Tumor & microenvironment最新文献

{"title":"Abstract B31: Autofluorescence imaging of macrophage metabolism during tumor-mediated 3D migration","authors":"Tiffany M. Heaster, Jiaquan Yu, D. Beebe, M. Skala","doi":"10.1158/2326-6074.TUMIMM17-B31","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B31","url":null,"abstract":"Macrophages are key regulators of tumor progression, and can be targeted for cancer treatment. However, reprogramming macrophages for anti-tumor activity is challenging due to their plasticity. Standard assessment of macrophage function (e.g., ELISA) lacks the sensitivity to capture cell-level heterogeneity in living macrophages. Therefore, single cell imaging and analysis tools are needed to study heterogeneous macrophage behavior within the tumor microenvironment. Macrophages adapt their metabolism to alter both phenotype and function. Thus, we propose the combination of optical metabolic imaging (OMI) and microdevice co-culture to observe cellular level macrophage heterogeneity in response to tumor stimuli. OMI enables noninvasive, dynamic imaging of intact, living samples by measuring autofluorescence from the metabolic co-enzymes NAD(P)H and FAD. Cellular level redox balance is evaluated with the optical redox ratio, defined as the ratio of NAD(P)H to FAD intensity. Additionally, NAD(P)H and FAD fluorescence lifetimes report on metabolic enzyme binding activities. Three-layer microdevices consisting of murine PyVMT breast carcinoma cells, collagen (200 micron thickness), and RAW 264.7 macrophages, respectively, were designed to monitor tumor-mediated macrophage polarization and migration. Metabolic changes with macrophage migration were measured with OMI at 24, 48, and 72 hours after culture. Redox ratio and NAD(P)H mean lifetime increased over time in co-cultured macrophages (p Citation Format: Tiffany M. Heaster, Jiaquan Yu, David J. Beebe, Melissa C. Skala. Autofluorescence imaging of macrophage metabolism during tumor-mediated 3D migration [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B31.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86149819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B38: Increasing tumor-infiltrating CD8+ T cell response and checkpoint inhibitor efficacy by enzymatic reduction of tumor hyaluronan in a murine syngeneic pancreatic cancer model","authors":"B. Thompson, Trevor B. Kimbler, B. Blouw, R. Clift, Yujun Huang, S. Rosengren, Curtis B. Thompson, Jisook Lee","doi":"10.1158/2326-6074.TUMIMM17-B38","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B38","url":null,"abstract":"Inducing an efficient CD8 + T-cell-mediated antitumor immune response at the tumor site is critical for successful immunotherapy. The trafficking and activation of these effector CD8 + T cells to tumors are often inhibited by various immunosuppressive mechanisms in the tumor microenvironment (TME). Hyaluronan (HA), a glycosaminoglycan that accumulates in the TME of many solid tumors, is associated with rapid tumor progression, poor prognosis and increased immunosuppression. We have previously demonstrated in preclinical models that enzymatic degradation of TME HA by intravenous PEGylated recombinant human hyaluronidase PH20 (PEGPH20) enhances anti-Programmed death-ligand 1 (anti-PD-L1) efficacy and increases access of immune cells to the tumor (Clift, AACR 2017 poster #641). In this study, we aimed to extend these findings to a murine syngeneic pancreatic cancer model to explore the pan-tumor potential of combining PEGPH20 and anti-PD-L1 to improve anti-tumor immune response. To test this hypothesis in a pancreatic tumor model, Pan02 murine pancreatic adenocarcinoma cells were engineered to over-express hyaluronan synthase-3 (Pan02/Has3). Peritibial Pan02/Has3 tumors accumulated 10-fold higher levels of HA (1668 ng/mg) compared with Pan02 parental tumors (166 ng/mg) as determined by HA ELISA. HA accumulating Pan02/Has3 tumors were treated with combinations of PEGPH20 and/or anti-PD-L1, and tumor growth was monitored. Treatment with PEGPH20 (1mg/kg, biweekly) resulted in nearly complete removal of HA at 24hrs, the time point at which anti-PD-L1 treatment (5mg/kg, biweekly) was initiated. Tumor burden growth was reduced by 50% with combination of PEGPH20 and anti-PD-L1 versus 21% with PEGPH20 alone (p + tumor infiltrating lymphocytes (TILs) in tumors treated with PEGPH20 alone compared with the vehicle group. Similarly, tumors treated with PEGPH20 in combination with anti-PD-L1 contained higher numbers of CD8 + TILs, CD4 + TILs, and Natural killer (NK) cells, and had increased CD8:Treg ratios compared to anti-PD-L1 treatment alone. Taken together, our data suggest that tumor HA accumulation may act as a barrier to immune cell access in a mouse model of pancreatic cancer, and that enzymatic reduction of HA can facilitate access of CD8 + T cells and enhance anti-PD-L1 efficacy. These findings are consistent with prior studies and support the ongoing clinical evaluation of combining PEGPH20 with immune checkpoint inhibitors to improve anti-tumor efficacy in HA-accumulating tumors. Citation Format: Benjamin Thompson, Trevor Kimbler, Barbara Blouw, Renee Clift, Yujun Huang, Sanna Rosengren, Curtis B. Thompson, Jisook Lee. Increasing tumor-infiltrating CD8+ T cell response and checkpoint inhibitor efficacy by enzymatic reduction of tumor hyaluronan in a murine syngeneic pancreatic cancer model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"195 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73118758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA36: Regulatory T cells, polymorphisms, and response to checkpoint blockade: From mechanisms to potential biomarkers","authors":"S. Quezada","doi":"10.1158/1557-3265.AACRIASLC18-IA36","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-IA36","url":null,"abstract":"In mice, anti-CTLA-4 monoclonal antibodies (mAbs) require Fc-gamma receptor (FcγR)-mediated depletion of intratumoral regulatory T (Treg) cells to promote tumor rejection. However, the relevance of this mechanism in the human setting remains controversial. Using a mouse model expressing human FcγRs, and analysis of clinical samples from ipilimumab-treated melanoma patients, we investigate the potential role of Treg depletion in the activity of antibodies targeting human CTLA-4. Citation Format: Sergio Quezada. Regulatory T cells, polymorphisms, and response to checkpoint blockade: From mechanisms to potential biomarkers [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA36.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73373301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR13: MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR-mutant lung cancer","authors":"S. Nanjo, S. Arai, Wei Wang, A. Hata, N. Katakami, S. Yano","doi":"10.1158/1557-3265.AACRIASLC18-PR13","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-PR13","url":null,"abstract":"Leptomeningeal carcinomatosis occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P This abstract is also being presented as Poster B29. Citation Format: Shigeki Nanjo, Sachiko Arai, Wei Wang, Akito Hata, Nobuyuki Katakami, Seiji Yano. MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR-mutant lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR13.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83662794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B62: Immune gene expression profiling identifies predictors of relapse in childhood acute myeloid leukemia","authors":"J. Vadakekolathu, G. Foulds, Tasleema Patel, S. Reeder, A. Pockley, S. Tasian, S. Rutella","doi":"10.1158/2326-6074.TUMIMM17-B62","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B62","url":null,"abstract":"Tumor phenotypes are dictated not only by the neoplastic cell component, but also by the tumor microenvironment (TME), which includes immune and inflammatory cells. Acute myeloid leukemia (AML) is the second most common leukemia of childhood. Although intensive multi-agent chemotherapy in conjunction with improved supportive care has increased survival rates to 70%, 30-40% of children with AML relapse and only one-third of them will survive to adulthood. Investigation of new therapeutic strategies for high-risk AML, including immunotherapy, remains a priority and is being actively pursued. Importantly, AML-induced immune suppression poses a fundamental barrier to successful immune-based interventions. We previously showed that in vitro treatment of primary AML cells with interferon (IFN)-γ induces functional indoleamine 2,3-dioxygenase-1 (IDO1), a molecule with potent immunosuppressive properties, in 50% of unselected cases (IFN-γ responders). With a median follow-up of 8 years, IFN-γ responders experienced a significantly shorter event-free survival and overall survival (OS). Herein, we aimed to get insights into the immune landscape of childhood AML using multi-scale immune profiling strategies with the aim to identify molecular circuits that can be targeted to revert leukemia-induced immune dysfunction and improve clinical outcome. We employed a novel high-throughput digital platform, the nCounter system (nanoString Technologies, Seattle, USA), and Optimized Multi-color Immuno-phenotyping Panels (OMIPs) to comprehensively characterize the bone marrow immune infiltrate in 34 children diagnosed with non-promyelocytic AML (17 males, 17 females; median age at diagnosis=10 years; 28 de novo AML, 4 infant leukemia, 1 secondary AML, 1 congenital leukemia; 7 patients with favorable-risk cytogenetics, 21 patients with intermediate-risk cytogenetics and 6 patients with unfavorable-risk cytogenetics). The RNA Pan-Cancer Immune Profiling Panel, which includes 109 cell surface markers for 24 immune cell types, 30 cancer testis antigens, and >500 immune response genes, allowed us to measure immune gene expression levels on the clinic-ready nCounter® FLEX platform (nanoString Technologies). Transcriptomic data were normalized and analyzed using the nSolver software package. Relapse-free survival (RFS) and OS were selected as covariates. For immune phenotyping studies, viable bone marrow mononuclear cells were labeled with fluorochrome-conjugated antibodies and then analyzed on a 10-color Gallios flow cytometer (Beckman Coulter Life Sciences, Buckinghamshire, UK) with standard settings. Hierarchical clustering of immune gene expression data highlighted patient subgroups with heightened expression of T-cell and natural killer (NK)-cell function genes, as well as Toll-like receptor (TLR) genes, interleukin genes and tumor necrosis factor (TNF) family genes. Patients with high levels of CD8A mRNA also expressed IFNG , CXCL9 , CXCL10 , FOXP3 and negative checkpoi","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78314051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B51: Quantitative multiplex immunofluorescence reveals that chemoradiation therapy favorably modulates the tumor immune microenvironment of pancreatic cancer","authors":"T. Enzler, R. Gartrell, Ladan Fazlollahi, S. Perni, P. Kim, Thomas D. Hart, Christian S. Monsalve, Samuel E Green, Y. Saenger, D. Horowitz","doi":"10.1158/2326-6074.TUMIMM17-B51","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-B51","url":null,"abstract":"Immunotherapy has altered the therapeutic landscape in several malignancies but to date has not been effective in treatment of pancreatic ductal adenocarcinoma (PDAC). Patients with advanced PDAC continue to have median survival under one year and thus new therapeutic approaches for this daunting disease are urgently needed. It is well known that radiation therapy causes the release of tumor antigens and pro-inflammatory cytokines leading to stimulation of anti-tumor immunity. In our study, we sought to quantify this effect by comparing immune cell infiltration in tissues of PDAC treated with chemoradiation to untreated tumors. Slides obtained from surgical resection specimens were stained using quantitative multiplex immunofluorescence (qmIF) for: CD3, CD4, CD8, FOXP3, CD68, and Ki-67. Nuclei were labeled using DAPI. Slides with tumor tissue were then imaged (15-20 images per slide) using automated imaging system VECTRA and they were analyzed using inForm software to evaluate cell density in tumor and stroma compartments. Overall, slides were obtained and analyzed from 6 different patients who underwent chemoradiation therapy and from 5 patients who did not receive neoadjuvant treatment. When comparing treated vs. untreated tumors, CD3+ densities were significantly higher in the stromal tissue of the treated tumors vs. untreated tumors (P = 0.0095). CD3+CD4+FOXP3- T helper cells were similarly significantly higher in treated tumors (P = 0.0095), while there was a trend towards increase in CD3+CD8+ cytotoxic T cells (P = 0.0667). Conversely, CD4+FOXP3+ cells were increased in untreated tumors although significance was not reached (P = 0.15). No clear differences in infiltrating CD68+ macrophages were observed between treated and untreated tumors. To our knowledge this is the first time that immune cell infiltrates of PDAC were characterized using qmIF. The higher counts of CD3+CD4+ T helper cells and of CD3+CD8+ cytotoxic T cells found in tumors treated with chemoradiation can be explained by the increased immunogenicity caused by treatment. A tendency towards a higher density of CD4+FOXP3+ cells in untreated tumors may contribute to immunosuppression in the tumor microenvironment as there were less CD3+CD8+ cytotoxic T cells and CD3+CD4+ T helper cells found in those tumors. We are in the process of collecting and staining additional samples to build on these findings. We will correlate our data with survival data to identify biomarkers predictive of outcome and provide rationale for the development of new treatment strategies for this challenging disease. Citation Format: Thomas Enzler, Robyn Gartrell, Ladan Fazlollahi, Subha Perni, Pan Kim, Thomas Hart, Christian Monsalve, Samuel Green, Yvonne Saenger, David P. Horowitz. Quantitative multiplex immunofluorescence reveals that chemoradiation therapy favorably modulates the tumor immune microenvironment of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immun","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"528 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77681668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B23: Novel epidermal growth factor receptor inhibitors cross the blood-brain barrier and inhibit the growth of metastatic non-small cell lung cancer","authors":"Michelle Muldong, C. Jamieson, Y. Long, I. Deichaite, David W. Anderson, A. Lewis, N. Cacalano","doi":"10.1158/1557-3265.AACRIASLC18-B23","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B23","url":null,"abstract":"Deaths from solid tumors are often not due to the primary lesion but to metastatic disease at distal sites such as the lung, liver, and brain. Patients with non-small cell lung cancer (NSCLC) experience brain metastases, a poor prognostic marker, at an incidence rate of 30-50%. A significant proportion of the metastatic tumors express activating mutations of the EGFR, including exon 19 deletions as well as point mutations within the enzyme active site (L858R), which confer increased sensitivity to EGFR inhibitors. However, current small-molecule therapeutics poorly inhibit the growth of NSCLC brain metastases due to difficulty crossing the blood-brain barrier and harmful off-target effects. Thus, NSCLC patients with brain metastases have access to very few emerging treatment options. We have synthesized a novel class of compounds that irreversibly inhibit the epidermal growth factor receptor (EGFR) in the nanomolar range in vitro, and demonstrate a high degree of selectivity for EGFR mutants found frequently in NSCLC, in particular exon 19 deletions and L858R mutations, while sparing wild-type (WT) EGFR. Two compounds, LL-001 and LL-019, from Capella Therapeutics, Inc., inhibited L858R EGFR-mediated autophosphorylation and phosphorylation of downstream targets Akt and ERK MAP kinase at a concentration of approximately 100nM and blocked the kinase activity of an EGFR mutant, T790M, which confers resistance to first-generation EGFR inhibitors. In contrast, these compounds only weakly inhibited WT EGFR and failed to inhibit either the insulin receptor or insulin-like receptor-I, suggesting that these inhibitors would produce minimal off-target side effects in treated patients. Both compounds induced full remission of subcutaneous tumors with the human NSCLC cell line H1975 (T790M/L858R+). Most notably, pharmacokinetic studies showed that these compounds, when administered at a concentration of 150mg/kg in mice, showed no signs of toxicity and were found in the brain at concentrations ranging from 12-171 times higher than the GI50 for inhibition of EGFR+ NSCLC cell line proliferation in vitro. To determine whether these compounds could treat NSCLC brain metastases, we developed intracranial and intracardiac injection orthotopic xenograft models of brain metastatic NSCLC. LL-001 and LL-019 could induce remission of brain tumors in mice injected intracranially with the human NSCLC cell line HCC827-luciferase, which expresses an exon 19 deletion mutant of EGFR. Likewise, both compounds inhibited the growth of the human NSCLC cell line PC9M in an intracardiac model of brain metastatic NSCLC, and greatly extended the survival of mice compared to those receiving vehicle alone. Our results indicate that LL-001 and LL-019 can cross the blood-brain barrier at levels sufficient to inhibit the growth of brain metastatic lung cancer, with minimal deleterious off-target effects. These compounds show promise for the treatment of critically underserved NSCLC patien","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84720417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B28: Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR-mutant lung cancer","authors":"M. Momčilović, Sean T. Bailey, Jason T. Lee, C. Magyar, D. Braas, T. Graeber, F. Parlati, S. Demo, Konstyantyn Krysan, Tonya C. Walser, S. Dubinett, S. Sadeghi, H. Christofk, D. Shackelford","doi":"10.1158/1557-3265.AACRIASLC18-B28","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B28","url":null,"abstract":"Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to noninvasively measure metabolic response to CB-839 and erlotinib combination therapy. Citation Format: Milica Momcilovic, Sean T. Bailey, Jason T. Lee, Clara Magyar, Daniel Braas, Thomas Graeber, Francesco Parlati, Susan Demo, Konstyantyn Krysan, Tonya C. Walser, Steven M. Dubinett, Saman Sadeghi, Heather R. Christofk, David B. Shackelford. Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR-mutant lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B28.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88950424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B35: Class IIa HDAC inhibition promotes an antitumor macrophage phenotype that induces breast tumor regression and inhibits metastasis","authors":"Jennifer L. Guerriero, Alaba Sotayo, H. Ponichtera, J. Castrillon, Alexandra L. Pourzia, S. Schad, Shawn F. Johnson, Ruben D Carrasco, Susan B. Lazo, R. Bronson, Scott P. Davis, M. Lobera, M. A. Nolan, A. Letai","doi":"10.1158/2326-6074.tumimm17-b35","DOIUrl":"https://doi.org/10.1158/2326-6074.tumimm17-b35","url":null,"abstract":"","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"126 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87768877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B24: Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma","authors":"Kristin Holmes, Filip Mundt, P. Mertins, S. Carr, A. Berger","doi":"10.1158/1557-3265.AACRIASLC18-B24","DOIUrl":"https://doi.org/10.1158/1557-3265.AACRIASLC18-B24","url":null,"abstract":"Mutations in Ras-family genes Kirsten rat sarcoma viral oncogene (KRAS) and Ras-like in all tissues (RIT1) occur in 30% and 2% of lung adenocarcinomas, respectively. Targeted therapies have shown promise in lung adenocarcinomas and other cancers; however, there are currently no FDA-approved drugs that directly target RIT1 or KRAS. To identify critical effector pathways and/or genetic dependencies that might be targeted for clinical benefit in these cancers, we undertook complementary proteomic and small-molecule screens in multiple human lung cancer models. To better understand the signaling networks modulated by RIT1 and KRAS, we performed deep characterization of total protein and phosphoproteins in non-transformed human lung epithelial cells engineered to express mutant or wild-type RIT1 or KRAS. 10,131 proteins were detected across all samples, 9,001 of which were detected in every sample. 29,172 phosphorylated sites were detected with 14,769 of these identified in every sample. Gene set enrichment analysis (GSEA) identified pathways significantly modulated by RIT1 M90I, KRAS G12V, or KRAS Q61H mutations. Whereas some pathways, such as MYC, were commonly activated by both mutant RIT1 and KRAS, others, such as Aurora kinase signaling, were specifically perturbed by RIT1. Previously, we found that mutant RIT1 and KRAS can transform human lung epithelial cells and confer resistance to EGFR blockade in EGFR-dependent lung adenocarcinoma. To identify opportunities for therapeutic intervention of RIT1- and KRAS-mutant tumors, we screened a collection of 160 small molecules for their ability to block RIT1/KRAS-induced drug resistance in PC9 cells, an EGFR-mutant lung adenocarcinoma cell line. Interestingly, RIT1 M90I-expressing cells were selectively killed as a result of treatment with the Aurora kinase inhibitors, alisertib and barasertib, while KRAS G12V cells were resistant to these inhibitors. The specific effect of Aurora kinase inhibition on RIT1 mutant cells was also confirmed in a fibroblast transformation assay and could not be attributed to proliferation rate, which was similar between RIT1- and KRAS-expressing cells. Moreover, Aurora kinase B (AURKB) was among the most differentially expressed transcripts when comparing RIT1- or KRAS-expressing cells, suggesting differential effects of RIT1 and KRAS on Aurora kinase activity. These findings nominate Aurora kinase inhibition as a potential therapeutic strategy in RIT1- , but not KRAS-mutant, lung cancer. Citation Format: Kristin D. Holmes, Filip Mundt, Phillip Mertins, Steve Carr, Alice Berger. Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B24.","PeriodicalId":92311,"journal":{"name":"Tumor & microenvironment","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78518234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}