bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1461: MHCII-expressing breast cancer cells can induce anti-tumor immune response
Authors: Li Mei , McCaw Tyler R. , Meza-Perez Selene , Randall Troy D. , Weinmann Amy , Buchsbaum Donald J. , Forero Andres , LoBuglio Albert F. 
Published: July 2016

Abstract
We recently reported that the mRNA expression of genes in the Major Histocompatibility Complex class II (MHCII) antigen processing and presentation pathway in breast tumor tissues was strongly prognostic of good clinical outcome in triple negative breast cancer (TNBC) patients (J Clin Oncol 33, 2015 suppl; abstr 1066). Although MHCII expression is most often observed on antigen-presenting cells, such as dendritic cells, macrophages and B cells, we observed MHCII protein expression on TNBC tumor cells. These observations suggested that TNBC cells expressing MHCII may have the ability to directly stimulate CD4 T cells and promote anti-tumor immune responses. To test this hypothesis, we transfected murine TS/A tumor cells (syngeneic, non-immunogenic, and metastatic breast cancer model) with a vector encoding the human MHCII Transcriptional Activator (hCIITA) under the control of a doxycycline (Dox)-inducible promoter. We found that TS/A-hCIITA cells did not express MHCII or CD74 until exposed to Dox, whereupon they expressed MHCII and CD74 mRNA and protein in a dose-dependent fashion. We also found that TS/A-hCIITA cells injected into the mammary fat pad expressed MHCII genes and cell surface MHCII proteins on tumor cells if mice received Dox in their drinking water. Importantly, tumor-bearing, Dox-exposed mice exhibited significantly impaired tumor growth compared to mice that were not exposed to Dox. We also found that tumor-bearing, Dox-exposed mice had a significantly enhanced tumor-specific CD8 T cell response in both the tumor-draining lymph node and tumor bed. Thus, breast cancer tumor cells expressing MHCII proteins promote anti-tumor immune responses, which likely contribute to the control of tumor growth in vivo.
Citation Format: Mei Li, Tyler R. McCaw, Selene Meza-Perez, Troy D. Randall, Amy Weinmann, Donald J. Buchsbaum, Andres Forero, Albert F. LoBuglio. MHCII-expressing breast cancer cells can induce anti-tumor immune response. [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 1461.
Abstract 1474: A novel oncolytic adenovirus expressing tumor microenvironment modulators that activates myeloid cells, lymphocytes and endothelial cells
Authors: Loskog Angelica , Eriksson Emma , Milenova Ioanna , Moreno Rafael , Alemany Ramon 
Published: July 2016

Abstract
Immunotherapy is becoming a cornerstone in cancer treatment of many indications. So far, pancreatic cancer has shown little response to so called checkpoint blockade antibodies. However, animal data suggests that activating immunotherapies releases the effect of checkpoint blockade also in pancreatic cancer. The tumor microenvironment (TEM) supports the growth of the tumor cells and consists of stroma cells, fibroblasts, blood vessels and immune cells. In some tumor lesions, such as those in pancreatic cancer, the TEM is dense and comprises most of the lesion. The TEM regulates immune activity via its high content of M2 macrophages, myeloid derived suppressor cells and T regulatory cells. Further, the dysfunctional blood vessels in lesions are not optimal for recruiting lymphocytes. With these aspects in mind, LOAd703 was developed. LOAd703 is an oncolytic adenovirus carrying TEM modulators.
LOAd703 was constructed from the ICOVIR system of oncolytic adenoviruses in which replication depends on a dysfunctional, hyperphosphorylated retinoblastoma pathway. The genome was further altered by removing E3-6.7K and gp19K, changing the serotype 5 fiber to a serotype 35 fiber to target CD46 expressed by most tumors, as well as by adding a CMV-driven transgene cassette with the human transgenes for TMZ-CD40L and 4-1BBL. Hence, the transgenes will be expressed in both tumor and stroma while oncolysis is initiated in the tumor cells. We demonstrate herein that LOAd703 infection of a panel of pancreatic cancer cell lines efficiently induced tumor cell death within 48-72 hrs post infection while LOAd703 infection of dendritic cells demonstrated an increased maturation of myeloid cells including dendritic cells (DCs). These DCs could in turn potently activate and promote expansion of both T- and NK cells. Further, LOAd703 infection of endothelial cells (HUVEC) induced upregulation of molecules involved in lymphocyte attachment, rolling and transmigration. In conclusion, LOAd703 is a novel oncolytic virus that targets both the tumor and its TME and a clinical trial is underway to elucidate its effect in pancreatic cancer.
Citation Format: Angelica Loskog, Emma Eriksson, Ioanna Milenova, Rafael Moreno, Ramon Alemany. A novel oncolytic adenovirus expressing tumor microenvironment modulators that activates myeloid cells, lymphocytes and endothelial 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 1474.
Abstract 1475: Local immune activation resulting in tumor growth inhibition with MEDI9197 - an intratumorally administered TLR7/8 agonist
Authors: Mullins Stefanie , Grigsby Iwen , Harrison Lester I. , Ren Song , Soukharev Serguei , Young Lesley , Elvecrog James M. , Wilkinson Robert W. , Tomai Mark A. , Herbst Ronald , Vasilakos John P. , Leishman Andrew J. 
Published: July 2016

Abstract
MEDI9197 (formerly 3M-052) is a sustained-release imidazoquinoline toll like receptor (TLR) TLR7/8 agonist designed with a lipid tail that, when injected, is retained within the tumor. This has been shown in pharmacokinetic studies in mice and rats injected with MEDI9197 via the subcutaneous (SC) or intratumoral (IT, mouse only) routes. Stimulation of TLR7 and TLR8 in primary human dendritic cells induces the release of interferon-alpha (IFN-a) from plasmacytoid dendritic cells (pDCs) and interleukin 12 (IL-12) from myeloid dendritic cells (mDCs). Intratumoral administration of MEDI9197 induces a local immune response characterized by upregulation of genes involved in activation of innate and adaptive immunity both from the injected tumor and tumor draining lymph node. Furthermore, flow cytometric analysis of tumor infiltrating lymphocytes (TILs) show increased expression of activation markers, such as CD69, on natural killer (NK) cells and CD8 cytotoxic T cells. This local stimulation of immune cells with MEDI9197 results in tumor growth inhibition as shown in the B16F10 luc syngeneic mouse tumor model using in vivo imaging system (IVIS) equipment. Additionally, combination of MEDI9197 with immune checkpoint inhibitors enhances the efficacy observed in syngeneic mouse tumor models. The data presented shows intratumoral administration of MEDI9197 induces local immune activation leading to tumor growth inhibition in preclinical models of cancer. MEDI9197 is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials.
Citation Format: Stefanie Mullins, Iwen Grigsby, Lester I. Harrison, Song Ren, Serguei Soukharev, Lesley Young, James M. Elvecrog, Robert W. Wilkinson, Mark A. Tomai, Ronald Herbst, John P. Vasilakos, Andrew J. Leishman. Local immune activation resulting in tumor growth inhibition with MEDI9197 - an intratumorally administered TLR7/8 agonist. [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 1475.
Abstract 1486: Pharmacodynamic response to HER2/CD3 bispecific antibody (HER2-TDB): evidence of T-cell recruitment and further rationale for combination treatment with anti-PD-L1
Authors: Li Ji , Hristopoulos Maria , Clark Robyn , Johnston Jennifer , Slaga Dion , Wang Bu-Er , Cubas Rafael , Totpal Klara , Junttila Melissa R. , Junttila Teemu T. 
Published: July 2016

Abstract
Based on the recent clinical success of tumor immunotherapies that block immune suppressive mechanisms to restore T cell function, there is a profound interest in the clinical development of T cell targeted therapies. We have produced a trastuzumab-based HER2 T cell dependent bispecific antibody (HER2/CD3; HER2-TDB; Junttila et al Cancer Res 2014, 74:5561) that conditionally activates T cells resulting in lysis of HER2 expressing cancer cells at low picomolar concentrations. In vivo, HER2/CD3 can inhibit growth of established mammary tumors in mice at doses as low as 0,01 mg/kg. Due to its unique mechanism of action, which is unrelated to HER2 signaling or sensitivity to chemotherapeutic agents, HER2/CD3 can eliminate cells refractory to currently approved HER2 therapies and inhibit growth of Kadcyla insensitive mammary tumor models. Treatment with HER2-TDBs also results in tumor regression as a second line treatment for Kadcyla relapsed mammary tumors in mice.
Spontaneous mammary tumors arising in MMTV-huHER2 transgenic animals are poorly immunogenic or “immunological deserts” due to their low mutational load and low T cell infiltration. Despite these attributes, HER2/CD3 shows remarkable activity in this model characterized by a robust increase in the number of infiltrating lymphocytes and CD8+ T cells as well as a significant enhancement of tumor CD8+ cytotoxic effector function as measured by increased IFNg production. In addition to inducing T cell proliferation, we further show that HER2/CD3 strongly recruits new T cells from the periphery and this leads to significantly increased T cell numbers in the mammary tumor tissue. Another notable feature of the response to HER2/CD3 treatment is a significant upregulation of PD-1 expression on tumor infiltrating CD8+ T cells. This observation adds a strong rationale for combining HER2/CD3 with anti-PDL1 treatment. Our in vitro experiments further demonstrate that PD-1/PD-L1 signaling can inhibit killing mediated by CD3 bispecific antibodies and that combining two immune therapies - direct polyclonal recruitment of T cell activity together with inhibiting the T cell suppressive PD-1/PD-L1 axis results in enhanced and durable long term responses in vivo.
Citation Format: Ji Li, Maria Hristopoulos, Robyn Clark, Jennifer Johnston, Dion Slaga, Bu-Er Wang, Rafael Cubas, Klara Totpal, Melissa R. Junttila, Teemu T. Junttila. Pharmacodynamic response to HER2/CD3 bispecific antibody (HER2-TDB): evidence of T-cell recruitment and further rationale for combination treatment with anti-PD-L1. [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 1486.
Abstract 1497: Development of a novel TCR-like bi-specific T-cell engager targeting endogenous PR1/HLA-A2 leukemia antigen
Authors: Herrmann Amanda Cernosek , Im Jin S. , Lu Sijie , Sergueeva Anna , Molldrem Jeffrey 
Published: July 2016

Abstract
PR1 (VLQELNVTV) is a HLA-A2 restricted peptide derived from endogenous tumor associated antigens proteinase-3 and neutrophil elastase that are aberrantly expressed in myeloid leukemia blasts. Previously, we have developed a high affinity T-cell receptor-like monoclonal antibody (h8F4) specific for PR1/HLA-A2, and demonstrated the effective killing of myeloid leukemia blasts via antibody dependent cellular cytotoxicity (ADCC). To improve the therapeutic efficacy of h8F4, we adopted a novel antibody engineering strategy, bi-specific T-cell engaging (BiTE) antibody that can bring T cells in close proximity to leukemia blasts through the binding of both PR1/HLA-A2 and CD3, resulting in T-cell mediated cytolysis of leukemia blasts. Here we successfully generated h8F4-BiTE proteins using a eukaryotic expression system and investigated binding characteristics, target specificities, and subsequent T-cell activation with the h8F4-BiTE. The h8F4 BiTE showed binding affinities in the nM range for PR1/HLA-A2 and CD3 moiety of T cells. Within 18 hours of h8F4-BiTE engagement with PR1 pulsed T2 cells, polyclonal T cells from healthy donors up-regulated surface expression of CD69 and down-regulated CD3 in a PR1/HLA-A2 specific and concentration dependent manner, suggesting successful T-cell activation. In conclusion, we developed a novel h8F4 BiTE antibody that recognizes both the CD3 on T cells and endogenous PR1/HLA-A2 complexes on myeloid leukemia, and demonstrated high affinity bindings and subsequent T cell activation. We envision our novel TCR-like BiTE antibody will provide a safer and more potent treatment option for patients with aggressive myeloid leukemias that will improve upon currently available highly toxic standard therapies.
Citation Format: Amanda Cernosek Herrmann, Jin S. Im, Sijie Lu, Anna Sergueeva, Jeffrey Molldrem. Development of a novel TCR-like bi-specific T-cell engager targeting endogenous PR1/HLA-A2 leukemia antigen. [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 1497.
Abstract 1500: How K-Ras4B attaches to the membrane and forms a dimer: A new paradigm
Authors: Jang Hyunbum , Nussinov Ruth 
Published: July 2016

Abstract
Ras is a small GTPase, controlling signal transduction pathways and promoting cell proliferation and survival. KRAS is frequently mutated in cancer. Ras consists of highly homologous catalytic domains (G-domains) and flexible C-terminal hypervariable regions (HVRs) that differ significantly across Ras isoforms. Recent nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations discovered that the HVR of K-Ras4B in the GDP-bound state extensively interacts with the catalytic domain. However, it weakly interacts with the catalytic domain in the GTP-bound state. Here, using MD simulations we modeled K-Ras4B membrane interaction and dimerization. Membrane binding of K-Ras4B through the anchoring of the positively charged HVR is thought to be critical to its function as an oncogene and initiates signaling events. At the membrane, the catalytic domain takes on multiple orientations, including perpendicular and parallel alignments of the allosteric helices with respect to the membrane normal. In the autoinhibited state, the HVR is sandwiched between the effector lobe and the membrane; in the active state, with the farnesyl anchored into the membrane and the HVR unrestrained, the catalytic domain fluctuates reinlessly, exposing its effector binding site. Notably, we also observe HVR-autoinhibited K-Ras4B-GTP states that display GDP-bound-like orientations of the helices. We thus propose that GDP/GTP nucleotide exchange may not be sufficient for K-Ras4B activation; composite mechanisms including HVR sequestration, farnesyl insertion, and orientation/localization of the catalytic domain on the membrane can determine the functional state of K-Ras4B. Remarkably, K-Ras4B-GTP, but not GDP-bound, is able to form stable homodimers with different dimer interfaces, suggesting that the nucleotide-dependent dimerization with various dimer interfaces can resolve nanoclustering and cluster reorganization accomplishment with Raf's activation. Ras was believed to function as a monomer; however, since Raf dimerizes, it has been suspected that Ras can also dimerize. Dimerization and clustering could rein the fluctuations producing more productive pre-organized conformations. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E.
Citation Format: Hyunbum Jang, Ruth Nussinov. How K-Ras4B attaches to the membrane and forms a dimer: A new paradigm. [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 1500.
Abstract 1508: Integration of transcriptomic and metabolomic data reveals a central role for EGR1 in regulating survival and cellular metabolism in endocrine-resistant breast cancer
Authors: Shajahan-Haq Ayesha N. , Cheema Amrita , Jin Lu , Boca Simina , Gusev Yuriy , Bhuvaneshwar Krithika , Demas Diane , Raghavan Kristopher , Madhavan Subha , Clarke Robert 
Published: July 2016

Abstract
Breast cancer is the most commonly diagnosed cancer in women. About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and are treated with antiestrogens. However, endocrine resistance is prevalent in the clinic and the underlying mechanisms remain unclear. MYC is overexpressed in endocrine resistant ER+ breast cancers, which suggests that the metabolomic profile of endocrine resistant breast cancers may contain features that are distinct from sensitive cells. We integrated data from transcriptomics and metabolomics analysis of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or resistant (LCC9; resistant to ICI182,780). To validate our model, we tested a gene-metabolite network associated with EGR1 (early growth response 1), which was significantly higher in LCC1 cells compared with LCC9 cells. In ER+ human breast tumors treated with endocrine therapy, higher EGR1 expression was associated with a more favorable prognosis. In both LCC1 and LCC9 cell lines, compared to respective controls, knockdown of EGR1 decreased cell proliferation, ERα and MYC protein levels while overexpression of EGR1 did not change these. Comparison of metabolite profiles in LCC9 cells following knockdown or overexpression of EGR1 showed interruption of several biochemical pathways such as glycolysis, lipid metabolism, glutathione, and polyamine metabolism. Treatment with tolfenamic acid (TOL), a nonsteroidal anti-inflammatory drug (NSAID) known to target EGR1, decreased EGR1 protein levels and had an additive effect with ICI182,780 in inhibiting cell proliferation in LCC9 cells. Collectively, these findings indicate that down-regulated EGR1 is an important regulator of the aberrant cellular metabolic pathways specific to endocrine resistance, and targeting EGR1 may be an effective therapeutic approach in inhibiting growth of these tumors. Furthermore, high levels of EGR1 may serve as a favorable prognostic marker in some endocrine resistant tumors.
Citation Format: Ayesha N. Shajahan-Haq, Amrita Cheema, Lu Jin, Simina Boca, Yuriy Gusev, Krithika Bhuvaneshwar, Diane Demas, Kristopher Raghavan, Subha Madhavan, Robert Clarke. Integration of transcriptomic and metabolomic data reveals a central role for EGR1 in regulating survival and cellular metabolism in endocrine-resistant breast 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 1508.
Abstract 1511: Mutational signatures from RNA-seq data distinguish HPV(+) and HPV(-) HNSCC
Authors: Hall Pelle , Virani Shama , Warden Charles , Zhang Yanxiao , Koneva Lada , Rentschler Katie M. , Virani Alisha , Rozek Laura S. , Sartor Maureen A. ,   The UM Head and Neck SPORE Investigators
Published: July 2016

Abstract
IntroductionHead and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, and an increasing percentage of HNSCC cases are associated with human papillomavirus (HPV) which have improved prognosis compared to HPV(-) HNSCC. Identifying distinctions between HPV(+) and HPV(-) HNSCC may lead to improved prognosis or new treatments, such as determining mutagen(s) that are driving accumulation of genetic variants in each tumor. A recent approach uses the fact that different mutagens cause different types of mutations, referred to as a mutagen's signature. By comparing the mutations in a tumor sample with the mutagen signatures, the mutagens responsible for most of the mutations in the tumor can be identified. We hypothesized that mutational signatures could distinguish HPV(+) from HPV(-) HNSCC tumors.
Materials and Methods
We performed RNA-sequencing on 18 HPV(+) and 18 HPV(-) tumor samples collected from HNSCC patients by the University of Michigan Head and Neck SPORE. Variant calling was performed on each sample using a GATK best practices for RNA-seq pipeline. These variants were then filtered to include only variants that were both rare (&lt;5%) and predicted to have a functional effect. The bases 5’ and 3’ of each variant were extracted to identify its sequence context. The observed mutations in each sample were then approximated by a non-negative linear combination of previously reported mutagen signatures. Certain signatures are associated with dysregulation of particular pathways; this dysregulation was validated with expression and mutation analysis of the RNA data.
Results
In the studied HNSCC tumors, signatures related to aging and impaired DNA repair were responsible for the largest proportion of the mutations found. The signatures that were significantly different between HPV(+) and HPV(-) tumors were associated with APOBEC editing and defective DNA mismatch repair. Expression and mutational analysis validated that APOBEC is more active in HPV(+) than HPV(-) tumors. Interestingly, signatures associated with smoking were not among the most relevant.
Conclusion
The evaluation of mutational signatures in HNSCC tumors identified the main sources of mutations for HNSCC. The differences in mutational signatures between HPV(+) and HPV(-) identify distinct methods of carcinogenesis for these two subtypes of HNSCC.
Citation Format: Pelle Hall, Shama Virani, Charles Warden, Yanxiao Zhang, Lada Koneva, Katie M. Rentschler, Alisha Virani, Laura S. Rozek, Maureen A. Sartor, The UM Head and Neck SPORE Investigators. Mutational signatures from RNA-seq data distinguish HPV(+) and HPV(-) HNSCC. [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 1511.