bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5931: Effect of necrosis on the migration, invasion and miRNA-mRNA association in glioblastoma cells
Authors: Ahn So-Hee , Park Hyunju , Kim Jeong Seon , Ahn Young-Ho , Kim Sewha , Cho Min-Sun , Kang Jihee Lee , Choi Youn-Hee 
Published: July 2017

Abstract
Grade IV astrocytoma, also called glioblastoma multiforme (GBM), is considered the most malignant glial tumor. The purpose of our study is to understand the molecular mechanisms underlying the signaling network between necrotic tissues and GBM cells by exploring the effect of necrosis on GBM migration, invasion and miRNA-mRNA association. The migration and invasion of the CRT-MG human astroglioma cells were significantly enhanced by treatment with necrotic cells, as shown by assays for scratch wound healing and spheroid invasion. Incubation with necrotic cells induced IL-8 secretion in CRT-MG in dose-dependent manner. Immunohistochemical and immunoflurorescence analysis for IL-8 in human GBM tissues showed that positively stained cells were mainly distributed in perinecrotic region. Necrotic cells induced NF-κB and AP-1 activation and their DNA binding to IL-8 promoter, leading to enhanced IL-8 production and secretion in GBM cells. To determine the effect of necrosis on the miRNA profiles and regulatory relationship, the expression profiles of miRNA and mRNA and association between mRNA and their corresponding miRNAs were analyzed by next-generation sequencing (NGS). Our results demonstrate that necrotic cells enhance the migration and invasion of GBM cells through NF-κB/AP-1/IL-8 signaling pathway and induce dysregulation of miRNA and mRNA expression profiles in GBM cells.
Citation Format: So-Hee Ahn, Hyunju Park, Jeong Seon Kim, Young-Ho Ahn, Sewha Kim, Min-Sun Cho, Jihee Lee Kang, Youn-Hee Choi. Effect of necrosis on the migration, invasion and miRNA-mRNA association in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5931. doi:10.1158/1538-7445.AM2017-5931
Abstract 5933: Cancer-associated fibroblasts (CAFs) release exosomal microRNAs that dictate an aggressive phenotype in breast cancer
Authors: Condorelli Gerolama , Donnarumma Elvira , Fiore Danilo , Nappa Martina , Roscigno Giuseppina , Adamo Assunta , Iaboni Margherita , Russo Valentina , Affinito Alessandra , Quintavalle Cristina , Rienzo Anna , Piscuoglio Salvatore , Thomas Renato 
Published: July 2017

Abstract
Cancer-associated fibroblasts (CAFs), the major components of the tumor microenvironment may drive tumor progression. Exosomes mediate horizontal transfer of miRs, mRNAs and proteins, thus affecting breast cancer progression. Differential expression profile analysis identified three miRs increased in exosomes from CAFs as compared from normal fibroblasts. Immunofluorescence indicated that exosomes may be transferred from CAFs to breast cancer cells, releasing their cargo miRs. Breast cancer cells exposed to CAF exosomes or transfected with those miRs exhibited a significant increased capacity to form mammospheres, increased stem cell and epithelial-mesenchymal transition (EMT) markers, and anchorage-independent cell growth. These effects were reverted by transfection with anti-miRs. Similarly to CAF exosomes, normal fibroblast exosomes transfected with CAFs-miRs promoted the stemness and EMT phenotype of breast cancer cells. Thus, we provided evidence of the role of CAF exosomes and their miRs in the induction of the stemness and EMT phenotype in different breast cancer cell lines.
Note: This abstract was not presented at the meeting.
Citation Format: Gerolama Condorelli, Elvira Donnarumma, Danilo Fiore, Martina Nappa, Giuseppina Roscigno, Assunta Adamo, Margherita Iaboni, Valentina Russo, Alessandra Affinito, Cristina Quintavalle, Anna Rienzo, Salvatore Piscuoglio, Renato Thomas. Cancer-associated fibroblasts (CAFs) release exosomal microRNAs that dictate an aggressive phenotype in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5933. doi:10.1158/1538-7445.AM2017-5933
Abstract 5943: Role of tissue stiffness and oxygen tension in promoting breast cancer stem cells
Authors: Pang Mei-Fong , Radisky Derek C. , Nelson Celeste M. 
Published: July 2017

Abstract
Breast tumors are stiff and hypoxic. Nevertheless, it remains unclear how stiff and hypoxic conditions within the tumor microenvironment promote breast cancer progression. Using an innovative engineered culture model to recapitulate these features, we found that, under stiff and hypoxic conditions, breast cancer cells have enhanced integrin-linked kinase (ILK) expression and acquire cancer stem cell (CSC)-like traits, suggesting tissue stiffness and oxygen tension can modulate ILK expression to induce breast CSC formation. Knocking down ILK impairs the mechanosensing of invasive breast cancer cells on stiff microenvironments, inhibits CSC markers and properties. In contrast, ectopic expression of ILK promotes breast CSC formation. In addition to promoting CSC-like phenotype, microarray analysis reveals that stiff and hypoxic microenvironments also regulate genes involved in mRNA processing, splicing and the spliceosome. These data suggest that the non-cellular compartment of the tumor microenvironment, namely tissue mechanics and oxygen tension, can promote breast cancer progression by controlling mechanotransduction and post-transcriptional regulation of breast cancer cells.
Note: This abstract was not presented at the meeting.
Citation Format: Mei-Fong Pang, Derek C. Radisky, Celeste M. Nelson. Role of tissue stiffness and oxygen tension in promoting breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5943. doi:10.1158/1538-7445.AM2017-5943
Abstract 5944: Matrilysin/MMP-7 compromises a novel border interaction between perlecan/HSPG2 and semaphorin 3A to support prostate cancer invasion
Authors: Grindel Brian J. , Harrington Daniel A. , Chung Leland , Farach-Carson Mary C. 
Published: July 2017

Abstract
Prostate cancer (PCa) cells interact with the stroma and extracellular matrix (ECM) during tumor expansion and invasion during metastasis. Dissecting the complex matrix-cancer interplay is essential to halting tumor progression. A vital component of the ECM is perlecan/heparan sulfate proteoglycan 2 (HSPG2). As a large extracellular proteoglycan, perlecan helps orchestrate tumor angiogenesis, proliferation, differentiation and invasion. Actively metastasizing cancer cells must proteolytically degrade several tissue borders which perlecan patrols, including the basement membrane, vasculature, reactive stromal matrix and bone marrow. Investigating the effects of perlecan on metastatic PCa cells showed full length perlecan and specifically conserved domain IV of perlecan triggers clustering of PCa cells. Perlecan cleavage by the pro-tumor protease matrilysin/matrix metalloproteinase (MMP-7) reverses this, favoring cell dispersion and tumor dyscohesion. Network analysis of a reverse phase protein array and subsequent western blots revealed clustered cells on intact perlecan/Dm IV induced a strong focal adhesion kinase (FAK) dephosphorylation/deactivation. Alternatively, FAK was highly phosphorylated/activated on MMP-7 cleaved perlecan/Dm IV consistent with an adhesive and dispersive/metastatic phenotype. Several lines of evidence indicate Dm IV interacts with the classically known axon guidance protein semaphorin 3A (Sema3A), to shut off pro-metastatic FAK activation. Notably, a C-terminus directed Sema3A antibody mimics the clustering activity of Dm IV. We showed Dm IV binds to Sema3A in ELISA and quartz crystal microbalance experiments and the interaction is abrogated by the Sema3A antibody. Interestingly, Sema3A also is sensitive to MMP-7 proteolytic activity. Finally, transient knockdown of Sema3A in PCa cells inhibits the clustering effect by a Dm IV substrate. This work shows that perlecan is an effective border molecule because it coordinates with Sema3A to repulse and cluster cells by switching off FAK activity. However, PCa cells expressing active MMPs, such as MMP-7, can destroy this Sema3A/perlecan complex to develop an invasive, metastatic phenotype associated with lethal disease.
Citation Format: Brian J. Grindel, Daniel A. Harrington, Leland Chung, Mary C. Farach-Carson. Matrilysin/MMP-7 compromises a novel border interaction between perlecan/HSPG2 and semaphorin 3A to support prostate cancer invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5944. doi:10.1158/1538-7445.AM2017-5944
Abstract 607: PDL1 expression associated with triple negative breast ductal carcinomas in African American women
Authors: Khan Farhan , Kanaan Yasmine , Ricks-Santi Luisel J. , Zafar Rabia , Aymut Hagos , Naab Tammey 
Published: July 2017

Abstract
Background: Tumor cells avoid host immune response through expression of inhibitory T cell regulator,
Programmed cell death ligand (PDL1).Our objective was to evaluate PDL1
expression by immunohistochemistry in the four major subtypes of breast
carcinoma (Luminal A, Luminal B, HER2, and Triple Negative) in a population of
202 African-American (AA) women with other clinicopathological factors.
Design: Tissue microarrays
(TMAs) were constructed from FFPE tumor blocks from primary ductal breast
carcinomas in 202 African-American females.
Two separate 1 mm cores represented each case. Five micrometer sections were stained with rabbit
monoclonal antibody against PDL1.
The sections were evaluated for the percentage and intensity of membrane
staining in both tumor and immune cells. Cut off was &gt; 1%. Bivariate
analysis was done via χ2 analysis and survivability data was calculated via the
generation of Kaplan-Meier curves (SPSS v19). Statistical significance was
assumed if p &lt; 0.05.
Results: PDL1 expression in
only tumor cells, only immune cells and in combination was associated with ER negative
(p&lt;0.0001), PR negative (p&lt;0.0001), Triple negative subtype (p&lt;0.0001)
and high grade (p&lt;0.0001) breast ductal cancers.
Conclusion: Our study finding of selective expression of PDL1 in triple negative breast ductal cancers (TNBC) in AA women suggests that inhibition of adaptive immune response is involved in the progression of these cancers. PDL1/PD1 is the inhibitory check point of immune response resulting in decreased T cell activation and cytokine production. Some studies have shown that PDL1 expression is associated with loss of PTEN and phosphatide inositol 3 kinase pathway (PI3K) activation. Our previous study showed loss of PTEN in TNBC. Combining PDL1 inhibitors with PI3K inhibitors may be useful therapy for aggressive TNBC.
Citation Format: Farhan Khan, Yasmine Kanaan, Luisel J. Ricks-Santi, Rabia Zafar, Hagos Aymut, Tammey Naab. PDL1 expression associated with triple negative breast ductal carcinomas in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 607. doi:10.1158/1538-7445.AM2017-607
Abstract 608: Augmenting and broadening T cell responses against mutated tumour neo-antigens
Authors: Robinson Bruce W. , Ma Shaokang , Chee Jonathan , Rive Craig , Miert Paula Van , Holt Rob A. , Creaney Jenette 
Published: July 2017

Abstract
Cytotoxic T lymphocytes (CTLs) recognize mutated tumor proteins (neo-antigens) and are important for anti-tumor immunity, especially in the context of immune checkpoint blockade immunotherapy (ICPB). Positive outcomes to ICPB are associated with high neo-antigen loads and with neo-antigen specific CTL responses. However only around 20% of patients respond to ICPB.
In order to examine ways in which the non-responders might become responders we examined several strategies to improve response rates, using anti-CTLA4 initially as the ICPB therapy in BALB/c mice in which Uqcrc2 has been defined as a DNA/RNAseq-identified neo-antigen in AB1 tumor lines induced by a relevant human carcinogen(1).
a) We first examined therapy-induced changes in T-cell responses against Uqcrc2. Anti-CTLA4 alone increased the magnitude of responses against Uqcrc2. Anti-CTLA4 combined with anti-GITR induced determinant spreading, unmasked responses against a new neo-antigen UNC45A that was undetectable during normal tumour growth. Immunogenic chemotherapy also unmasked responses against UNC45A, suggesting that subdominant neo-antigens can be unmasked by the appropriate immunotherapy.
b) We then evaluated neo-antigen vaccination strategies. Uqcrc2 vaccination only protected against tumor growth when administered in combination with partial Treg depletion (Foxp3.DTR mice), suggesting that neo-antigen vaccination will only be maximally effective when administered in combination with therapies that modulate existing immune restraints, including Tregs.
c) We determined optimal anatomical location for tracking neo-antigen CTL responses and identified the draining lymph node as an optimal, though not exclusive, location for response testing compared to blood or tumor.
We are currently examining these observations using sequencing-defined neo-antigens in our patients and will present data on changes in human neo-antigen responses to therapy. These observations have important translational implications for identification of key neo-antigens, choice of therapy and monitoring of anti-tumor responses.
1.
J. Creaney et al., Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen. Oncoimmunology 4, e1011492 (2015).
Citation Format: Bruce W. Robinson, Shaokang Ma, Jonathan Chee, Craig Rive, Paula Van Miert, Rob A. Holt, Jenette Creaney. Augmenting and broadening T cell responses against mutated tumour neo-antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 608. doi:10.1158/1538-7445.AM2017-608
Abstract 61: Zymelink drug conjugate platform: redefining the therapeutic window for ADCs
Authors: Barnscher Stuart , Babcook John , Rich Jamie , Winters Geoff , Garnett Graham , Hernandez Andrea , Fung Vincent , Yin Kevin , Hamblett Kevin , Davies Rupert 
Published: July 2017

Abstract
Antibody drug conjugates (ADCs) combine the specificity of monoclonal antibodies with potent antineoplastic small molecules, and promise efficacy without the systemic toxicity of chemotherapy. Despite this tremendous potential, most clinical ADCs have failed to provide sufficient therapeutic benefit before the onset of off-target dose-limiting platform toxicities.
Here we report the development of proprietary protease cleavable N-acyl sulfonamide linked hemiasterlin and auristatin payloads, Zymelink, that allow the generation of an efficacious ADC platform with improved tolerability. Both Zymelink drug-linkers were conjugated via maleimides to endogenous cysteines. As Zymelink drug-linkers are more polar than maleimide valine citrulline monomethyl auristatin E drug-linker, the resulting ADCs can be produced with potential advantages in PK, efficacy and safety. The resulting ADCs exhibit potent in vitro cytotoxicity. A trastuzumab-based ADC prepared with Zymelink drug-linker and demonstrated at least equivalent efficacy compared to a trastuzumab-based ADC prepared with MMAE, promoting durable complete regressions in a patient-derived xenograft model.
Zymelink hemiasterlin and auristatin ADCs were tolerated at 5-6 fold higher doses compared to a MMAE ADC in cynomolgus monkeys. The maximum tolerated dose of the MMAE ADC was just 3 mg/kg based on severe neutropenia. Zymelink hemiasterlin ADC was tolerated at 15 mg/kg with no evidence of neutropenia or elevations in transaminases. Zymelink auristatin ADC was tolerated at 18 mg/kg based on increased levels of transaminases at 24 mg/kg. Moreover, Zymelink ADCs exhibited greater serum exposure at equivalent doses. These results suggest Zymelink ADCs have a greatly expanded therapeutic window compared to MMAE conjugates.
Citation Format: Stuart Barnscher, John Babcook, Jamie Rich, Geoff Winters, Graham Garnett, Andrea Hernandez, Vincent Fung, Kevin Yin, Kevin Hamblett, Rupert Davies. Zymelink drug conjugate platform: redefining the therapeutic window for ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2017-61
Abstract 610: Blockade of tumor expression of PD-1 promotes lung cancer growth in a murine model
Authors: Du Shisuo , Guan Qing , Dicker Adam P. , LU Bo 
Published: July 2017

Abstract
Lung cancer remains one of the most prevalent and fatal malignancies worldwide. There are substantial evidences that immunotherapies offer significant benefits among lung cancer patients. Pembrolizumab, a humanized programmed death receptor-1(anti-PD-1) antibody is now approved by FDA as a first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). Recent data demonstrate that PD-1 is not only expressed by immune cells, but also by human melanoma cells. However, little is known about the biological significance of PD-1 pathway in cancer including NSCLC. Thus, we examined PD-1 expression in a series of established murine lung cancer cell lines. RT-PCR amplification and sequencing of the full coding sequence of the murine PD-1 (PDCD1) gene revealed the presence of PDCD1 mRNA in the M109 lung cancer cells. Flow cytometry and immunofluorescence analysis demonstrated PD-1 protein expression in these murine lung cancer cells. To determine the molecular function of tumor PD-1 in lung cancer survival, we treated M109 cells in culture with either anti- mouse PD-1(100ug/ml) or isotype control antibody and found that PD-1 inhibition significantly enhanced cancer cell viability as measured by MTT and clonogenic assay. Alternative PD1 inhibition by either knockdown of PDCD1 via siRNA or knockout of PDCD1 by CRISPR-Cas9 all lead to increased survival of M109 cells. Furthermore, PDCD1-knockout M109 cells had no survival difference in the presence of anti-PD1 compared to its PD1-expressing parental cells. Conversely, treatment with recombinant PD-L1 fusion protein exhibited significantly increased apoptotic rates (7.5±3.2% vs 2.1±1.2%) suppressing the tumor cell growth in the wild-type M109 in culture. To validate these results in in vivo models, NSG mice were used to determine the direct impact of anti-PD1 on M109 xenografts without the interplay of host immune system. M109 xenografts treated with antiPD-1 (10mg/kg i.p.) antibodies showed accelerated growth compared to those treated by IgG control (2487±473 vs 1499±292mm3 at days 21 after tumor inoculation, p=0.013). M109 subcutaneous tumors in the PD-1 knockout mice also manifested more rapid growth than the same tumors implanted in wild-type mice. Taken together, our results uncover a novel function of PD-1/PD-L1 axis in lung cancer survival and implicate possible tumor-promoting effects from anti-PD-1 therapy upon PD1-expressing lung cancer in the absence of effective immune response. We plan to interrogate bio-specimens collected through NRG trials to establish the translational potential of these findings.
Citation Format: Shisuo Du, Qing Guan, Adam P. Dicker, Bo LU. Blockade of tumor expression of PD-1 promotes lung cancer growth in a murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 610. doi:10.1158/1538-7445.AM2017-610
Abstract 613: Development of FPA154, a novel tetravalent anti-GITR antibody, for the treatment of solid tumors
Authors: Barbee Susannah D. , Chen Amanda , Johnson Susan , Bellovin David I. , Timmer John C. , Wondyfraw Nebiyu , Mkrtichyan Mikayel , Razai Amir S. , Jones Kyle S. , Hata Chelsie Y. , Gonzalez Denise , Deveraux Quinn , Eckelman Brendan P. , Borges Luis 
Published: July 2017

Abstract
Glucocorticoid-induced TNFR-related (GITR, TNFRSF18) is a member of the TNFR superfamily with pleiotropic T cell modulatory activity. We are developing a novel anti-GITR antibody with enhanced agonist activity for the treatment of solid tumors. Our candidate molecule, FPA154, is constructed with single-domain antibodies (sdAbs) in a tetravalent format, with an effector-competent IgG1 Fc domain. Both FPA154 and the mouse-reactive surrogate molecule (cmFPA154, mIgG2a isotype) bind to cell-surface GITR with high affinity. GITR is most highly expressed in vivo on activated and intratumoral Treg, and our data indicates that FPA154 and cmFPA154 potently mediate ADCC activity against Treg expressing high levels of GITR. In contrast, activated effector T cells express modest levels of cell-surface GITR, and FPA154 and cmFPA154 drive GITR-induced NF-κB activation. This activity is independent of Fc-mediated crosslinking, which is normally required for bivalent GITR antibodies to induce GITR signaling. cmFPA154 has potent antitumor activity in several syngeneic mouse tumors, both as a monotherapy treatment and in combination with anti-PD-1. In summary, FPA154 is a promising candidate with multiple mechanisms of action that contribute to generation of an antitumor immune response mediated by different T cell subsets.
Citation Format: Susannah D. Barbee, Amanda Chen, Susan Johnson, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges. Development of FPA154, a novel tetravalent anti-GITR antibody, for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2017-613