bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3825: Disrupting p-STAT3-mediated VEGF-A paracrine and autocrine feed-forward loops by targeting SHP-1 suppresses triple negative breast cancer cell metastasis
Authors: Su Jung-Chen , Chiu Hao-Chieh , Liu Chun-Yu , Chen Kuen-Feng , Shiau Chung-Wai 
Published: July 2016

Abstract
Patients with metastatic triple-negative breast cancer (TNBC) relapse quickly, representing an unmet need for effective therapy. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting tumor angiogenesis, oncogenesis and the tumor microenvironment and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib also acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells by mitigating autocrine and paracrine feed-forward loops of p-STAT3-mediated VEGF-A signaling through targeting the SHP-1/p-STAT3/VEGF axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in a panel of human TNBC cells. Clinically VEGF-A expression is associated with disease-free and distant metastasis-free survival, independent of tumor stage. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. Overexpression and knockdown experiments validated the indispensable roles of SHP-1, p-STAT3 and VEGF-A in regorafenib-induced anti-migration. To exclude the role of RTK inhibition in regorafenib-induced inhibition of migration, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1/p-STAT3/VEGF-A signaling. SC-78 demonstrated superior in vitro anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. SC-78 revealed more potent in vivo efficacy than regorafenib in both xenograft and orthotopic models, as well as in a tail vein metastatic model. This study implies that the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC, and the SHP-1/p-STAT3/VEGF axis is a potential therapeutic target for metastatic TNBC.
Citation Format: Jung-Chen Su, Hao-Chieh Chiu, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau. Disrupting p-STAT3-mediated VEGF-A paracrine and autocrine feed-forward loops by targeting SHP-1 suppresses triple negative breast cancer cell metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3825.
Abstract 3827: Preclinical characterization of DCR-BCAT as a component of combination therapy
Authors: Ganesh Shanthi , Cyr Wendy , Koser Martin , Chopda Girish , Chipumuro Edmond , Siddiquee Zakir , Craig Kevin , Shui Serena , Chen Dongyu , Lai Cheng , Dudek Hank , Wang Weimin , Brown Bob , Abrams Marc 
Published: July 2016

Abstract
Dicer-substrate siRNAs (DsiRNAs) are a potent class of RNA interference (RNAi) triggers capable of silencing any expressed mRNA with high specificity. DCR-MYC, a first-in-class DsiRNA targeting the MYC oncogene is currently in Phase 1b/II clinical trials [ASCO 2015, abstract 11006]. DCR-BCAT is an advanced preclinical development candidate that targets CTNNB1, the gene which encodes β-catenin. The β-catenin/Wnt pathway is consistently activated in human tumors, including &gt;50% of hepatocellular carcinomas (HCC) and &gt;80% of colorectal cancers (CRC). Robust preclinical and genetic evidence strongly suggests that inhibiting β-catenin function would yield broad therapeutic benefit in oncology, but efforts to target it using conventional drug modalities have been unsuccessful to-date. We have previously reported extensive preclinical pharmacology for DCR-BCAT in mouse tumor models of diverse origin. Here, we explore DCR-BCAT as a monotherapy and in combination with both standard-of-care and experimental therapeutics. Interestingly, when mice bearing HCC tumors were treated with a combination of CTNNB1 and MYC DsiRNAs, the antitumor efficacy was additive or synergistic relative to either single agent alone. Additionally, since up to 50% of colorectal tumors have both activated Wnt signaling and mutant KRAS, we also explored combination therapy of DCR-BCAT and FDA-approved MEK inhibitors. A major advantage of DCR-BCAT is that the improved nanoparticle formulation is more selective for siRNA delivery to tumors over liver and other normal tissues. These data support continued development of DCR-BCAT as a first-in-class RNAi therapeutic, and highlight the potential for use in combination with other promising agents.
Citation Format: Shanthi Ganesh, Wendy Cyr, Martin Koser, Girish Chopda, Edmond Chipumuro, Zakir Siddiquee, Kevin Craig, Serena Shui, Dongyu Chen, Cheng Lai, Hank Dudek, Weimin Wang, Bob Brown, Marc Abrams. Preclinical characterization of DCR-BCAT as a component of combination therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3827.
Abstract 3835: An anti-MET IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth
Authors: Robinson Brett S. , Mandiyan Sreekala , McMahon Gerald , Yang Yan 
Published: July 2016

Abstract
MET gene amplification and exon 14 mutations have been reported and implicated as oncogenic drivers in several types of cancer representing approximately 5-7% of NSCLC, 4-10% of gastric cancer, and 5-10% of colon cancers. Preclinical research and clinical data derived from patients with tumors containing MET gene amplification and exon 14 mutations showed significant growth inhibition and meaningful clinical benefit after treatment with MET-targeting tyrosine kinase inhibitors (TKIs), supporting the hypothesis that MET gene amplification and exon 14 mutations are actionable biomarkers. We have identified several anti-MET monoclonal antibodies that block MET-dependent signaling and tumor growth through: (1) binding to the Sema/PSI domain, (2) preventing HGF interaction with MET and (3) inducing receptor ubiqutination and degradation. One of the anti-MET antibodies, KTN0073, induces potent degradation of oncogenic exon 14 mutant MET, which has been reported to propagate prolonged MET signaling due to a defect in receptor degradation. Our data suggest that KTN0073 engages a pathway different from HGF-induced receptor degradation and protease-mediated shedding, which is independent of the 47 amino acids that are encoded by exon 14 in the intracellular juxtamembrane region and only partially inhibited by the TKI crizotinib. In summary, we report the use of an anti-MET monoclonal antibody to elucidate an exon 14-independent mechanism of MET degradation that could provide a novel way to design anti-MET therapeutics to inhibit growth of human tumors that are driven by HGF, MET amplification and exon 14 mutations. Based on this work, KTN0073-IgG2 anti-MET antibody has been humanized for further preclinical development to explore its potential as a therapeutic for the treatment of human MET expressing cancers.
Citation Format: Brett S. Robinson, Sreekala Mandiyan, Gerald McMahon, Yan Yang. An anti-MET IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3835.
Abstract 3842: Design and engineering of TRAIL fusion proteins for cancer therapy
Authors: Tam Eric M. , Hudson Hannah , Dake Tamara , Ghassemifar Sara , Raue Andreas , Hashambhoy-Ramsay Yasmin , Sazinsky Stephen L. , Daruwalla Anahita , Kohli Neeraj , Xu Lihui , Mc Donagh Charlotte F. , Schoeberl Birgit , Chai Diana H. 
Published: July 2016

Abstract
Protein-based agonists of apoptotic death receptors have shown remarkable preclinical efficacy but limited clinical response. The short circulating half-life of recombinant human TRAIL and the necessity of Fc-mediated clustering for potentiating agonistic antibodies against DR4 and DR5 have been proposed to be major impediments to the clinical success of this class. To address these limitations we have created Fc-scTRAIL, a single fusion polypeptide consisting of an IgG1 Fc region followed by three successive TRAIL monomers connected by two fifteen-amino acid linkers. While Fc-scTRAIL showed potent activity in vitro, we observed a low TM (48 °C) and rapid inactivation in serum indicating protein instability. Subsequently, we applied a directed evolution approach using yeast surface display to identify mutations that would stabilize the TRAIL trimer. When individual mutations were transferred to the Fc-scTRAIL format, we observed a dramatic increase in the TM (66-70 °C) while the combination of three mutations improved serum stability by ten-fold. Stabilized Fc-scTRAIL shows greater pro-apoptotic activity across a panel of cancer cell lines when compared to mapatumumab (anti-DR4) and drozitumab (anti-DR5), or the combination of antibodies even in the presence of anti-Fc cross-linking. Moreover, anti-Fc did not improve Fc-scTRAIL activity suggesting that the hexavalent design of the molecule maximizes death receptor activation. Currently, in vivo evaluation of Fc-scTRAIL for pharmacokinetic properties and activity is underway. We believe this format, when combined with an appropriate patient selection strategy, will result in improved clinical outcomes.
Citation Format: Eric M. Tam, Hannah Hudson, Tamara Dake, Sara Ghassemifar, Andreas Raue, Yasmin Hashambhoy-Ramsay, Stephen L. Sazinsky, Anahita Daruwalla, Neeraj Kohli, Lihui Xu, Charlotte F. Mc Donagh, Birgit Schoeberl, Diana H. Chai. Design and engineering of TRAIL fusion proteins for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3842.
Abstract 3845: A novel selectivity determinant informs the development of next-generation stapled peptide inhibitors of anti-apoptotic BFL-1/A1
Authors: Huhn Annissa J. , Guerra Rachel M. , Bird Gregory H. , Walensky Loren D. 
Published: July 2016

Abstract
The development of selective inhibitors for the individual anti-apoptotic BCL-2 family proteins implicated in oncogenesis and chemoresistance remains a formidable but pressing challenge. Precisely tailored compounds would serve as ideal molecular probes and targeted therapies to respectively study and treat human cancers driven by discrete apoptotic blockades. The remarkable potential of this strategy is exemplified by ABT-199, a potent and selective small molecule BCL-2 inhibitor that is proving effective at reactivating apoptosis in BCL-2-dependent cancers. The BCL-2 protein homologue, BFL-1/A1, has emerged as a resistance factor in a series of human cancers, including melanoma, leukemia, and lymphoma, but remains undrugged. To identify binding and specificity determinants for targeting BFL-1/A1, we screened a library of hydrocarbon-stapled BH3 domain helices and identified a subclass of compounds that engage BFL-1/A1 with exquisite selectivity in vitro and in situ. The mechanistic basis for this specificity revealed a unique topographic feature of the BFL-1/A1 binding groove. Leveraging this natural BFL-1/A1 selectivity factor, we designed next-generation stapled peptide inhibitors that block BFL-1/A1's capacity to both bind BH3 domains and suppress BAX-mediated membrane poration. Our studies inform a new pharmacologic strategy for potent and selective inhibition of anti-apoptotic BFL-1/A1 in human cancer.
Citation Format: Annissa J. Huhn, Rachel M. Guerra, Gregory H. Bird, Loren D. Walensky. A novel selectivity determinant informs the development of next-generation stapled peptide inhibitors of anti-apoptotic BFL-1/A1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3845.
Abstract 3856: The atomic basis for paclitaxel sensitization following loss of CRMP2 phosphorylation in ovarian cancer cells
Authors: Zheng Yiyan , Sethi Ritika , von Delft Frank , Ahmed Ahmed Ashour 
Published: July 2016

Abstract
The chemotherapeutic agent paclitaxel increases cancer cell microtubule stability, induces mitotic arrest and cancer cell death and improves survival of cancer patients. However, in ovarian and other cancers, it only elicits a response in less than half of patients who receive it. We have previously shown that enhancing microtubule stability in cells prior to paclitaxel treatment, further increases paclitaxel-induced microtubule stability and cancer cell death (Ahmed et al., Cancer Cell, 2007;12:514 and Ahmed et al., Cancer Research 2011;71:5806). We now report that the microtubule-associated protein CRMP2, and FER kinase are expressed in almost half of high-grade serous ovarian cancers and that inhibiting the phosphorylation of CRMP2 by FER is sufficient for enhancing paclitaxel-induced microtubule stability and cytotoxicity in multiple ovarian cancer cell lines.
We are also able propose a detailed mechanism underlying these observations. A combination of biochemistry, super-resolution fluorescence microscopy, total internal reflection fluorescence (TIRF) microscopy and electron microscopy reveals that CRMP2 induces microtubule nucleation, elongation, bundling and stability. Moreover, FER phosphorylates CRMP2 at 6 tyrosine residues, two of which (Tyr479 and Tyr499) are critical for modulating CRMP2 function; this agrees with site-directed mutagenesis in cancer cells which points to Tyr479 as a critical site for association between CRMP2 and microtubules. A comparison of the crystal structures of wild-type CRMP2 and Tyr479Glu/Tyr499Glu phosphomimetic mutants indicate that phosphorylation of these sites induces significant conformational changes that prevent CRMP2 from forming tetramers that are known to be critical for its microtubule bundling activity.
This then leads us to propose a molecular model of how CRMP2 associates with microtubules, explaining how targeting CRMP2 phosphorylation can be exploited for enhancing the therapeutic efficacy of paclitaxel.
Citation Format: Yiyan Zheng, Ritika Sethi, Frank von Delft, Ahmed Ashour Ahmed. The atomic basis for paclitaxel sensitization following loss of CRMP2 phosphorylation in ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3856.
Abstract 3864: The Jak1/2 inhibitor AZD1480 suppresses tumor growth and metastasis in genetically engineered mouse models of PTEN-deficient prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Oki Takashi , Yoshimura Kazuhiro , Nozawa Masahiro , Davies Barry R. , Huszdar Dennis , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: July 2016

Abstract
Activation of signal transducer and activator of transcription (STAT) 3 via the interleukin 6 (IL-6)/IL-6R/Janus kinase (JAK) signaling axis is a feature common in patients with advanced human prostate cancer and has been associated with poor prognosis. STAT3 can promote CRPC growth by activating the androgen receptor signaling pathway. It can also promote survival by modulating tumor cell proliferation, epithelial to mesenchymal transition, angiogenesis and immune response. However, recent preclinical data suggests that STAT3 may also act as a tumor suppressor in PTEN-deficient prostate cancer. In this study, we investigated the effectiveness of AZD1480, a potent JAK1/2 inhibitor, in genetically engineered mouse models of prostate cancer driven by the loss of PTEN and PTEN/P53. In vivo pharmacodynamic studies using conditional PTEN-deficient mice demonstrated that AZD1480 strongly inhibited STAT3 phosphorylation. Moreover, AZD1480 monotherapy in PTEN-deficient mice harboring castration-naïve or castration-resistant prostate tumors resulted in tumor growth reductions of 24.8%, P&lt;0.001 and 15.8%, P&lt;0.001, respectively, compared to vehicle treated control mice. Mice treated with AZD1480 also exhibited reduced levels of tumor cell proliferation and microvessel density, and increased apoptosis compared to controls. Clinically relevant outcomes were evaluated in a late-stage model of prostate cancer driven by the conditional inactivation of PTEN and P53. In this model, PTEN/P53 double knockout mice with established tumors were randomized to vehicle or AZD1480 treatment groups. Mice treated with AZD1480 demonstrated a modest but statistically significant improvement in overall survival compared to control mice, median time 20 days vs. 27 days, P = 0.03, respectively. Additionally, the metastatic tumor incidence decreased from 46.6% (7/15) in control mice to 20% (3/15) in AZD1480-treated mice. Our findings provide preclinical evidence supporting the potential use of Jak1/2 inhibitors for the targeted therapy of human prostate cancer.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Barry R. Davies, Dennis Huszdar, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. The Jak1/2 inhibitor AZD1480 suppresses tumor growth and metastasis in genetically engineered mouse models of PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3864.
Abstract 3897: A novel c-Met targeting antibody drug conjugate for NSCLC
Authors: Li Lingna , Fells Cathrine , Guo Julia , Muyot Pia , Gros Edwige , Zhang Yanliang , Sun Yingqing , Zhang Hong , Fu Yanwen , Zhu Tong , Cao Jian , Kaufmann Gunnar , Chen Gang , Miao Zhenwei 
Published: July 2016

Abstract
c-Met, the proto-oncogene transmembrane receptor tyrosine kinase, is involved in cell proliferation, survival, motility, and invasion in normal and tumor cells. It is widely expressed and associated with poor prognosis in breast, lung, liver, kidney and brain cancers. Hepatocyte growth factor (HGF) is the only known ligand of c-Met, also found in many tumors and cancers where activity is driven by the c-Met receptor. c-Met is accepted as an attractive anti-cancer target, but the development of cancer therapy targeting c-Met receptor or kinase remain very challenging. Clinical development of c-Met/HGF targeting antibodies has shown initial evidence of clinical efficacy but failed in phase III. Small molecule inhibitors often suffer from selectivity issues. Antibody drug conjugates (ADCs) which combine an antibody with highly potent cytotoxic agents, becomes an attractive approach against c-Met overexpressing cancers such NSCLC. We have identified an anti-c-Met antibody STI-0602 and generated ADCs from a panel of cytotoxic agents such as microtubulin inhibitor and DNA damaging agents. ADCs retained the binding to c-Met receptor and showed potent cell killing in a variety of c-Met-positive cell lines. ADCs also showed in vivo efficacy in a panel of c-Met-positive human NSCLC xenograft models like A549, H292, EBC-1, HCC827 and H1993, which suggest a potential therapy for c-Met overexpressing lung cancer and other cancers.
Citation Format: Lingna Li, Cathrine Fells, Julia Guo, Pia Muyot, Edwige Gros, Yanliang Zhang, Yingqing Sun, Hong Zhang, Yanwen Fu, Tong Zhu, Jian Cao, Gunnar Kaufmann, Gang Chen, Zhenwei Miao. A novel c-Met targeting antibody drug conjugate for NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3897.
Abstract 3904: Overcoming resistance to HER2 inhibitors through cell based screening
Authors: Novotny Chris J. , Pollari Sirkku , Park Jin H. , Lemmon Mark A. , Schultz Peter G. , Shen Weijun , Shokat Kevan M. 
Published: July 2016

Abstract
Signaling from the human epidermal growth factor receptor (HER) family of proteins is dependent on a well-orchestrated series of interactions between family members to form either homo- or heterodimers. The heterodimeric complex formed by HER2 and HER3 is a particularly potent oncogenic signaling unit that can act as a driver of cancer growth and has also been shown to rescue a large number of cancers from a variety of targeted agents. The currently available therapies targeting HER2, such as Lapatinib or ado-trastuzumab emtansine, have dramatically improved patient outcomes in the clinic but preferentially target the protein in its monomeric state. Because of this, increasing the concentration of the HER2/HER3 heterodimer, either by growth factors or increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes their activity. In order to find a next generation inhibitor of the active HER2/HER3 oncogenic complex we screened 1 million small molecules against an engineered Ba/F3 cell line dependent on ligand stimulated HER2/HER3 signaling for survival. The removal of non-selective inhibitors using alternative Ba/F3 cell lines resulted in the identification of a single core scaffold hit. A medicinal chemistry campaign enabled by a co-crystal structure of a hit compound complexed to EGFR led to the development of a molecule capable of inhibiting the active state of HER2. As a result, this next generation HER2 inhibitor is capable of inhibiting growth factor stimulated HER2/HER3 heterodimers and mutationally activated forms of HER2, which are resistant to current clinical small molecule HER2 inhibitors.
Citation Format: Chris J. Novotny, Sirkku Pollari, Jin H. Park, Mark A. Lemmon, Peter G. Schultz, Weijun Shen, Kevan M. Shokat. Overcoming resistance to HER2 inhibitors through cell based screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3904.