bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4319: Lupus antibody-based cancer therapy.
Authors: Hansen James E. , Chan Grace , Liu Yanfeng , Hegan Denise C. , Dalal Shibani , Dray Eloise , Kwon Youngho , Xu Yuanyuan , Xu Xiaohua , Peterson-Roth Elizabeth , Geiger Erik , Liu Yilun , Gera Joseph , Sweasy Joann B. , Sung Patrick , Rockwell Sara , Nishimura Robert N. , Weisbart Richard H. , Glazer Peter M. 
Published: August 2014

Abstract
A subset of autoantibodies produced by patients with systemic lupus erythematosus (SLE) penetrates into cell nuclei and binds DNA, and we believe that such antibodies may have applications in cancer therapy. We have discovered that the cell-penetrating, nuclear-localizing anti-DNA lupus antibody 3E10 inhibits key steps in DNA single- and double-strand break repair and has potential for development as a targeted therapy for tumors harboring deficiencies in DNA repair. 3E10 preferentially binds DNA substrates with free single-strand tails and interferes with both base excision repair and homology-directed repair (HDR) in vitro, and HDR efficiency is reduced in cells treated with 3E10 as measured in the chromosome-based DR-GFP fluorescent reporter assay. The binding of 3E10 to DNA can be directly visualized under electron microscopy (EM), and EM studies confirmed that 3E10 interferes with RAD51 filament formation, which is a critical step in HDR. The 3E10 single chain variable fragment penetrates into human tumor xenografts in nude mice, and 3E10 sensitizes cancer cells and tumors to DNA-damaging therapy. In addition, 3E10, by itself, is toxic to BRCA2-deficient cancer cells but not to repair-proficient cells, and when combined with a DNA-damaging agent, 3E10 has a very large cytotoxic effect on BRCA2-deficient cancer cells. The synthetically lethal effect of 3E10 on BRCA2-deficient cancer cells is consistent with our finding that 3E10 inhibits DNA repair, and it suggests that 3E10 has potential as a targeted therapy for tumors harboring deficiencies in DNA repair, such as certain breast, ovarian, and prostate cancers. Of note, patients with SLE have lower than expected incidence rates of breast, ovarian, and prostate cancers, and it is tempting to speculate that the circulating cell-penetrating anti-DNA autoantibodies provide patients with SLE some protection against the development of DNA repair-deficient tumors. In summary, our work with the 3E10 antibody has provided proof of principle for the development of a lupus antibody as a cancer therapy and opened up new avenues for exploration into the biology of lupus antibodies.
Citation Format: James E. Hansen, Grace Chan, Yanfeng Liu, Denise C. Hegan, Shibani Dalal, Eloise Dray, Youngho Kwon, Yuanyuan Xu, Xiaohua Xu, Elizabeth Peterson-Roth, Erik Geiger, Yilun Liu, Joseph Gera, Joann B. Sweasy, Patrick Sung, Sara Rockwell, Robert N. Nishimura, Richard H. Weisbart, Peter M. Glazer. Lupus antibody-based cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4319. doi:10.1158/1538-7445.AM2013-4319
Abstract 4321: Development of pyrrolobenzodiazepine-based antibody-drug conjugates for cancer.
Authors: Jeffrey Scott C. , Burke Patrick J. , Sutherland May K. , Meyer David W. , Lyon Robert P. , McEarchern Julie A. , Law Che-Leung , Senter Peter D. 
Published: August 2014

Abstract
Pyrrolobenzodiazepine (PBD) dimers are highly cytotoxic minor groove binding DNA crosslinking agents derived from the anthramycin class of natural products. In our efforts to develop highly effective and well-tolerated treatment options for cancer patients, we have investigated several antibody-drug conjugates (ADCs) based on a PBD dimer. The fully synthetic PBD-linker, comprised of a protease-cleavable val-ala sequence and a reactive maleimide group, was conjugated via engineered cysteine residues to humanized monoclonal antibodies specific for their binding to the well-characterized cancer antigen targets, CD33 and CD70. The resulting ADCs were well-defined, monomeric and showed pronounced in vitro and in vivo activity against both hematologic and solid tumor cancer models. These included models of acute myelogenous leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and renal cell carcinoma. The ADCs were immunologically specific, and showed potent activity in MDR-positive models, including models resistant to other ADCs. These results underscore the importance of the drug component in developing highly efficacious ADCs for cancer therapy.
Citation Format: Scott C. Jeffrey, Patrick J. Burke, May K. Sutherland, David W. Meyer, Robert P. Lyon, Julie A. McEarchern, Che-Leung Law, Peter D. Senter. Development of pyrrolobenzodiazepine-based antibody-drug conjugates for cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4321. doi:10.1158/1538-7445.AM2013-4321
Abstract 4323: Antibodies against TfR inhibit growth of tumor cells both in vitro and in vivo.
Authors: Zhang Lilin , Ukai Yoshinori , Nomura Fumiko , Aikawa Youichi , Kayukawa Yoko , Mitomo Katsuyuki , Kouda Katsushi , Kodaka Romi , Kurosawa Gene , Kurosawa Yoshikazu , Morishita Kazuhiro , Sudo Yukio 
Published: August 2014

Abstract
Transferrin receptor (TfR) is a type II transmembrane glycoprotein regulating intracellular uptake of iron, and is therefore involved in cell survival and proliferation. TfR has been reported to be more abundantly expressed in dividing cells, e.g. malignant cells, than in quiescent cells, as in most normal cells. Therefore, it is regarded as a potential target for usage in cancer therapy. In the present study, we generated a panel of human anti-TfR antibodies and evaluated its anti-tumor effect both in vitro and in vivo. We found that several antibodies inhibited cell proliferation in various tumor cells, and elicited antibody dependent cellular cytotoxicity (ADCC) activity. Among these antibodies, PPMXT001 and PPMXT002 exerted a significant anti-tumor activity in several xenograft models. PPMXT001 completely suppressed tumor growth in a pancreatic cancer model (MIAPaCa2). PPMXT002 also inhibited tumor growth by 60∼80% in several solid cancer xenograft models including bladder cancer, colon cancer, prostate cancer, and pancreatic cancer. These findings showed that PPMXT001 and PPMXT002 could be potent candidates for developing antibody therapeutics to treat cancer.
Citation Format: Lilin Zhang, Yoshinori Ukai, Fumiko Nomura, Youichi Aikawa, Yoko Kayukawa, Katsuyuki Mitomo, Katsushi Kouda, Romi Kodaka, Gene Kurosawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo. Antibodies against TfR inhibit growth of tumor cells both in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4323. doi:10.1158/1538-7445.AM2013-4323
Abstract 4327: A novel protease resistant antibody platform with selectable cell killing functions.
Authors: Kinder Michelle , Grugan Katharine , Soring Keri , Strohl William , Jordan Robert , Brezski Randall 
Published: August 2014

Abstract
Invasive cancers express matrix metalloproteases, such as MMP-3 and MMP-7, which have the ability to cleave human antibodies in the lower hinge region. The human IgG lower hinge region contains two heavy chains, and cleavage occurs in a two-step process. First, one heavy chain is cleaved, resulting in a singly-cleaved intermediate. Cleavage of the second heavy chain liberates the Fc region from the antigen-binding region, resulting in an Fc fragment and a F(ab’)2 fragment. Previous work has demonstrated that the singly-cleaved intermediate accumulates on the surface of IgG1-opsonzied tumor cells in the presence of MMPs. The singly-cleaved intermediate is indistinguishable from the intact IgG counterpart when assessed by analytical techniques under native conditions and maintains normal antigen binding. However, the singly-cleaved intermediate displays a profound loss of Fc-mediated cell-killing functions both in vitro (e.g. ADCC and CDC) and with in vivo cell clearance, presumably because the lower hinge contains key recognition points for both FcγRs and the C1q component of complement. Singly-cleaved IgGs are of particular concern with regards to human IgG1 monoclonal therapeutic antibodies, because the proposed mechanisms of action for several anti-tumor mAbs in the clinic may be partially dependent on Fc effector functions, such as ADCC and CDC. For this reason, our group and others have proposed that cleavage and the subsequent inactivation of Fc-effector functions of human IgG antibodies may function as an immune evasion mechanism. To overcome the loss-of-function associated with human IgG1 cleavage, we aimed to develop a protease-resistant IgG1 platform which would still maintain Fc-mediated cell-killing functions. Mutation of the lower hinge of IgG1 provided protease-resistance, but also resulted in a loss of Fc-effector functions. Through specific mutations of amino acids in the CH2 region to enhance complement or Fcγ receptor binding, we were able restore or even enhance cell-killing functions selectively while maintaining protease-resistance. Therefore, we were able to generate protease-resistant antibodies with the ability to mediate either complement-dependent and/or antibody-dependent cellular cytotoxicity, which were also significantly resistant to inactivation by proteases associated with many invasive cancers.
Citation Format: Michelle Kinder, Katharine Grugan, Keri Soring, William Strohl, Robert Jordan, Randall Brezski. A novel protease resistant antibody platform with selectable cell killing functions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4327. doi:10.1158/1538-7445.AM2013-4327
Abstract 4332: Development of AGS15E, a novel antibody drug conjugate targeting SLITRK6 for the treatment of bladder cancer.
Authors: Morrison Kendall 
Published: August 2014

Abstract
Agensys (an affiliate of Astellas Pharma), Santa Monica, CA Abstract: SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins involved in neurite outgrowth. It was discovered by Agensys using suppressive subtractive hybridization on biopsies from bladder cancer patients. Expression in bladder cancer was confirmed by RNA and immunohistochemical analysis. These studies showed SLITRK6 to be highly expressed in bladder carcinoma in situ as well as in invasive and metastatic bladder cancer. In addition, SLITRK6 was shown to be expressed in a subset of lung cancer, breast cancer and glioblastoma specimens.
Agensys has generated a novel antibody drug conjugate (ADC), targeting SLITRK6, which is being developed for the treatment of advanced bladder cancer. This Monomethyl Auristatin E based ADC binds to cell surface SLITRK6 with high affinity and cross reacts with the cynomolgus monkey orthologue. Selection and development of this ADC will be discussed including antibody choice, drug platform choice, conjugation development and other aspects of pre-clinical evaluation.
Citation Format: Kendall Morrison. Development of AGS15E, a novel antibody drug conjugate targeting SLITRK6 for the treatment of bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2013-4332
Abstract 4340: Formulation of oral microparticulate drug delivery system for cancer.
Authors: Patel Jay V. , Desai Kunal P. , Do Duc P. 
Published: August 2014

Abstract
The development of oral controlled-release cancer drug formulations with enhanced bioavailability and efficacy is highly desired. Our research aim to develop controlled-release capsule formulations containing sulforaphane-encapsulated in a biodegradable polymeric microparticulate system. Sulforaphane, a histone deacetylase inhibitor (HDAC), was investigated as this therapeutic agent reverses aberrant epigenetic changes in cancer cells and the effects of this drug are reversible. Biodegradable polymeric microspheres were prepared by a microencapsulation method, and prepared microspheres were characterized for various properties, including encapsulation efficiency, percent yield, particle size, size distribution, surface morphology, and Zeta potential. Dissolution studies were carried out to analyze the release profiles of the microspheres and capsule-containing microsphere formulations. Data indicated that microspheres were less than 2-μm in diameter size. It has been shown that particles within this size range are effectively taken in by the cells. The prepared microsphere formulations had Zeta potential values of about -30 mV, which suggest that they are stable. Furthermore, microsphere formulations were shown to provide controlled-release of the drug over 36 hours. Capsule formulations containing microspheres exhibited similar drug release characteristics; however, the lag time for drug release was longer. Thus, oral gelatin capsules containing sulforaphane-encapsulated biodegradable microspheres show potential for effective delivery of epigenetic agents.
Citation Format: Jay V. Patel, Kunal P. Desai, Duc P. Do. Formulation of oral microparticulate drug delivery system for cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4340. doi:10.1158/1538-7445.AM2013-4340
Abstract 4344: Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer.
Authors: Bae Woo Kyun , Hennighausen Lothar , Lee Ji Hee , Kim Dae Eun , Hwang Jun Eul , Shim Hyun Jeong , Cho Sang Hee , Park In-Kyu , Chung Ik-Joo 
Published: August 2014

Abstract
Thermo-responsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an optimized drug delivery system with anti-cancer activity for controlled release of the hydrophobic drug, docetaxel. In this study, we evaluated the effect of Plu-CLA as a potential new intraperitoneal docetaxel delivery system for peritoneal dissemination of gastric cancer. We have established a peritoneal metastasis models using BALB/c mice by injection with TMK-1 human gastric cancer cells. Mice were injected intraperitoneally with docetaxel alone and docetaxel loaded Plu-CLA at 1 week after TMK1 cells were injected. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and ascites volume were also measured. Compared to docetaxel alone, the combination of docetaxel and Plu-CLA significantly and synergistically reduced cell survival. The combination of docetaxel and Plu-CLA showed excellent anti-tumor activity inducing stronger apoptosis than docetaxel alone. The combination of docetaxel and Plu-CLA also significantly reduced number of peritoneal metastatic nodules and increased the survival in the peritoneal gastric cancer xenograft model. Our results showed that intraperitoneal administration of docetaxel combined with Plu-CLA synergistically inhibited peritoneal metastasis and prolonged the survival in peritoneal gastric cancer model. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer.
Citation Format: Woo Kyun Bae, Lothar Hennighausen, Ji Hee Lee, Dae Eun Kim, Jun Eul Hwang, Hyun Jeong Shim, Sang Hee Cho, In-Kyu Park, Ik-Joo Chung. Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4344. doi:10.1158/1538-7445.AM2013-4344
Abstract 435: The role of HIF-1 and Notch pathway in radio-resistance of non small lung cancer cell lines.
Authors: Ikezawa Yasuyuki , Sakakibara-Konishi Jun , Mizugaki Hidenori , Ooizumi Satoshi , Nishimura Masaharu 
Published: August 2014

Abstract
Background: Notch pathway regulates cell-fate determination in multi-cellular organisms and aberrant activation of Notch pathway has been reported in tumorigenesis of many cancers. We previously reported that Notch3 and its downstream effector, HEY1, were upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines. Furthermore, we demonstrated that g-secretase-inhibitor (GSI), when combined with radiation therapy significantly suppressed the growth of lung cancer cells compared to either GSI or radiation alone by a potential mechanism that GSI suppressed radiation-induced Notch activation and its resultant radio-resistance. Since the expression of Notch was reported to be activated via HIF under hypoxia, we, in this study, hypothesized that HIF would be involved in radiation-induced Notch activation in NSCLC and thus HIF inhibitor (YC-1) would have an anti-tumor effect when combined with radiation therapy as is the case with GSI.
Materials and Methods: Two Notch-expressing lung cancer cell lines (H460 and H1793) were used. We first examined, by Western Blotting (WB) and real time RT-PCR, the changes in expressions of HIF-1 and Notch family after treatment by radiation under hypoxia. We then repeated the same experiment while using SiRNA targeting HIF-1, in an attempt to examine the role of HIF-1 on Notch pathway and its downstream proteins. Finally, we investigated an antitumor effect of YC-1, using a MTT proliferation assay and a clonogenic assay, when combined with radiation treatment.
Results: Under hypoxia, treatment by radiation up-regulated protein expression of HIF-1 at 6 hours and that of Notch3 as well at 24 hours, but not of other Notch family. As expected, specific suppression of HIF-1 by siRNA down-regulated Notch3 activation associated with radiation; however, did not affect other Notch family and its downstream effectors, including HES1. An anti-tumor effect of YC-1 was evident only when radiation treatment was concurrently applied, but not when sequentially applied, in the growth of lung cancer cells and also colony formation.
Conclusions: Radiation-induced up-regulations of HIF-1 and Notch pathway may be therapeutic targets for more effective radiation therapy in NSCLC.
Citation Format: Yasuyuki Ikezawa, Jun Sakakibara-Konishi, Hidenori Mizugaki, Satoshi Ooizumi, Masaharu Nishimura. The role of HIF-1 and Notch pathway in radio-resistance of non small lung cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 435. doi:10.1158/1538-7445.AM2013-435
Abstract 4353: Cycloxygenase-2 inhibitor regulates p73 isoform expression pattern, inhibit growth, and induce apoptosis in NHL cell line model with 1p36 chromosomal disruption.
Authors: Hassan Hesham M. , Varney Michelle , Joshi Shantaram S. , Singh Rakesh K. , Dave Bhavana J. 
Published: August 2014

Abstract
Diclofenac is a cycloxynase-2 (COX-2) inhibitor that is used in clinics as an analgesic anti-inflammatory drug and has been shown to increase TP73 gene signature in multiple tumor cell lines. TP73, a gene at 1p36 locus, is controlled by a balance between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic through antagonizing both TAp73 and p53). Our previous work has shown a differential ΔNp73 up-regulation among NHL cases with 1p36 chromosomal disruption correlates with decreased apoptosis, increased cellular proliferation and increased angiogenesis. Modulation of ΔNp73:TAp73 ratio using TAp73 expression vector in Granta-519 (NHL cell line model that harbor disrupted 1p36 and express high levels of ΔNp73) resulted in growth inhibition and increased response to chemotherapy. In this study, we hypothesized that diclofenac treatment will modulate the expression profile of p73 isoforms and alter the behavior of the NHL cells with 1p36 disruption. Diclofenac treatment of Granta-519 cells resulted in a decrease in ΔNp73, increase in TAp73 mRNA expression. MTT assay showed a concentration- and duration-dependent cell growth inhibition. Decreased expression of the proliferation marker ki-67 and cell cycle arrest as indicated by flow cytometric cell cycle analysis; were evident following diclofenac treatment. Furthermore, Annexin-V-Flous flow cytometric analysis showed increased number of apoptotic cells that was associated with increased cleaved caspase-3 following diclofenec treatment. Moreover, pro-apoptotic target genes expression was induced by diclofenac treatment including p21, PUMA, NOXA, and BIM. Next we tested the effect of diclofenac treatment on standard CHOP-resistant Granta-519 sub-clones, that resulted in down-regulation of ΔNp73 mRNA expression and a significant dose-dependent growth inhibitory effect. Together, our data demonstrate that diclofenac treatment caused p73 isoforms reconstitution (↑TAp73 and/or ↓ΔNp73), inhibited growth of NHL cells with 1p36 abnormality and highlights the potential of diclofenac as a potential new adjuvant therapy in NHL with disrupted TP73 gene region.
Citation Format: Hesham M. Hassan, Michelle Varney, Shantaram S. Joshi, Rakesh K. Singh, Bhavana J. Dave. Cycloxygenase-2 inhibitor regulates p73 isoform expression pattern, inhibit growth, and induce apoptosis in NHL cell line model with 1p36 chromosomal disruption. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4353. doi:10.1158/1538-7445.AM2013-4353