3 nor does it affect the binding affinity of the HER3/ NRG interaction. LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for HER3 activation induced by either HER2 or NRG. Thus LJM716 is the first HER3 antibody to display efficacy in both HER2 and ligand driven xenograft models. Based on preclinical data, combining LJM716 with either trastuzumab, cetuximab or PI3K- targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2733. doi:1538-7445.AM2012-2733
Abstract 2738: c-Met antibody LY2875358 (LA480) has pre-clinical enhanced efficacy with gastric cancer standard-of-care in vitro and in vivo
Authors: Wortinger Mark A. , Peek Victoria , Zeng Wei , Yan Lei , Tetreault Jonathan , Xia Jinqi , Jirong Lu , Chow Chi-Kin , Manro Jason R. , Stephens Jennifer R. , Merzoug Farhana , Vaillancourt Peter , Yan S. Betty , Liu Ling 
Published: August 2012

Abstract
cMet is a member of the receptor tyrosine kinase family and is the receptor for hepatocyte growth factor (HGF). cMet has been implicated in the initiation and progression of cancer due to the range of activities that cMet stimulates including proliferation, migration, morphogenesis, and survival. Inappropriate activation of c-Met can be induced by ligand-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation, or by ligand-dependent autocrine or paracrine mechanisms. Indeed, amplification of the c-Met gene, with consequent protein overexpression and constitutive kinase activation, has been reported in a number of human cancers, including gastric, esophageal and non-small-cell lung carcinomas. It has been reported that ∼10-20% of gastric tumors have increased copy numbers of the MET gene and overexpression of c-Met significantly correlates with poor prognosis in gastric cancer. c-Met antibody LY2875358 treatment reduces proliferation of gastric cancer cell lines with ligand-independent activation of c-Met resulting from gene amplification. The ability of LY2875358 to internalize and deplete cell surface c-Met is implicated in its activity against ligand-independent driven gastric cell lines. Here, we demonstrate that the pre-clinical combination of c-Met antibody LY2875358 with gastric cancer standard-of-care treatment has better efficacy than either treatment alone, both in vitro and in vivo. These data suggest that LY2875358 in combination with standard-of-care may be a promising treatment for gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2738. doi:1538-7445.AM2012-2738
Abstract 2745: INK128, a TORC1/2 kinase inhibitor, enhances the efficacy of cytotoxic therapies in endometrial tumor models
Authors: Kessler Linda , Jessen Katti , Janes Matthew , Staunton Jocelyn , Kucharski Jeff , Guo Xin , Elia Marikka , Banerjee Urmi , Lan Lucy , Wang Shunyou , Stewart Josh , Luzader Angelina , Darjania Levan , Li Liansheng , Chan Katrina , Martin Michael , Ren Pingda , Rommel Christian , Liu Yi 
Published: August 2012

Abstract
Background: The mammalian target of rapamycin (mTOR), which comprises two protein complexes, TORC1 and TORC2, regulates tumor cell growth, metabolism and motility. In endometrial cancer, the mTOR pathway is aberrantly activated by constitutive mitogen stimuli, such as FGFR2 and multiple genetic mutations such as PIK3CA, PIK3R1/2, PTEN and LKB1. The activation of multiple signaling pathways, cross-feedback and redundancy of these pathways led us to explore the combination of mTOR kinase inhibitor with chemotherapeutic agents for achieving maximal efficacy in preclinical mouse models of endometrial cancer. Results: INK128 is a potent and selective TORC1/2 inhibitor with excellent drug-like properties currently advancing in clinical development. INK128 inhibits endometrial tumor cell proliferation in vitro and displays tumor growth inhibition in endometrial tumor models. In most instances, the anti-tumor activity of INK128 is cytostatic compared to the cytotoxic effect of taxol and carboplatin. In endometrial tumor cells of diverse genetic backgrounds, combining INK128 with taxol resulted in a synergistic inhibition of tumor cell proliferation, sustained suppression of PI3K/AKT/mTOR pathway activity, skewed cell cycle and an increase in apoptosis. INK128 decreased the expression of anti-apoptotic protein MCL-1 and therefore mechanistically enhanced taxol-triggered apoptosis. In endometrial mouse tumor models with PTEN and FGFR2 mutations, the combination induced marked tumor regression and significantly delayed tumor re-growth upon discontinuation of the treatment compared to taxol treatment alone. The combination therapy was well-tolerated and the enhanced anti-tumor efficacy correlated with mechanism-based inhibition of several TORC1 and TORC2 pharmacodynamic markers and induction of apoptosis in vivo. Additionally, combining INK128 with taxol or carbotaxol resulted in tumor regression in taxol-resistant endometrial tumor models. The opportunity of optimizing dose and schedule combination regimens as well as biomarkers predicting sensitivity/resistance to INK128/taxol combination will be discussed. Conclusion: The combination of mTOR kinase inhibitors with chemotherapeutic agents is a compelling strategy to improve therapeutic outcome and to overcome chemo-resistance for tumor types with aberrant activation of the PI3K/mTOR pathway such as endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2745. doi:1538-7445.AM2012-2745
Abstract 2746: Thiazolidinediones augment anticancer effects of gemcitabine on human pancreatic cancer cells through PPARδ activation
Authors: Koga Hironori , Selvendiran Karuppaiyah , Sivakumar Ramadoss , Yoshida Takafumi , Torimura Takuji , Ueno Takato , Sata Michio 
Published: August 2012

Abstract
In order to improve the prognosis of patients with unresectable pancreatic cancer, there is an urgent need for enhancement of the anticancer effect of gemcitabine (Gem), a first-line drug for the disease. Here, we demonstrated that ligands for peroxisome proliferator-activated receptor ≤ (PPARδ) such as pioglitazone (Pio) and rosiglitazone potentiated the cytotoxic action of Gem on human pancreatic cancer cells in a dosage-dependent manner. Notably, the synergistic effect was PPARδ-dependent, since the effect was augmented by PPARδ overexpression and was attenuated by both a PPARδ inhibitor (GW9662) and PPARδ-specific siRNA. To further increase the collaborative effect, the histone deacetylase (HDAC) inhibitor valproic acid (VPA), a known potentiator for PPARδ function, was added to the combinatorial treatment, robustly inducing apoptosis mediated by highly expressed death receptors, including Fas/CD95 and DR5. In xenograft tumor experiments in nude mice, Gem plus Pio significantly suppressed tumor growth as compared with the control treatment, while Gem-only treatment did not. Triple treatment with Gem, Pio, and VPA failed to demonstrate a significant antitumor effect when compared with Gem plus Pio in the current setting. Considered together, Gem plus PPARδ ligands, including Pio, may have therapeutic advantage in the treatment of advanced pancreatic cancer. Since Pio is widely used in the treatment of diabetes mellitus, it may become a feasible partner of Gem-based chemotherapy, fine-tuning the strength of the therapy in a dosage-dependent fashion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2746. doi:1538-7445.AM2012-2746
Abstract 2755: Enhanced anti-tumor effects using a combinatorial targeted treatment strategy in a preclinical model of prostate cancer
Authors: Yamamoto Yutaka , De Velasco Marco A. , Hatanaka Yuji , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Kodama Mitsumasa , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2012

Abstract
Recently developed strategies use molecular targeting agents specifically designed to target core regulatory signaling pathways of prostate cancers. Growth factors mediate such signaling pathways that include the PI3K/Akt/PTEN/mTOR and Ras/Raf/MEK/MAPK as well as other essential pathways. However various mitigating factors such a genetic variation, molecular diversity, diverging and converging of signaling pathways make it improbable that treatment with any single agent will result in any long-term enhanced tumor. To overcome such problems we investigated the toxicity and antitumor effects of combined targeted therapy with the mTOR inhibitor everolimus and the mulitkinase inhibitor sorafenib in a prostate-specific PTEN conditional knockout mouse model of human prostate cancer. Non-castrated and castrated (castrate-resistant prostate cancer model, CRPC) PSACre;PTENloxP/loxP mutant mice, harboring prostate tumors, were treated with everolimus and sorafenib alone or in combination for 4 weeks beginning at 16 weeks of age. All mice appeared healthy and there were no significant differences in body weights, appearance or histological findings between treatment and control groups at the end of the experiment. Our analysis shows that combination therapy has a significant additive inhibitory effect on tumor growth in non-castrate prostate cancer model (8.8 mm2, 7.7 mm2, 7.1 mm2 and 5.2 mm2 in control, everolimus, sorafenib and combination treatment groups, respectively, p=0.005). Ki67 expression was decreased and positive TUNEL apoptotic bodies was increased in combination treatment groups compared to everolimus and sorafenib monotherapy in both non-castrated and CRPC treatment groups. We also show that combination therapy, but not monotherapy, cooperated to inhibit phosphorylation of the eukaryotic translation initiation factor 4B (eIF4B). Our study provides preclinical evidence that a targeted combination treatment strategy with everolimus and sorafenib is tolerable and leads to improved treatment efficacy over single agent therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2755. doi:1538-7445.AM2012-2755
Abstract 2758: Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: Evidence for the role of C-Jun N-terminal kinase activation
Authors: Cheng Hairong , Hong Bo , Zhou Lanlan , Allen Joshua , Dicker David , El-Deiry Wafik 
Published: August 2012

Abstract
Discovery of the molecular targets of chemotherapeutic medicines and their chemical footprints can validate and improve the use of such medicines. In the present study, we investigated the effect of mitomycin C (MMC), a well-known chemotherapeutic agent on cancer cell apoptosis induced by TRAIL. We found that MMC not only potentiated TRAIL-induced apoptosis in HCT116 (p53-/-) colon cancer cells but also sensitized TRAIL-resistant colon cancer cells HT-29 to the pro-apoptotic cytokine. MMC also improved the pro-apoptotic effects of two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab. At a mechanistic level, MMC downregulated cell survival proteins including Bcl2, Mcl-1 and Bcl-XL, upregulated cell pro-apoptotic proteins including Bax and Bim, and induced the cell surface expression of TRAIL death receptors DR4 and DR5. Gene silencing of DR5 by short hairpin RNA reduced the apoptosis induced by combination treatment of MMC and TRAIL. Induction of DR4 and DR5 was independent of p53, Bax and Bim, but was dependent on c-Jun N-terminal kinase (JNK) as JNK pharmacologic inhibition and the JNK siRNA abolished the induction of the TRAIL receptors by MMC. The results provide insights into strategies for the development of novel combinatorial cancer therapy combinations that may be further tested in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2758. doi:1538-7445.AM2012-2758
Abstract 276: Targeting signaling networks via RNAi to improve therapy for ovarian cancer
Authors: Liu Hanqing , Serebriiskii Ilya , Einarson Margret B. , Pecherskaya Anna , Zhou Yan , Pathak Harsh , Godwin Andrew K. , Golemis Erica A. 
Published: August 2012

Abstract
Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy, and the leading cause of death from gynecological cancers. At the time of presentation, most ovarian cancers are no longer dependent on single genetic determinants for growth and/or survival, and targeted therapies used as single agents typically do not work in this disease. We hypothesized that network-based synthetic lethality screens would help identify critical pathways to target in combination therapy. We have used RNAi screening with a targeted library to identify a set of gene candidates that influence the response of EOC cells to the Src-targeting agent dasatinib, a promising agent for treatment of EOC. We identified sets of siRNAs that specifically modulated cell resistance to dasatinib, or directly affected EOC cell survival. We then compared this set of siRNAs with previously identified modulators of response to EGFR-targeting agents and cytotoxic drugs, contrasting action in EOC cell lines versus other types of cancer cell lines. From a set of 60 siRNAs intrinsically reducing cell growth and survival, some (16 siRNAs) were specific for EOC cells. In contrast, 38 siRNAs antagonized the response of EOC cells to dasatinib, and are promising drug treatment-resistance biomarkers. We concluded validation of EOC-specific hits. Mapping the pattern of drug treatment-resistance hits together with drug treatment-sensitive hits revealed suggestive clusters of very closely interacting proteins clustering with well validated modulators of cancer cell survival, implying we have identified key cancer signaling nodes. Screening candidates, e.g., PTPN12, Spry4, and HSPA8, which cluster with well-validated cancer-related signaling hubs, are being examined. These studies offer an opportunity to employ a functional approach to identify critical drug response-modifying genes that can be therapeutically targeted as biomarkers and drug targets to improve EOC treatment outcomes with emerging targeted agents. (This work was supported by the fellowship grant from Sass Foundation for Medical Research, Inc, Roslyn, New York to H. Liu, NIH FCCC-UPenn ovarian cancer SPORE (P50 CA083638), and NIH (R01 CA140323).)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 276. doi:1538-7445.AM2012-276
Abstract 2760: Gemcitabine induced lytic EBV replication and confers ganciclovir susceptibility to EBV-positive gastric cancer
Authors: Kim Hyemi , Lee Hyun Gyu , Park Jeon Han , Lee Jae Myun ,   Brain Korea 21 Project for Medical Sciences
Published: August 2012

Abstract
Epstein-Barr virus (EBV) is a dsDNA human gamma herpes virus which infects more than 90% of human populations. It is associated with the development of malignancies such as Burkitt's lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Gastric cancer is the second most common cancer in the world and the highest incidence is in Korea. The constant presence of the viral genome in EBV associated gastric cancer tissue offers the potential for novel EBV targeted therapies using antiviral nucleoside drug. Ganciclovir (GCV) is the drug of choice in herpes virus infection, however, GCV alone have been unsuccessful in the treatment of EBV associated malignancies because the virus maintains a latent state of replication in tumor, and thymidine kinase (BXLF1) and protein transferase (BGLF4), express only during lytic state of replication. In recent years, novel treatment strategies are being investigated where in lytic replication of the virus in EBV associated cancer is induced prior to the use of GCV. We investigate Gemcitabine (Gem), which is one of newly discovered potential lytic inducers found from FDA approved drug library screen using BZLF1 promoter reporter system. We examined whether the combination of GCV and Gem is more effective than Gem alone for killing EBV-positive gastric cancer cells. We found GCV significantly enhanced the ability of Gem to kill EBV-positive, but not EBV negative, gastric carcinoma cells in vitro. Also we found that low dose (2.5ng/ml) and short term exposures (24hr) of the EBV positive gastric cancer cell line SNU719 to Gem induced expression of the EBV lytic phase proteins. Viral kinases were also induced by short term and low dose exposure. Short term and low dose exposure to Gem in combination with GCV induced tumor cell death and cell proliferation inhibition. In conclusion, pharmacologic induction of the lytic viral kinases in tumor cells using Gem, followed by treatment with GCV is useful in EBV associated gastric cancer in vitro. And this virus-targeted antitumor strategy may provide a new therapeutic approach to EBV-associated gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2760. doi:1538-7445.AM2012-2760