bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1366: Structural basis of impaired GTP hydrolysis in oncogenic mutants of KRAS
Authors: Tran Timothy , Dharmaiah Sathiya , Chertov Oleg , Waybright Timothy , Gillette William , Esposito Dominic , Nissley Dwight , McCormick Frank , Stephen Andrew , Simanshu Dhirendra 
Published: July 2017

Abstract
RAS mutations are found in one-third of all human cancers. Among the three RAS isoforms - HRAS, KRAS and NRAS, KRAS is the most commonly mutated gene (in 86% of RAS-driven cancers) and the mutations are often detected in pancreatic, colorectal and lung cancers. RAS proteins function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. The active or inactive state of RAS proteins is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In the GTP-bound state, RAS proteins interact with a variety of effector proteins, such as Raf, PI3K, and RalGDS, leading to activation of several signaling cascades within the cell. In 98% of the cases, oncogenic RAS mutations are found at amino acid positions G12, G13, and Q61 which impair intrinsic and GAP-mediated GTPase function resulting in accumulation of constitutively GTP-bound RAS in cells. To gain insights into the effect of oncogenic mutations on overall structure and GTP hydrolysis, we solved high-resolution crystal structures of wild type and six oncogenic mutants (G12C, G12D, G12V, G13D, Q61L and Q61R) of KRAS4b in complex with GMPPNP (a non-hydrolysable GTP analog) and magnesium. Comparison of GDP and GMPPNP bound structures of wild type (WT) KRAS4b suggests conformational changes that occur when KRAS4b transitions from inactive to active state. Comparison of mutant and wild-type KRAS structures has shown the appearance of new pockets in some cases that could be exploited for structure-based drug design. Structural superposition of mutants vs. wild type KRAS4b in complex with GMPPNP/Mg2+, and KRAS4b mutants vs. WT-HRAS bound to RASA1-GAP provides a rationale for impaired intrinsic and GAP-mediated GTP hydrolysis in the KRAS mutants.
Citation Format: Timothy Tran, Sathiya Dharmaiah, Oleg Chertov, Timothy Waybright, William Gillette, Dominic Esposito, Dwight Nissley, Frank McCormick, Andrew Stephen, Dhirendra Simanshu. Structural basis of impaired GTP hydrolysis in oncogenic mutants of KRAS [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 1366. doi:10.1158/1538-7445.AM2017-1366
Abstract 1382: A novel BET family bromodomain inhibitor NHWD-870 represents a promising therapeutic agent for a broad spectrum of cancers
Authors: Wang Nenghui , Yin Mingzhu , Yan Qin 
Published: July 2017

Abstract
Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins have emerged as a promising option for cancer therapy. NHWD-870 is a potent and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2/3/4/T. NHWD-870 exhibited robust single agent activity in cell viability assay across cancer cell lines derived from solid tumors, leukemia and lymphomas. Further characterization of cancer cell responses to NHWD-870 indicated that NHWD-870 manifested diverse mechanisms of action in different cancer settings. These include: 1) inhibition of tumor cell growth by downregulating the PDGFRβ, MEK1/2 and STAT1/MYC signaling in tumor cells; 2) inhibition of tumor angiogenesis by decreasing PDGF production in tumor cells and the PDGFRβ and MEK1/2 signaling in endothelial cells. Consistent with its broad spectrum of activities in vitro, NHWD-870 has potent tumor suppressive efficacies in xenograft mouse models of small cell lung cancer, triple negative breast cancer and ovarian cancer. These results support its further development for diverse solid tumor indications in the clinic.
Citation Format: Nenghui Wang, Mingzhu Yin, Qin Yan. A novel BET family bromodomain inhibitor NHWD-870 represents a promising therapeutic agent for a broad spectrum of cancers [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 1382. doi:10.1158/1538-7445.AM2017-1382
Abstract 1475: miRNA-450a suppresses adhesion but promotes invasion through targeting of TMEM182 in oral squamous cell carcinoma
Authors: Hsing En-Wei , Shiah Shine-Gwo , Kuo Ching-Chuan , Chang Jang-Yang 
Published: July 2017

Abstract
Our microRNA (miRNA) expression signatures of oral squamous cell carcinoma (OSCC) revealed that miR-450a was significantly increased in cancer tissues compared with normal epithelium. In this study, we focused on the functional significance of miR-450a in cancer cells and identification of miR-450a-regulated novel targets in OSCC. Overexpression of miR-450a in DOK and SAS cells showed significant inhibition of cell adhesion and induction of cell invasiveness, suggesting that miR-450a functions as an onco-miRNA. We performed genome-wide gene expression analysis to search for miR-450a-regulated molecular targets. Gene expression data and luciferase reporter assays revealed that TMEM182 was directly targeted by miR-450a. The miR-450a-reduced cellular adhesion was blocked by TMEM182 restoration, suggesting that miR-450a exhibits its oncogenic activity through negatively regulating TMEM182 level. Furthermore, miR-450a expression could be induced by the cytokine TNF-α primarily through activating extracellular signal-regulated kinase (ERK) signaling pathway. ERK inhibitor prevented the TNF-α-induced miR-450a expression and enhanced adhesion ability. Taken together, these data indicate that TNF-α/ERK-dependent expression of miR-450a plays an important role in mediating cellular adhesion and invasiveness, and scavenging miR-450a function using antagomir may have therapeutic potential for the treatment of OSCC. (The study was supported by the following grants: MOST 103-2320-B-006-036-MY3 and MOST 105-2325-B-400-001 from the Ministry of Science and Technology of Taiwan, ROC)
Citation Format: En-Wei Hsing, Shine-Gwo Shiah, Ching-Chuan Kuo, Jang-Yang Chang. miRNA-450a suppresses adhesion but promotes invasion through targeting of TMEM182 in oral squamous cell carcinoma [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 1475. doi:10.1158/1538-7445.AM2017-1475
Abstract 1518: Mechanisms of bromodomain and extra-terminal motif inhibitor (BETi) sensitivity in triple-negative breast cancer (TNBC)
Authors: Schafer Johanna , Lehmann Brian , Liu Phillip , Stubbs Matthew , Scherle Peggy , Pietenpol Jennifer 
Published: July 2017

Abstract
Triple-negative breast cancers (TNBCs) lack expression of estrogen receptor (ER), progesterone receptor (PR), and amplifications in the human epidermal growth factor receptor 2 (HER2). With currently no FDA-approved targeted therapies for TNBC, patients with TNBC have a higher risk of local and distant recurrence, and an overall increased rate of mortality. Recent studies have demonstrated increased sensitivity of TNBC to the anti-proliferative effects of BETi compared to the other breast cancer subtypes. To determine mechanisms of sensitivity to BET inhibition, we analyzed the effect of two BET inhibitors, INCB054329 and OTX-015, across a panel of TNBC cell line models and identified cell lines that were both sensitive and insensitive to BETi. With the intent of identifying biomarkers of sensitivity, we performed RNA-seq and precision nuclear run-on and sequencing (PRO-seq) on both sensitive and resistant cell line models and data generated identified significant differences in key growth regulatory and apoptotic signaling pathways, including notable differences in Myc-dependent signaling. Our data suggest potential biomarkers of BETi sensitivity that may be of value in further pre-clinical studies. Further, our results provide mechanistic rationale for combinations of BETi with select, targeted therapies in a disease that is in need of new therapeutic intervention.
Citation Format: Johanna Schafer, Brian Lehmann, Phillip Liu, Matthew Stubbs, Peggy Scherle, Jennifer Pietenpol. Mechanisms of bromodomain and extra-terminal motif inhibitor (BETi) sensitivity in triple-negative breast cancer (TNBC) [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 1518. doi:10.1158/1538-7445.AM2017-1518
Abstract 1539: Investigating the mechanisms of tumor suppression mediated by PTEN PDZ-binding domain in a murine breast cancer model
Authors: Yan Mingfei , Many Alexander , Guan Hong , Or Penelope M. , Chan Andrew M. 
Published: July 2017

Abstract
PTEN (Phosphatase and tensin homolog) functions as a key negative regulator of PI3K-Akt pathway through its lipid phosphatase activity. Mutations or loss of PTEN is frequently observed in brain, breast, prostate and endometrial cancer. PTEN possesses a PDZ-binding domain (PDZ-BD) at the end of its carboxyl terminus. Functionally, PDZ-BD mediates PTEN’s interactions with other PDZ domain-containing proteins, including ZO-1, PSD-95, DLG, etc, which are involved in the formation of cell junctions, post-synaptic densities, and serves as scaffolding proteins for multiple signaling complexes. However, whether the PTEN PDZ-binding domain is required to suppress tumorigenesis still remains obscure.
To study the role of PTEN PDZ-BD in breast epithelial tumorigenesis, a PTEN-ΔPDZ mice lacking this domain was generated. PTEN expression level and activity of PI3K-Akt pathway are not changed in the mammary epithelial cells, indicating that PDZ-BD is dispensable for PTEN stability and negative regulation of the PI3K-Akt pathway. Further, we crossed the PTEN-ΔPDZ mice with the MMTV-PyMT breast cancer model and observed increased total tumor burden as well as higher tendency of lung metastasis in PTEN-ΔPDZ mice. This data indicates that PTEN PDZ-BD is indeed important for tumor suppression during breast cancer progression.
Previously, PTEN has been reported to govern the integrity of tight junctions and apical-basal polarity of epithelial cells, which requires PTEN’s interactions with other proteins through the PDZ-BD. However, through in vitro three-dimensional culture of primary mouse mammary epithelial cells, we failed to observe any disruption of either apical-basal polarity or tight junction. Meanwhile, we investigated the alteration of the transcriptome of breast cancer tissue in PTEN-ΔPDZ mice by performing RNA-sequencing. Several enriched signaling pathways were identified by Ingenuity Pathway Analysis (IPA), which seems to be mainly associated with cell skeleton signaling as well as signaling interaction between extracellular matrix and the cancer cell. A list of genes were validated by RT-PCR, and functional validation of these genes during the tumorigenesis in our animal model is to be carried out in the near future.
This work was supported by a General Research Fund grant (#460713) from the Hong Kong University Grants Committee to AC. YM was supported by a Hong Kong PhD Fellowship (PF12-13584), and a Lo Kwee-Seong Biomedical Research Seed Fund to AC.
Citation Format: Mingfei Yan, Alexander Many, Hong Guan, Penelope M. Or, Andrew M. Chan. Investigating the mechanisms of tumor suppression mediated by PTEN PDZ-binding domain in a murine breast cancer 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 1539. doi:10.1158/1538-7445.AM2017-1539
Abstract 1599: Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models
Authors: Bellovin David I. , Wondyfraw Nebiyu , Sennino Barbara , Walker Quinn , Johnson Susan , Levin Anita , Masteller Emma , Barbee Susannah D. , Sikorski Robert , Brennan Tom 
Published: July 2017

Abstract
The colony stimulating factor 1 receptor (CSF-1R) signaling pathway promotes tumor progression via the recruitment, differentiation, and survival of immuno-suppressive tumor-associated macrophages (TAMs). FivePrime has developed cabiralizumab (FPA008), an IgG4 antibody against CSF-1R that blocks the ability of both CSF-1 and IL-34 to bind and activate this receptor, thereby modulating the immune response to tumorigenesis. In order to investigate the impact of CSF-1R signaling inhibition in preclinical models, we generated a surrogate antibody, cmFPA008, which targets mouse CSF-1R and demonstrates equivalent affinity and ligand-blocking ability as FPA008. Utilizing a combination of flow cytometry and immunofluorescence analyses, we have identified alterations in the tumor microenvironment that occur upon CSF-1R inhibition, including significant reduction of immunosuppressive TAMs and an increase in tumor PD-L1 expression. Interestingly, we observe a transient increase in CD8+ T cell number and activation upon TAM depletion, followed by a subsequent increase in MDSC populations that corresponds with reduction of the CD8+ T cell numbers. Moreover, we have used murine syngeneic tumor models to examine the anti-tumor impact of CSF-1R inhibition in combination with other immuno-oncology agents. Our results show that, when added to PD-1/PD-L1 blockade, cmFPA008 can significantly enhance anti-tumor efficacy. We are currently exploring the effects of combining cmFPA008-induced TAM depletion with additional immuno-oncology agents, including T cell agonists. Our preclinical results demonstrate that inhibition of the CSF-1R pathway can combine with various immuno-oncology agents with distinct mechanisms of action. FivePrime has initiated a clinical trial in collaboration with Bristol-Myers Squibb (BMS) to investigate the use of cabiralizumab in combination with nivolumab (anti-PD-1, OPDIVO®) in six different tumor types.
Citation Format: David I. Bellovin, Nebiyu Wondyfraw, Barbara Sennino, Quinn Walker, Susan Johnson, Anita Levin, Emma Masteller, Susannah D. Barbee, Robert Sikorski, Tom Brennan. Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models [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 1599. doi:10.1158/1538-7445.AM2017-1599
Abstract 1605: Combined oral cytokine therapy effectively treats colon cancer in a murine model
Authors: Bhutiani Neal , Li Qingsheng , Anderson Charles D. , Gu Tao , Egilmez Nejat K. 
Published: July 2017

Abstract
Background: Regardless of its etiology, colorectal cancer development is intimately associated with dysregulation of the intestinal immune system. Sustained release, orally delivered IL-10 not only inhibits colon tumor growth but restores T cell homeostasis both locoregionally and systemically. However, it does not induce tumor regression. We aimed to combine orally delivered IL-12, a potent immunostimulatory molecule with robust anti-tumor effect, with oral IL-10 therapy to induce tumor regression.
Methods: 6 week old APCmin mice were inoculated with enterotoxic Bacteroides fragilis (serotype 086) after five days of intestinal flora depletion with antibiotics dissolved in drinking water. 7-10 days after bacterial inoculation, mice were treated three times weekly with either 1) blank polylactic acid microspheres for 3 weeks, 2) IL-10 containing microspheres (0.5 microgram/dose) for 3 weeks, 3) IL-12 containing microspheres (0.25 micrograms/dose) for 3 weeks, or 4) IL-10 containing microspheres for 1 week followed by a combination of IL-10 and IL-12 containing microspheres for 2 weeks. After euthanasia, colons were assessed for polyp counts and select polyps were isolated for confocal microscopy analysis. Mesenteric lymph node lymphocytes were isolated and analyzed using flow cytometry.
Results: Mice treated with oral IL-10 and IL-12 demonstrated a reduction in polyp number compared to those mice treated with IL-10 alone, and both groups had fewer polyps than mice treated with either IL-12 or blank microspheres. Addition of IL-12 resulted in increased CD8+ T cell numbers and IFN-γ production compared to treatment with IL-10 alone. IL-10 retained its effect on CD4+ T cells when combining it with IL-12, resulting in a decrease in conventional regulatory T cells (FoxP3+ RORγT -) as well as pathogenic regulatory T cells (FoxP3+ RORγT+) and IL-17 producing CD4+ T cells.
Conclusions: The addition of IL-12 to IL-10 therapy augments the therapeutic effect of oral cytokine treatment on colon adenocarcinoma in the APCmin B. fragilis model. The effect appears additive and mediated by both IL-10’s effect on regulatory T cell populations and IL-12’s effect on CD8+ T cells. Further studies in the setting of more advanced disease, including liver metastases, will elucidate the therapeutic potential of combination oral cytokine therapy with IL-10 and IL-12 for treatment of colorectal cancer.
Citation Format: Neal Bhutiani, Qingsheng Li, Charles D. Anderson, Tao Gu, Nejat K. Egilmez. Combined oral cytokine therapy effectively treats colon cancer 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 1605. doi:10.1158/1538-7445.AM2017-1605
Abstract 1742: Cancer cell-selective transcriptome analysis reveals new colorectal cancer molecular subtypes with improved biological resolution and superior predictive and prognostic performance
Authors: Isella Claudio , Bellomo Sara E. , Brundu Francesco , Galimi Francesco , Ficarra Elisa , Marchionni Luigi , Trusolino Livio , Bertotti Andrea , Medico Enzo 
Published: July 2017

Abstract
Molecular classification of colorectal cancer (CRC) based on gene expression profiling of tumor samples is known to be heavily affected by transcripts of stromal origin. As a consequence, current CRC transcriptional subtypes reflect an admixture of cancer cell-intrinsic traits and tumor microenvironment features. Whether selective analysis of the cancer cell transcriptome could improve CRC subtyping, remains an open issue. In patient-derived xenografts (PDXs), human transcripts only originate from cancer cells, because stromal transcripts are of mouse origin. We therefore assessed cancer-cell intrinsic transcriptional features of CRC by generating human-specific expression profiles of 515 PDXs from 244 CRC patients, and performing unsupervised class discovery. We identified five “CRC intrinsic subtypes” (CRIS A-E) only partially overlapping with the current ones, and robustly enriched for distinct molecular, functional and phenotypic traits: (i) CRIS-A: mucinous, glycolytic, CIMP, and enriched for microsatellite instability or mutations in KRAS; (ii) CRIS-B: marked TGF-β pathway activity, epithelial-mesenchymal transition and poor prognosis; (iii) CRIS-C: MSS, elevated EGFR signaling and sensitivity to EGFR-targeted treatments; (iv) CRIS-D: MSS, WNT activation, and IGF2 overexpression and amplification; (v) CRIS-E: MSS, Paneth cell-like phenotype and higher frequency of TP53 mutation. CRIS subtypes successfully categorized independent sets of primary and metastatic CRCs and cell lines, for a total of over 3000 samples profiled by microarrays and RNAseq. The new subtypes displayed unprecedented predictive and prognostic performances, indipendent from known markers including stromal signatures, whose integration with CRIS further enhanced prognostic significance.
Citation Format: Claudio Isella, Sara E. Bellomo, Francesco Brundu, Francesco Galimi, Elisa Ficarra, Luigi Marchionni, Livio Trusolino, Andrea Bertotti, Enzo Medico. Cancer cell-selective transcriptome analysis reveals new colorectal cancer molecular subtypes with improved biological resolution and superior predictive and prognostic performance [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 1742. doi:10.1158/1538-7445.AM2017-1742
Abstract 1749: Stability of copy-number profiles defines two molecular subtypes during urothelial carcinoma’s evolution
Authors: Faltas Bishoy M. , Prandi Davide , Tagawa Scott T. , Nanus David , Molina Ana M. , Beltran Himisha , Demichelis Francesca , Rubin Mark A. 
Published: July 2017

Abstract
Background: Somatic copy-number alterations (SCNAs) are distinct molecular events occurring in muscle-invasive urothelial carcinoma (UC). Defining the biologic role and the timing of SCNAs in UC’s evolution is critical for understanding disease biology and for precision therapy.
Methods: To examine whether distinct SCNAs define specific subtypes of UC and characterize the evolutionary dynamics of SCNA acquisition, we conducted whole-exome sequencing (WES) of a discovery cohort of 44 advanced UC tumors and matching germline samples, including 13 pairs of matched primary and metastatic tumors prospectively collected before and after chemotherapy. We queried WES data from 285 UCs from The Cancer Genome Atlas (TCGA) as a validation cohort. We performed a novel in-depth allele-specific copy-number analysis in 2503 cancer genes using the CLONET computational framework, which accounts for tumor ploidy and cellularity to infer the clonal hierarchy of SCNAs.
Results: Analysis of SCNAs from tumor pairs within each patient revealed punctuated evolution of SCNAs occurring early in UC’s development followed by minor changes (clonal stasis) throughout the tumor’s lifetime. Two distinct clusters of UCs with strikingly different SCNA profiles in the discovery cohort emerged. Cluster A was defined by diploid copy number background and focal deletions in the 9p21 region (CDKN2A, CDKN2B and MTAP). Cluster B was defined by genome-wide duplications and several enriched amplifications including 1q21.1 (SETDB1 and MLLT11), (P = 0.0002) and 6p22.3 (E2F3), (P = 0.001). TP53 mutations (P = 0.0001) were enriched in the cluster B, consistent with the role of functional p53 as a “guardian of the genome” preventing chromosomal instability. SCNAs clusters A and B were confirmed in the TCGA validation cohort. Cluster A was enriched with tumors belonging to TCGA bladder cancer cluster III (“basal/squamous-like”) (P = 0.02).
Conclusions: Using novel allele-specific SCNAs analysis, we define two distinct clusters of UC presenting a framework for understanding this aspect of UC’s biology. In contrast to somatic mutations, SCNAs are clonally static during each tumor’s evolution. This data has important implications for precision medicine for UC.
Citation Format: Bishoy M. Faltas, Davide Prandi, Scott T. Tagawa, David Nanus, Ana M. Molina, Himisha Beltran, Francesca Demichelis, Mark A. Rubin. Stability of copy-number profiles defines two molecular subtypes during urothelial carcinoma’s evolution [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 1749. doi:10.1158/1538-7445.AM2017-1749