bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 756: Development of next-generation antibody-drug conjugates for resistant HER2-positive tumors
Authors: Lacasse Vincent , Leyton Jeffrey V. , Beaudoin Simon , Barok Mark , Joensuu Heikki 
Published: August 2018

Abstract
Antibody-Drug Conjugates (ADC) represent a promising therapeutic modality for improving the clinical management of cancer. However, there now exists resistant mechanisms by cancer cells that are effective at ultimately reducing the cellular accumulation of the delivered drug and hence, reducing cytotoxic effectiveness. Kadcyla® (trastuzumab-emtansine [T-DM1]) is a benchmark as it is the first solid-tumor approved ADC. Despite this new therapeutic option, approximately 43% of patients achieve complete or partial response and most who initially respond develop resistance soon after. In order to transform current ADCs to more effective products improved intracellular delivery strategies could provide solutions. Our group developed is a natural composite compound (termed Accum) that conjugates to surface lysines and enables antibodies to escape endosomal entrapment followed by active routing to the nucleus. Modified antibodies retain high tumor cell selectivity, enhanced cellular accumulation, and improved tumor delivery of molecular payloads in vivo. We asked whether the modification of Accum-modified T-DM1 maintained its intracellular delivery mechanism and cytotoxic effectiveness in T-DM1-resistant cells. The cancer cell lines N87, OE19 (gastric), JIMT1, SK-BR-3 (breast), SKOV3 and SKOV3.IP1 (ovarian) were treated with increasing concentrations of T-DM1 in a 3 day on, 10 days off fashion for a period of 1 to 2 months. Resistant clones were identified. Parental and resistant cells were placed and passaged in SILAC (Stably Labeled Amino acid for Cell culture) media for proteomic analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). Cells were also treated with Accum-T-DM1 and mechanistic underpinnings determined. The IC50 of Accum-T-DM1 was increased 50- and 10-fold relative to T-DM1 in parental OE19, and JIMT1 cells, respectively. T-DM1 resistant cell lines were successfully generated for each tumor type. Typically, the T-DM1 IC50 values were increased ≥100-fold in resistant cells compared to parental cells. Preliminary proteomic studies revealed HER2 expression is marginally reduced in resistant cells. IP of Accum-T-DM1 co-precipitated showed the interaction with α-importin. This study is a work in progress of modifying T-DM1 with Accum and demonstrating enhanced cytotoxicity in T-DM1 resistant HER2-positive tumor cells. Ongoing studies will determine DM1 accumulation levels, potential resistance mechanisms, and ultimately cytotoxic effectiveness.
Citation Format: Vincent Lacasse, Jeffrey V. Leyton, Simon Beaudoin, Mark Barok, Heikki Joensuu. Development of next-generation antibody-drug conjugates for resistant HER2-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 756.
Abstract 759: Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer
Authors: Bosco Emily E. , Christie Ronald J. , Carrasco Rosa , Sabol Darrin , Zha Jiping , DaCosta Karma , Brown Lee , Phipps Sandrina , Du Qun , Bezabeh Binyam , Breen Shannon , Chen Cui , Reed Molly , Hinrichs MaryJane , Zhong Haihong , Xiao Zhan , Dixit Rakesh , Herbst Ronald , Tice David A. 
Published: August 2018

Abstract
Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of individual tumors could ultimately lead to improved treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to identify membrane-localized tumor associated antigens (TAAs), we have identified a novel breast cancer TAA that can potentially be exploited through antibody-drug conjugate (ADC) therapy. Here, we describe the development of a GFRA1-targeted ADC that demonstrates activity in GFRA1-positive cell lines and PDX tumor models. Work in non-Good Laboratory Practice (GLP) rat toxicology models revealed acceptable toxicity profiles and supports further evaluation of GFRA1-PBD in GFRA1-positive tumors.
Citation Format: Emily E. Bosco, Ronald J. Christie, Rosa Carrasco, Darrin Sabol, Jiping Zha, Karma DaCosta, Lee Brown, Sandrina Phipps, Qun Du, Binyam Bezabeh, Shannon Breen, Cui Chen, Molly Reed, MaryJane Hinrichs, Haihong Zhong, Zhan Xiao, Rakesh Dixit, Ronald Herbst, David A. Tice. Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 759.
Abstract 769: Zeb-1 contributes to the development of chemotherapeutic resistance in mantle cell lymphoma
Authors: Luanpitpong Sudjit , Poohadsuan Jirarat , Janan Montira , Thumanu Kanjana , Rojanasakul Yon , Issaragrisil Surapol 
Published: August 2018

Abstract
Despite progress overall in improving cancer treatments, the complete response of mantle cell lymphoma (MCL) is still limited due to the inevitable development of drug resistance. Understanding how MCL cells acquire resistance at the molecular level may be a key innovation to targeted therapy. We established a series of bortezomib (BTZ)-resistant MCL cells and performed gene/protein profiling along with metabolic fingerprinting using synchrotron-based Fourier-transform infrared spectroscopy. Zeb-1, an epithelial-mesenchymal transition-inducing transcription factor better known for promoting metastasis in solid carcinomas, was found to be aberrantly expressed in the resistant MCL cells in accordance with an excessive production of lipids. Ectopic expression of Zeb-1 in parental MCL cells rendered the cells to acquire apoptosis resistance to BTZ. Here we demonstrated, for the first time, two possible encompassing mechanisms for Zeb-1-mediated BTZ resistance: (i) Zeb-1 induces cancer stem cells, as evaluated by tumor spheres and aldehyde dehydrogenase activity; and (ii) Zeb-1 induces lipid reprograming that may interfere with cell growth and drug response. Together, our results unveil a novel role of Zeb-1 in MCL aggressiveness. These findings have a clinical significance insight to the development of chemotherapeutic resistance of MCL.
Citation Format: Sudjit Luanpitpong, Jirarat Poohadsuan, Montira Janan, Kanjana Thumanu, Yon Rojanasakul, Surapol Issaragrisil. Zeb-1 contributes to the development of chemotherapeutic resistance in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 769.
Abstract 775: HIPStA, a high-throughput alternative to CETSA®
Authors: Cho Kelvin F. , Rose Christopher , Ma Taylur , Kirkpatrick Donald , Blake Robert A. 
Published: August 2018

Abstract
The measurement of drug - target interaction in the cellular context is critical to many drug development programs. The Cellular Thermal Stability Assay (CETSA®) represents an established broadly applicable method for measuring drug target interaction. However, in its classic format, it has some limitations that make it difficult to scale to the throughput typically required for a drug development project. It requires heating samples to different temperatures and centrifugation and / or filtration steps which limit throughput. The HSP90 Inhibitor Protein Stability Assay (HIPStA) is a novel method for measuring drug target interaction. Like CETSA®, HIPStA is based on the premise that the binding of a ligand to a target protein can influence that protein's stability. Instead of using heat to destabilize a protein, HIPStA uses a Heat Shock Protein 90 inhibitor (HSP90i) to cause protein instability. Instead of scanning a range of different temperatures to establish a thermal denaturation curve, HIPStA applies a range of concentrations of an HSP90i to determine an HSP90i induced denaturation curve, and ultimately measures the ability of a compound to stabilize a protein. We present data demonstrating the proof of concept for the HIPStA method, using 3 different classes of drug discovery targets: Receptor tyrosine kinases, Nuclear Hormone Receptors and Cytoplasmic Protein Kinases. HIPStA represents a scale-able method for detecting drug-target interaction in cells.
Citation Format: Kelvin F. Cho, Christopher Rose, Taylur Ma, Donald Kirkpatrick, Robert A. Blake. HIPStA, a high-throughput alternative to CETSA® [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 775.
Abstract 780: Molecular chaperone is a novel biomarker for disease outcome in multiple myeloma
Authors: Li Yingqi , Zhang Ping L. , Li Zihai , Liu Bei 
Published: August 2018

Abstract
Multiple myeloma (MM) is an incurable plasma cell neoplasm whose pathogenesis is closely linked to dysregulated unfolded protein response (UPR) in the endoplasmic reticulum (ER). MM typically evolves from an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS), to an intermediate asymptomatic smoldering MM (SMM), to eventually symptomatic MM. However, no single pathologic or molecular biomarker can be used to distinguish MM patients from SMM, who have clonal premalignant plasma cells from those with clonal myeloma cells. Therefore, there is a compelling need for further development of novel diagnosis and prognosis biomarkers for MM. Heat shock protein grp94 is a key downstream chaperone in the ER to mediate UPR. Using genetic approaches, we have demonstrated that grp94 is an obligate chaperone for Wnt co-receptor low-density lipoprotein receptor-related protein 6 and that it is required for multiple myeloma cell survival, which is mediated in part by the Wnt target survivin. Moreover, we found that grp94 is highly expressed in malignant plasma cells in MM, and the higher level of grp94 is significantly associated with more advanced stage of this disease. Additionally, the grp94 expression is significantly associated with the levels of serum M protein in MM patients, but not in patients with MGUS and SMM. Thus, our studies demonstrated that molecular chaperone grp94 is a novel diagnostic and prognostic biomarker for MM as well as a potential target for treatment of this disease.
Citation Format: Yingqi Li, Ping L. Zhang, Zihai Li, Bei Liu. Molecular chaperone is a novel biomarker for disease outcome in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 780.
Abstract 800: ABBV-744, a first-in-class and highly selective inhibitor of the second bromodomain of BET family proteins, displays robust activities in preclinical models of acute myelogenous leukemia
Authors: Lin Xiaoyu , Huang Xiaoli , Bellin Richard , Faivre Emily , Hessler Paul , Lam Lloyd , Bui Mai Ha , Wilcox Denise , Uziel Tamar , Ferguson Debra C. , Magoc Terrance J. , Albert Daniel H. , McDaniel Keith F. , Kati Warren , Shen Yu 
Published: August 2018

Abstract
Many small-molecule inhibitors that target both bromodomains of the BET family proteins (pan BET inhibitors) are undergoing studies in clinical trials. Emerging data are beginning to suggest that clinical responses to these pan BET inhibitors in subsets of hematologic malignancies may be modest and short lived, perhaps due, at least in part, to tolerability issues that limit dosing levels. We hypothesized that selective inhibition of four of the eight bromodomains in BET family proteins might retain the anticancer activities in certain tumor subsets while alleviating some of the tolerability liabilities of pan BET inhibitors, thus possibly providing better therapeutic benefits. ABBV-744 is a highly selective inhibitor for the second bromodomain (BDII) of the four BET family proteins, exhibiting greater than 300-fold more potent binding affinity to the BDII bromodomain of BRD4 relative to the first bromodomain (BDI) of BRD4. In contrast to the broad antiproliferative activities observed with pan BET inhibitors, ABBV-744 only displayed significant antiproliferative activities in a limited number of cancer cell lines, including AML and androgen receptor (AR)-positive prostate cancer. Studies in AML xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Taken together, these results suggest that ABBV-744 could be a promising second-generation BET inhibitor for AML therapy.
Affiliation: Oncology Discovery, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: Xiaoyu Lin, Xiaoli Huang, Richard Bellin, Emily Faivre, Paul Hessler, Lloyd Lam, Mai Ha Bui, Denise Wilcox, Tamar Uziel, Debra C. Ferguson, Terrance J. Magoc, Daniel H. Albert, Keith F. McDaniel, Warren Kati, Yu Shen. ABBV-744, a first-in-class and highly selective inhibitor of the second bromodomain of BET family proteins, displays robust activities in preclinical models of acute myelogenous leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 800.
Abstract 827: Anti-tumor efficacy of BA3011, a novel Conditionally Active Biologic (CAB) anti-AXL-ADC
Authors: Sharp Leslie L. , Chang Cathy , Frey Gerhard , Wang Jing , Liu Haizhen , Xing Charles , Yalcin Safak , Walls Marlena , Ben Yong , Boyle William J. , Short Jay M. 
Published: August 2018

Abstract
AXL is a TAM family receptor tyrosine kinase that has been implicated in the pathogenesis of many cancer types. The high level of expression on the cancer cell surface and increased expression in various settings such as PD-1 resistant tumors makes AXL a particularly attractive target for antibody therapeutics. However, AXL is expressed on many normal tissues and has been implicated in wide ranging requisite biological processes including response of endothelial cells to vascular injury, hematopoiesis, and regulation of immune responses. This normal tissue expression combined with the presence of soluble AXL may limit AXL as a target for antibody-drug-conjugates (ADC). The Conditionally Active Biologics (CAB) technology is a patented, proprietary platform that generates antibodies that reversibly bind to target antigen in the context of diseased tissues, but not normal tissues, by taking advantage of the unique cancer microenvironment that is produced largely as a result of the Warburg effect. Using our CAB technology, we have identified anti-AXL CAB Abs that reversibly bind to recombinant AXL and AXL expressing cells under conditions that are present in the tumor microenvironment, but not in normal tissues.
BA3011 is a CAB-AXL-ADC. The pharmacological properties of BA3011 were characterized in a number of in vitro and in vivo pharmacology studies. BA3011 binds selectively to human and cyno AXL in conditions reflective of the tumor microenvironment, but has reduced binding under normal tissue conditions. BA3011 demonstrated the ability to induce cytotoxicity of human tumor cell lines expressing AXL in vitro and inhibit tumor growth in LCLC-103H (lung), DU145 (prostate), and MIAPaCa-2 (pancreatic) human tumor xenografts and in selected gemcitabine resistant pancreatic cancer patient derived xenograft models in vivo.
In conclusion, our data is consistent with our work on CAB-EGFR-ADC, CAB-ROR2-ADC, CAB-PD-1, and other CAB programs, and suggests that ADCs generated using the CAB technology provide biologics with increased therapeutic index. Specifically, the CAB-AXL-ADC is an excellent candidate for evaluation as a treatment for human cancers that are AXL positive.
Citation Format: Leslie L. Sharp, Cathy Chang, Gerhard Frey, Jing Wang, Haizhen Liu, Charles Xing, Safak Yalcin, Marlena Walls, Yong Ben, William J. Boyle, Jay M. Short. Anti-tumor efficacy of BA3011, a novel Conditionally Active Biologic (CAB) anti-AXL-ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 827.
Abstract 828: Targeting the MET oncogene by concomitant inhibition of receptor and ligand by an antibody-‘decoy' strategy
Authors: Basilico Cristina , Modica Chiara , Maione Federica , Vigna Elisa , Comoglio Paolo M. 
Published: August 2018

Abstract
Background: MET, a master gene sustaining ‘invasive growth', is a relevant target for cancer precision therapy. In a limited number of cases, a MET genetic lesion drives the malignant phenotype in ligand-independent manner (oncogene ‘addiction'). In the vast majority of tumors, however, wild-type MET behaves as a ‘stress-response' gene and relies on the ligand (HGF) to sustain cell ‘scattering', invasive growth and apoptosis protection (oncogene ‘expedience'). In this context -i.e. ligand-dependent MET activation- concomitant targeting of MET and HGF could be crucial to reach effective inhibition. Methods: To test this hypothesis we combined an anti-MET antibody (MvDN30), characterized by the property of inducing ‘shedding' (i.e. removal of MET from the cell surface), with a ‘decoy' (i.e. the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction -and subsequent neutralization- we identified by site directed mutagenesis a single aminoacid in the extracellular domain of MET -lysine 842- that is critical for MvDN30 binding, and engineered the corresponding recombinant decoyMET (K842E). The effect of MvDN30 and decoyMETK842E in combination on the inhibition of MET phosphorylation and on the impairment of different MET driven biological responses (motility, invasion, cell proliferation, apoptosis and anchorage independent cell growth) was evaluated on a panel of cancer cells (lines and patient derived-primary cultures) expressing wild-type MET sensitive to HGF stimulation. Therapeutic efficacy was assessed in an orthotopic model of pancreatic cancer generated in SCID mice engineered to express human HGF. Results: The decoyMETK842E retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMETK842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell ‘scattering'. The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In the preclinical model of MET ‘expedience' concomitant treatment with antibody and decoy significantly reduces metastatic spread. Conclusions: The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined targeted therapy of MET ‘expedience'.
Citation Format: Cristina Basilico, Chiara Modica, Federica Maione, Elisa Vigna, Paolo M. Comoglio. Targeting the MET oncogene by concomitant inhibition of receptor and ligand by an antibody-‘decoy' strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 828.
Abstract 830: ISU104, a fully human antibody targeting a specific epitope on the ErbB3, displays potent inhibition of tumor growth in multiple xenograft tumor models
Authors: Kim Miyoung , Hur Youngmi , Seo Sohyeon , Lim Heynjeong , Kim Kyungyong , Sohn Youngsoo , Hong Seung-Beom , Bae Donggoo 
Published: August 2018

Abstract
Members of the epidermal growth factor receptor family (ErbB family) are known as potent mediators in the development and progression of cancer. Activated ErbBs recruit various adaptors and signaling molecules through the phosphorylated cytoplasmic domain, which further leads to activation of downstream oncogenic signaling pathways. There are approved therapeutics for ErbB1 (EGFR) and ErbB2 (HER2) in the treatment of human cancers, while monoclonal antibodies targeting ErbB3 are just undergoing clinical trials. ISU104 is a fully human anti-ErbB3 antibody isolated from phage display antibody library. We performed the hydrogen/deuterium exchange mass spectrometry (HDX-MS) analysis with ErbB3 extracellular domain and ISU104, and that indicated that ISU104 mainly binds with domain 3 and weakly interacts with domain 1 of ErbB3. The binding property of ISU104 induced dose-dependent inhibition of ligand (heregulin, HRG) binding, blocking of dimerization of ErbB3 with other ErbBs and subsequently inactivated the downstream signaling of ErbB3. Also, ISU104 occasioned internalization of ErbB3 from plasma membrane, and downregulated the expression level of ErbB3. We demonstrated the biologic effect of ISU104 in several ErbB3-expressing cancer cell lines, including head and neck squamous cell carcinoma (HNSCC) and breast cancers. ISU104 completely suppressed the HRG-induced ErbB3/AKT phosphorylation, reduced cell proliferation and survival. Next, we evaluated efficacy of ISU104 in multiple xenograft models. Mice were treated with 10 mg/kg of ISU104 twice weekly. ISU104 regressed tumor growth in FaDu HNSCC model, and showed more than 70% tumor growth inhibition (TGI) in CAL27 (HNSCC), BxPC3 (pancreatic cancer), MDA-MB-468 (breast cancer), A549 (skin cancer), and BT474 (breast cancer) models. Our results suggest that ISU104 effectively blocks activation of ErbB3 and the downstream pathway by ErbB3, and may provide clinical benefit to ErbB3-activated patients.
Citation Format: Miyoung Kim, Youngmi Hur, Sohyeon Seo, Heynjeong Lim, Kyungyong Kim, Youngsoo Sohn, Seung-Beom Hong, Donggoo Bae. ISU104, a fully human antibody targeting a specific epitope on the ErbB3, displays potent inhibition of tumor growth in multiple xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 830.