bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1765: A humanized anti-CD47 monoclonal antibody that directly kills human tumor cells and has additional unique functional characteristics
Authors: Puro Robyn , Liu Katherine , Capoccia Benjamin , Donio Michael , Hiebsch Ronald , Bouchlaka Myriam , Carter Alun , Manning Pamela , Crowley Kathleen , Karr Robert 
Published: August 2018

Abstract
CD47 is a cell surface glycoprotein that interacts with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggering a “don't eat me” signal that inhibits phagocytosis. Many tumors evade immune surveillance by overexpressing CD47, thereby preventing their recognition by phagocytes. Blocking the interaction of SIRPα/CD47 promotes phagocytosis and tumor cell destruction leading to a reduction in tumor burden.
We have developed a humanized anti-CD47 antibody, AO-176, that blocks the interaction between CD47 and SIRPα and exhibits several additional novel functional characteristics. These characteristics include the induction of cell death in multiple human tumor cell lines in a cell autonomous manner (not ADCC), assessed by an increase in phosphatidylserine/7AAD positive staining. A second novel characteristic is enhanced binding to tumor cells at acidic pH. AO-176 binds to human tumor cell lines in the high pM to low nM range at physiologic pH, however, binding is enhanced up to 20-fold at an acidic pH of 6.5. The acidic pH of the tumor microenvironment which ranges from 6.4-7.2 is characteristic of solid tumors and correlates with tumor progression and metastasis. As a result of this enhanced binding at acidic pH, AO-176 has the potential added advantage of tumor-specific targeting. A third novel characteristic exhibited by AO-176 is its selective binding to tumor cells while exhibiting reduced binding to normal cells including red blood cells (cynomolgus monkey and human), endothelial, epithelial and skeletal muscle cells. In addition to these novel characteristics, AO-176 also exhibits dose-dependent efficacy in multiple mouse tumor models.
Taken together, the unique combination of functional characteristics of AO-176, including induction of cell-autonomous killing, enhanced binding to tumor cells at acidic pH, significantly reduced binding to normal cells and potent in vivo efficacy provides the preclinical rationale for further development.
Citation Format: Robyn Puro, Katherine Liu, Benjamin Capoccia, Michael Donio, Ronald Hiebsch, Myriam Bouchlaka, Alun Carter, Pamela Manning, Kathleen Crowley, Robert Karr. A humanized anti-CD47 monoclonal antibody that directly kills human tumor cells and has additional unique functional characteristics [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 1765.
Abstract 1769: Antibody blockade of IL1RAP signaling reduces metastasis in a breast cancer model
Authors: Liberg David , Önnervik Per-Ola , Riva Matteo , Larsson Liselotte , Forsberg Göran , Wachenfeldt Karin von 
Published: August 2018

Abstract
Blockade of tumor inflammation has potential for cancer therapy, both as a primary mechanism to counter tumor growth but also in combination with other therapeutics. IL-1 signaling has been shown preclinically to be involved in tumor development and chemoresistance of pancreatic cancer, and blockade of IL-1 was recently shown to have a significant clinical impact on development of lung cancer. IL-1 receptor associated protein (IL1RAP) is a coreceptor for the IL-1 receptor (IL1R1) and is required for IL-1 signaling. IL1RAP is expressed in a number of tumor tissues, including lung and pancreatic cancer, both on tumor cells and on infiltrating immune cells. We have, using antibodies directed against IL1RAP, shown the ability to target and kill IL1RAP-expressing tumor cells by ADCC, to inhibit IL-1 signaling in those cells and to reduce growth of transplanted human tumors in vivo. To study effects of IL1RAP targeting on the tumor microenvironment and in an immune competent setting, an antibody towards mouse IL1RAP was generated. This antibody potently blocks mouse IL-1 (IC50 = 13 nM), binds to IL1RAP protein with high affinity (Kd = 4,2 nM), labels IL1RAP-expressing cells and can be administered to mice with good pharmacokinetics. In vivo imaging shows that the antibody is not generally distributed in tissues but localizes to tumor sites after injection. Treatment of mice with orthotopically implanted 4T1 breast cancer cells did not reduce primary tumor growth significantly but reduced both the number of (47% reduction, p=0.02) and size of lung metastases. Interestingly, 4T1 tumor cells express low levels of IL1RAP and are not responsive to IL1RAP blockade, but the effects instead relate to effects on the tumor microenvironment. We conclude that targeting of IL1RAP can, in addition to induce ADCC of tumor cells and block their response to IL-1, also inhibit metastasis by affecting the tumor microenvironment.
Citation Format: David Liberg, Per-Ola Önnervik, Matteo Riva, Liselotte Larsson, Göran Forsberg, Karin von Wachenfeldt. Antibody blockade of IL1RAP signaling reduces metastasis in a breast cancer model [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 1769.
Abstract 1796: Repurposing CRISPR to study aberrant AR signaling in models of castration-resistant prostate cancer
Authors: Kounatidou Evangelia E. , Robson Craig , Gaughan Luke 
Published: August 2018

Abstract
Prostate cancer (PC) is currently the most commonly diagnosed noncutaneous cancer affecting men worldwide. Despite the initial response to androgen ablation, patients relapse with tumors becoming refractory to clinically approved anti-androgens, resulting invariably in castration-resistant PC (CRPC). In CRPC, androgen receptor (AR) signaling is inappropriately restored. Resistance to available hormone therapies in PC has been linked to aberrant splicing of nascent AR transcripts and subsequent expression of constitutively active AR splice variants. Although we have information on the expression of receptor variants in advanced disease, the mechanisms that regulate these aberrantly functioning proteins are markedly understudied. Therefore, a better understanding of how splice variants are generated and function in this disease setting is critical for the development of more refined targeted therapies. By modeling clinically relevant AR splice variants, we will identify and exploit mechanisms of receptor regulation for advanced prostate cancer therapy. The CRISPR-Cas9 technology has been exploited to generate a CWR22Rv1 derivative cell line that lacks AR-FL and hence only expresses AR-Vs. This has allowed us to study the function of AR-Vs in an AR-FL-free background and therefore attribute the observed outcomes exclusively to AR splice variants. In addition, a novel CRISPR-based approach, currently developed in our lab, allows selective targeting of a catalytically inactive form of Cas9 (dead Cas9, dCas9) fused to a FLAG tag, to native chromatin regions and subsequent isolation of protein/RNA complexes associated with these sites. We have taken advantage of spatial mRNA splicing and transcription coupling in order to isolate splicing factors responsible for the generation of the AR variant 7 (AR-V7) in the CWR22Rv1 cell line and its AR-FL CRISPR knockout derivative. Three gRNAs were designed against the AR cryptic exon 3 genomic region. Targeting of FLAG-tagged dCas9 to that site was exploited for in situ capture and isolation of endogenous splicing factors specific to AR-V7, upon rapid FLAG immunoprecipitation and characterization by mass spectrometry. Identification of the AR-V7 spliceosome will fill a critical knowledge gap in our understanding of how AR-Vs are generated and provide key targets for future therapeutic intervention in advanced PC patients.
Citation Format: Evangelia E. Kounatidou, Craig Robson, Luke Gaughan. Repurposing CRISPR to study aberrant AR signaling in models of castration-resistant prostate 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 1796.
Abstract 1849: Determining the molecular requirements for paclitaxel-induced spindle multipolarity
Authors: Scribano Christina 
Published: August 2018

Abstract
Paclitaxel (TaxolTM) and other microtubule poisons are standard chemotherapy agents used in the treatment of breast cancer. However, only a subset of patients experience positive therapeutic effects from these drugs, underscoring the importance of further mechanistic study. Recently we showed that paclitaxel does not accumulate in primary breast cancers at sufficient concentrations to cause mitotic arrest, as it does at typically used concentrations in cell culture. Instead, paclitaxel therapy induces multipolar spindles in breast cancers. Breast cancer cell lines treated with low nanomolar, clinically relevant doses of paclitaxel exhibit chromosome missegregation due to multipolar divisions. We have now extended this to demonstrate that low nanomolar concentrations of other clinically used microtubule poisons (including ixabepilone, vinorelbine, and eribulin) also induce multipolarity in breast cancer cells, suggesting that multipolar mitotic divisions may be a common mechanism of cytotoxicity for microtubule-targeted drugs. Importantly, supernumerary centrosomes are not required for microtubule poison-induced multipolar spindles. To gain mechanistic insight into the formation of paclitaxel-induced multipolar spindles, a variety of mitotic regulators were tested for their ability to affect spindle multipolarity in breast cancer cells treated with clinically relevant concentrations of paclitaxel. Our results demonstrate that the mitotic kinesin Eg5 and the kinase Plk1 promote both the formation and the maintenance of paclitaxel-induced spindle multipolarity, while the mitotic kinesin CENP-E and the kinase Mps1 do not. Interestingly, we found that decreasing the time to anaphase onset decreases the number of multipolar divisions in paclitaxel, resulting in reduced cytotoxicity. Previous studies have shown that Mps1 inhibition sensitizes cells to paclitaxel, and this combination therapy has entered clinical trials (NCT02138812 and NCT02366949). However, our evidence suggests that Mps1 inhibition reduces the efficacy of paclitaxel as a result of decreased time to anaphase onset and fewer multipolar divisions. Additionally, our results suggest that inhibitors of spindle pole clustering increase the number of paclitaxel-induced multipolar divisions and therefore have the potential to increase its efficacy. Identification of the cellular requirements for multipolarity induced by paclitaxel, and of agents that drive the metaphase-to-anaphase transition in the presence of multipolar spindles, may improve the clinical utility of paclitaxel and other microtubule poisons.
Citation Format: Christina Scribano. Determining the molecular requirements for paclitaxel-induced spindle multipolarity [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 1849.
Abstract 1857: Hydrophilic As4S4 nanoparticles inhibit K562 cell activity through ROS modulation and autophagy induction
Authors: Wang Tao , Wen Tao , Meng Jie , Liu Jian , Xu Haiyan 
Published: August 2018

Abstract
Realgar is crystalized As4S4 that has been demonstrated to be effective in treating hematologic malignancies by oral administration [1]. Nevertheless, the low bioavailability due to its poor solubility in neutral or acidic aqueous solution not only leads to the over dose administration of arsenic in clinical practice but also hinders the study of pharmaceutical mechanism for realgar. We previously reported a solid dispersion of realgar (e-As4S4), in which the crystal realgar (r-As4S4) was fabricated into nanoparticles encapsulated by the hydrophilic polymer using the hot melting co-extrusion technique [2]. The e-As4S4 exhibited much higher bioavailability and improved treatment efficacy in the acute myeloid leukemia (AML) animal model compared with r-As4S4.
This study investigated the effect of e-As4S4 has inhibitory on K562 cells and the underlying mechanisms. We showed that e-As4S4 down regulated the cellular ROS and HIF1-alpha in a concentration dependent manner. The low concentration of e-As4S4 induced both erythroid and megakaryocytic differentiation in the cells, evidenced by the up-regulation of CD235a and CD41 respectively, and the higher concentration induced cell cycle arrested in G2/M phase and apoptosis. Consistently, the proliferation rate and oxygen-consuming rate of the cells were reduced. Meanwhile the autophagy was detected when the cells were treated with e-As4S4, as well as the variation phosphorylation for p38 and Erk. These effects together induced the significant elimination of Bcr-Abl. In conclusion, e-As4S4 induced the bi-direction differentiation by modulating cellular ROS and inducing autophagy of the cells. These results therefore suggest that e-As4S4 represents a promising orally administrated drug for the treatment of CML.
Reference
1. Zhu HH et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013; 31:4215-21.
2. Ma Q et al. Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice. Sci Rep. 2016; 6: 29348.
Acknowledgement This work was supported by National Key R&D Program of China (2017YFA0205504) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-3-004).
Citation Format: Tao Wang, Tao Wen, Jie Meng, Jian Liu, Haiyan Xu. Hydrophilic As4S4 nanoparticles inhibit K562 cell activity through ROS modulation and autophagy induction [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 1857.
Abstract 1862: CX5461 in combination with radiotherapy I effective against gynecological tumors
Authors: Ismael Mohammed , Webb Roger , Ajaz Mazhur , Coley Helen 
Published: August 2018

Abstract
An increased rate of cellular proliferation is a hallmark of cancer and may be accompanied by increase in ribosome biogenesis and dysregulation in rRNA synthesis. In this regard CX-5461 has been developed as a novel RNA POL1 inhibitor and is currently in Phase I/II clinical trials. We have set out to explore the use of this agent in combination with radiation therapy and to understand the associated molecular mechanisms using this approach. A panel of human tumour cell lines treated with CX-5461 indicated a broad spectrum of sensitivity (MTT assay) with IC50 values varying from 25nM - &gt;2µM. No clear relationship between p53 status and sensitivity to CX-5461 was indicated and the mode of cell death was cell context dependent - either via autophagy (LC3I→ LC3II conversion, with P62 sequestosome decrease), sometimes via apoptosis (annexinV staining, caspase-3 activation), also in the presence of increased senescence (β-galactosidase activity). Combination treatment experiments involving CX-5461 alongside radiation therapy (0-16Gy) showed marked synergistic effects for some cancer cell lines, particularly the cervical cancer CASKI line (HPV16+ve). Highly significant effects were seen when low dose radiation and low dose CX-5461 were used together in CASKI cells: combination index CI=&lt; 0.2 with 6nM CX-5461 and 2Gy (isobologram analysis). Cell cycle analysis of CASKI cells treated in combination indicated cell cycle disruption with prolonged S-phase, giving some insight into some of the associated mechanisms involved. In addition, we have found that BRCA-mutant PEO1 ovarian cancer cells were sensitive to CX-5461, IC50 approx. 100nM, whereas carboplatin-resistant PEO1CarbR (with reversed BRCA mutant status) cells gave an IC50 value &gt;3µM In addition, proteomic studies have shown that PEO1CarbR cells overexpress a number of nucleolar proteins and we are investigating the relevance of this in relation to CX-5461 sensitivity. Our further studies aim to identify potential biomarkers of response to CX-5461 and may also inform the design of clinical trials of this novel agent.
Citation Format: Mohammed Ismael, Roger Webb, Mazhur Ajaz, Helen Coley. CX5461 in combination with radiotherapy I effective against gynecological 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 1862.
Abstract 1869: Role of Nef secretion modification region (SMR) peptides and the chaperone mortalin in breast cancer and leukemia cells
Authors: Huang Ming B. , Bond Vinvent C. 
Published: August 2018

Abstract
BACKGROUND: Mortalin/GRP-75(mt-hsp70, HSPA9) is a mitochondrial chaperone protein, also
found in the cytoplasm, endoplasmic reticulum and cytoplasmic vesicles. It functions in many
cellular processes such as mitochondrial biogenesis, intracellular trafficking, cell proliferation,
signaling, immortalization and tumorigenesis, Thus, inhibition of mortalin is a promising avenue
for cancer therapy. Previous studies in our lab have suggested that mortalin contributes to breast
cancer development and progression. We showed tumor exosome secretion was decreased by
knockdown of mortalin expression using HIV-1 Nef peptides. Specifically, these peptides can
block exosome secretion and also mediate cell cycle arrest in MDA-MB-231 and MCF-7 breast
cancer cells.
AIMS: This study aims to investigate further the function and mechanism of interaction of PEG-
SMR-CLU peptide and SMR-CPP peptide, and chaperone mortalin and to explore the effect of
SMR-derived peptides and mortalin on human breast cancer and leukemia cell lines.
RESULTS: Our results demonstrate that the modified SMRwt peptides not only affect breast
cancer cell proliferation and arrest breast cancer cell growth, but they also inhibit migration of
breast cancer cells. SMRwt peptides also block exosome-mediated release of complement, and
allow the cells to die via complement induced cell death, and reduced mortalin protein expression.
We further determined that expression levels of the mesenchymal markers vimentin (VIM) was
decreased in presence of SMRwt peptides and MKT-077.
CONCLUSIONS: Mortalin may promote cell proliferation and invasion via induction of epithelial
mesenchymal transition (EMT) of cancer cells, which has a potential therapeutic target in cancer
immunotherapy. SMRwt peptides block tumor exosome release and reduce the expression of
mortalin. This may be a means to decreases breast cancer cell invasion and metastasis, which
may have important clinical applications for late stage breast cancer chemotherapy. Furthermore,
SMRwt peptides and inhibition of mortalin suppressed the migration and invasive capacity of
cancer cells and is associated with a diminished EMT. These findings support a role for SMR
peptide and mortalin in the induction of EMT, prompting a further investigation into their
therapeutic value in cancer metastasis.
Citation Format: Ming B. Huang, Vinvent C. Bond. Role of Nef secretion modification region (SMR) peptides and the chaperone mortalin in breast cancer and leukemia cells [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 1869.
Abstract 1878: Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib
Authors: Hasinoff Brian B. 
Published: August 2018

Abstract
Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Bortezomib, carfilzomib, and ixazomib, which are approved for clinical use, have shown some cardiotoxicity. Carfilzomib and oprozomib are epoxyketones that form an irreversible bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. A primary neonatal rat myocyte model was used to study these cardiotoxic mechanisms. Using LDH release as a measure of damage in the myocyte model, after drug treatments of either 1, 4 and 72 hr all these drugs induced myocyte damage at low- to sub-micromolar concentrations. Oprozomib induced significantly less myocyte damage than any of the other drugs. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome were also determined in order to see if differences in the binding kinetics could explain the degree of myocyte damage. Oprozomib inhibited the 20S proteasome with a second-order binding “on” rate constant that was 60-fold slower than for ixazomib, the fastest binding drug. The first-order dissociation “off” rate constants for the three boronic acids were also determined. Delanzomib dissociated from its complex with the 20S proteasome with a half-time that was more than 20-fold slower than for ixazomib, the fastest dissociating drug. In conclusion, while all these drugs were potently toxic to myocytes at submicromolar concentrations, oprozomib was considerably less toxic than any of the other drugs. As a group the boronic acid drugs were not significantly more toxic than the epoxyketone drugs. The dissociation half-times of the boronic acid complexes were also not correlated with myocyte damage. The fact that oprozomib bound to the 20S proteasome more slowly than any of the other drugs may be the reason, in part, that it is less toxic. Support: CIHR; a Canada Research Chair in Drug Development.
Citation Format: Brian B. Hasinoff. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib [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 1878.