tbuckley/cabot-search huggingface dataset:
Abstract 1991: Enhanced role of the extracellular matrix in ovarian cancer recurrence
Authors: Zhiqing Huang, Brad Foster, Carole Grenier, Gregory Sfakianos, Regina Whitaker, Andrew Berchuck, Susan K. Murphy
Journal: Cancer Research (2017)

Abstract Purpose: Despite improvements in care and advancements in the understanding of ovarian cancer (OC) pathobiology and genetic alterations, the survival rate is disappointingly low when compared to that of other types of cancer. One factor contributing to the poor survival rate is the development of chemotherapeutic resistance and a high rate of recurrent tumor growth in the months and years following primary OC treatment. Our objective was to identify potential new therapeutic targets for prevention of recurrence through examination of changes in gene regulation that occur in recurrent versus matched primary tumors. Procedures: We used 16 primary-recurrent tumor pairs from patients with stage III/IV serous epithelial OC from the Duke Gynecologic Oncology Tissue Bank. Illumina Infinium HumanMethylation450 BeadChips and Affymetrix Human Genome U133A arrays were used to quantify methylation and gene expression, respectively. Expression and methylation of POSTN and COL11A1 were analyzed using an independent OC dataset comprising 38 women with &amp;lt;3 years survival and 26 women with &amp;gt;7 years survival, 3 normal ovarian surface epithelium (OSE) and 2 fallopian tube fimbriae epithelium (FTFE) samples. siRNA knockdown of POSTN and COL11A1 in OC cells was followed by expression and proliferation assays. Results: Paired student t tests showed a &amp;gt;2-fold difference for 13 of the 1,569 significantly differentially expressed genes, seven with increased expression in recurrent OC (POSTN, COL11A1, MMP1, MMP13, TNC, ASPN, and EPYC), and six with decreased expression (GATA6, PEG3, SST, MAOB, TSPAN8, and C7). Interestingly, all seven up-regulated genes are involved in extracellular matrix (ECM) functions, an important component of the tumor microenvironment. With an independent OC microarray dataset, we found elevated COL11A1 mRNA in OCs as compared to OSE and FTFE tissues (p&amp;lt;0.05). There are inverse correlations between COL11A1 expression and methylation at five promoter CG sites (R=-0.58 to -0.65, p&amp;lt;0.05). Immunohistochemistry showed higher expression of POSTN and COL11A1 in recurrent OC. Knockdown of POSTN and COL11A1 in OC cell lines led to significantly reduced proliferation (p&amp;lt;0.05). Conclusion: Our findings indicate that the genes involved in extracellular matrix function that contribute to the composition and regulation of the tumor microenvironment play critical roles in OC recurrence, and may offer new therapeutic opportunities. Citation Format: Zhiqing Huang, Brad Foster, Carole Grenier, Gregory Sfakianos, Regina Whitaker, Andrew Berchuck, Susan K. Murphy. Enhanced role of the extracellular matrix in ovarian cancer recurrence [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 1991. doi:10.1158/1538-7445.AM2017-1991
Abstract 4606: Preclinical characterization of a novel fully human IgG1 anti-PD-L1 mAb CK-301
Authors: Leonid Gorelik, George Avgerinos, Yune Kunes, Wayne A. Marasco
Journal: Cancer Research (2017)

Abstract Antibodies targeting Programmed Death-1 (PD-1), or its ligand, PD-L1, have demonstrated remarkable efficacy in subsets of cancer patients, with inhibition of the interaction between PD-1 on T-cells and PD-L1 on tumor cells leading to the recovery of anti-tumor immune response and immune-mediated eradication of tumors. However, not all patients respond to existing PD-1 and PD-L1 targeting agents and relapses to therapy still occur. Therefore, there exists a need to identify additional therapeutics and approaches to engage the immune system to enhance the efficacy of current anticancer therapies. Using phage and yeast display approaches, we have discovered and optimized a novel, fully human, PD-L1 specific IgG1 antibody, CK-301, which exhibits subnanomolar binding affinity for PD-L1. CK-301 blocks binding of PD-L1 to both PD-1 and B7-1 in enzyme-linked immunosorbent assays (ELISA) and cell-based competition assays. Using an assay measuring inhibition of a nuclear factor of activated T-cells (NFAT) reporter caused by PD-L1 binding to PD-1, we demonstrate that CK-301 completely reverses reporter inhibition at concentration of less than 1 µg/ml, IC50 of the dose response curve is 80ng/ml. CK-301 enhances IFN-gamma secretion in allogeneic mixed lymphocyte reaction (MLR) using primary human T-cells and immature dendritic cells. CK-301 can also trigger antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) mediated killing of PD-L1+ cell lines, including lymphoma cells. CK-301 has similar subnanomolar affinity for cynomolgus monkey PD-L1 as for human PD-L1, hence we chose Macaca fascicularis for pre-clinical toxicology and safety pharmacology studies. Single-dose administration of CK-301 to monkeys up to the highest tested dose of 100 mg/kg was shown to be safe and demonstrated linear dose-dependent pharmacokinetic (PK) properties over the dose range from 1 to 100 mg/kg with a half-life of 15 days at 100 mg/kg. A first-in-human Phase 1 study of CK-301 is planned to commence in mid-2017. Citation Format: Leonid Gorelik, George Avgerinos, Yune Kunes, Wayne A. Marasco. Preclinical characterization of a novel fully human IgG1 anti-PD-L1 mAb CK-301 [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 4606. doi:10.1158/1538-7445.AM2017-4606
Abstract 2105: Evaluation of antitumor properties of metformin over human multidrug-resistant chronic myeloid leukemia cells
Authors: Ligia P. Oliveira, Débora L. Renó, Rodrigo S. Curvello, Luana P. Lima, Ana Carolina S. Galvão
Journal: Cancer Research (2017)

Abstract Besides the progress in the knowledge of cancer biology, the rates of mortality due to this disease are still considerably elevated. Therefore, application of new drugs in antitumor therapies has been constantly studied. However, any of them have achieved a considerable success so far. In this work we evaluated the ability of metformin, a traditional hypoglycemic prescribed to treatment of type II diabetes along decades, over programmed cell death and modulation of metastatic potential in multidrug resistant (MDR) human myeloid chronic leukemia cells (Lucena), through MTT reduction test, flow cytometry, western blotting and gelatin zymography. Metformin was able to reduce the cell viability in a concentration and time-dependent manner, but was not able to induce Lucena cells to apoptosis or necrosis, though activation of the apoptotic machinery. Indeed, it was not observed activation of caspase 3, in contrast to an expressive activation of PARP. Interestingly, proteins associated to autophagy were overexpressed by Lucena cells, and an arrest of cell cycle was observed after exposition to the drug. Finally, it was verified that metformin was able to modulate activity of MMP2 and MMP9, enzymes associated to the metastatic process. Taken together these results suggest that the hypoglycemic is able to acts over the first steps of cancers in more aggressive stages. Finally, inhibition of MMPs indicates a promissory action of metformin for the treatment of metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Ligia P. Oliveira, Débora L. Renó, Rodrigo S. Curvello, Luana P. Lima, Ana Carolina S. Galvão. Evaluation of antitumor properties of metformin over human multidrug-resistant chronic myeloid leukemia 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 2105. doi:10.1158/1538-7445.AM2017-2105
Abstract SY07-02: Adipose stromal cells: A player in cancer progression and a therapeutic target
Authors: Mikhail Kolonin
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is promoted by white adipose tissue (WAT) overgrown in obesity. As an underlying mechanism, we have discovered the recruitment of adipose stromal cells (ASC) by tumors. We reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing its receptor CXCR1. As a candidate upstream mechanism, we identified interleukin 22 secreted by WAT-infiltrating leukocytes and signaling through IL-22R in cancer cells. Our experiments in Hi-Myc mice indicate that obesity promotes epithelial-mesenchymal transition (EMT). We show that ASC directly induce EMT in adenocarcinoma cells. To test whether cancer progression can be blocked by ASC targeting, we have used a hunter-killer peptide D-WAT composed of an ASC-homing and a pro-apoptotic domain. D-WAT administration depleted prostate stromal cells expressing a chemokine SDF1α and suppressed the EMT. Our results indicate that ASC promote the EMT, at least in part, via SDF1a paracrine signaling and validate ASC as a therapeutic target. Citation Format: Mikhail Kolonin. Adipose stromal cells: A player in cancer progression and a therapeutic target [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 SY07-02. doi:10.1158/1538-7445.AM2017-SY07-02
Abstract 3668: Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse breast cancer models
Authors: Francisco W. Puerta Martinez, Yisel A. Rivera, Teresa Nguyen, Xuejun Fan, Jared M. Henderson, Shifat Rehnuma, Mohammad B. Hossain, Hong Jiang, Juan Fueyo, Candelaria Gomez Manzano
Journal: Cancer Research (2017)

Abstract Metastasis of advanced stage cancers remains as the main cause of morbidity and mortality in oncologic patients. Metastatic cancers, especially those that metastasize to the brain, are generally resistant to conventional therapies. Thus, more innovative and efficacious therapies are urgently needed. Therapeutic goals are the specific targeting of malignant cells, shrinkage of stablished tumors, prevention and/or eradication of metastases and, ultimately, induction of a specific anti-tumor immune response. In this study we tested the efficiency of a treatment regimen consisting of oncolytic adenoviruses combined with specific immune regulators to prevent tumor progression and metastasis. In order to do so, mouse metastatic breast cancer cells 4T1 or 66c14, were orthotopically implanted in female BALB/c mice. The resulting primary tumors were treated with multiple doses of third generation adenoviruses targeting different immune checkpoints, such as, OX40/OX40L and GITR/GITRL pathways in the immune synapse. The treatment with these adenoviral constructs resulted in T cells activation and reduction of the metastases in 50% of the mice. In addition, the size and number of the metastases detected in lungs were significantly lower comparing with those observed in the control groups. Survival rates were also significantly different (P &amp;lt; 0.046) when compared to controls. FACS analysis of isolated tumor-infiltrating lymphocytes, as well as, splenocytes showed that OX40/OX40L or GITR/GITRL immune therapies were able to activate and increase the number of cytotoxic T cells and suppress tumor anergy. In summary, we demonstrated for the first time that Delta-24-RGDOX and Delta-24-GREAT, expressing OX40L and GITRL respectively, display antitumor effect on immune competent models of metastatic breast cancer. Citation Format: Francisco W. Puerta Martinez, Yisel A. Rivera, Teresa Nguyen, Xuejun Fan, Jared M. Henderson, Shifat Rehnuma, Mohammad B. Hossain, Hong Jiang, Juan Fueyo, Candelaria Gomez Manzano. Oncolytic adenoviruses expressing OX40L or GITRL immune modulators show antitumor effect on immune-competent mouse breast cancer 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 3668. doi:10.1158/1538-7445.AM2017-3668
Abstract 4969: Impaired PARP1 DNA repair defines chemosensitivity in IDH1 mutant cell
Authors: Yanxin Lu, Yang Liu, Yu-Ting Su, Wendy Bautista, Mark R. Gilbert, Jing Wu, Chunzhang Yang
Journal: Cancer Research (2017)

Abstract INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of IDH mutations in glioma are prognostic for better clinical outcomes with longer patient survival, and greater sensitivity to chemotherapy. In the present study, we explore the molecular mechanisms that determine the chemosensitivity in IDH1-mutated glioma cells, and seek a potential therapeutic strategy by targeting DNA repair pathway in IDH1-mutated cells. METHODS: We established IDH1-mutated cell lines by introducing pathogenic IDH1 mutations into glioma cells via lentivirus. We confirmed the metabolic deficiency and enhanced chemosensitivity in cells expressing IDH1 mutant enzyme. Further, we measured the intracellular level of nicotinamide adenine dinucleotide (NAD+), Poly (ADP-ribose) polymerase (PARP)-associated DNA repair and DNA damage level in these cells when treated with temozolomide (TMZ). Moreover, we evaluated a PARP inhibitor Olaparib and its synergic effect on TMZ-associated cytotoxicity. RESULTS: Our results show that the IDH1-mutated cells are more vulnerable to chemotherapy. TMZ treatment resulted in over 20-fold increase of cell death in IDH1-mutated cells compared with their wild type counterpart. IDH1-mutated cells exhibited an over 1.3-fold increase in DNA damage and over 1.42-fold increase in cellular apoptosis under TMZ treatment. Accordingly, IDH1-mutated cells produced 83.8% less poly (ADP-ribose) polymer (pADPR), an important substrate for PARP-associated DNA repair, during TMZ treatment; suggesting their incompetence to maintain genomic integrity due to decreased availability of NAD+. Targeting the PARP-associated DNA repair pathway using Olaparib remarkably potentiated TMZ-induced cytotoxic effects by 2.16 fold in IDH1 mutated cells. CONCLUSION: Our findings demonstrate that metabolic defects in IDH1-mutated cells affect PARP-associated DNA repair pathway via NAD+ depletion, and therefore prompt the sensitivity to chemotherapies. Targeting PARP-associated DNA repair pathway may represent a novel therapeutic avenue for IDH1-mutated gliomas. Citation Format: Yanxin Lu, Yang Liu, Yu-Ting Su, Wendy Bautista, Mark R. Gilbert, Jing Wu, Chunzhang Yang. Impaired PARP1 DNA repair defines chemosensitivity in IDH1 mutant cell [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 4969. doi:10.1158/1538-7445.AM2017-4969
Transcriptional control of microglia phenotypes in health and disease
Authors: Inge R. Holtman, Dylan Skola, Christopher K. Glass
Journal: Journal of Clinical Investigation (2017)

Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals. We then describe functions of specific transcription factors in normal and pathological contexts and conclude with a consideration of open questions to be addressed in the future.
Abstract 3027: Dissecting mechanisms of anti-PD-1 therapy with massively parallel single-cell RNA-sequencing
Authors: Brian C. Miller, Marc H. Wadsworth, Kevin Bi, Travis K. Hughes, Robert Manguso, Arlene H. Sharpe, Alex K. Shalek, Nicholas Haining
Journal: Cancer Research (2017)

Abstract Anti-PD-1 therapy is an important new treatment option for many different types of malignancies, but overall response rates are less than 40%. Limited understanding of how anti-PD-1 treatment changes the tumor immune microenvironment is a barrier to identifying rational combination therapies and understanding mechanisms of immunotherapy resistance. To overcome this barrier, we set out to understand the mechanisms by which anti-PD-1 therapy augments the anti-tumor immune response using single-cell genomics. We have developed a massively parallel single-cell RNA-sequencing platform (“Seq-Well”) that uses a fabricated chip with nearly 100,000 nanowells into which barcoded beads and individual cells are distributed prior to lysis and RNA capture. We used this platform to comprehensively define the global expression profile of all major immune lineages in the tumor microenvironment in a mouse tumor model of immunotherapy. Mice were implanted with the B16F10 melanoma transplantable model of cancer and treated with anti-PD-1 or control antibodies. Tumors were harvested and CD45+ tumor-infiltrating leukocytes isolated by FACS. In a single experiment we were able to sequence the transcriptomes of over 600 individual cells, allowing us to clearly distinguish different immune lineages within the tumor microenvironment. We detect two transcriptionally distinct populations of CD8+ T cells, one that is highly proliferative (as marked by Ki-67), and one that has higher expression of cytotoxic markers (i.e. perforin). The Ki-67hi population is enriched for a gene expression signature from terminally exhausted CD8+ T cells in chronic viral infection, suggesting that this is a more exhausted subset. Treatment with anti-PD-1 globally alters the tumor microenvironment, including enriching for CD8+ T cells in the Prfhi subpopulation compared with the Ki-67hi more terminally exhausted population. Studies to understand changes in the immune infiltrate of immunotherapy resistant tumors are currently ongoing. In conclusion, massively parallel single-cell RNA-sequencing allows us to dissect the mechanisms by which checkpoint blockade controls tumor growth, revealing shifts in the differentiation state of exhausted CD8+ T cells induced by checkpoint blockade. Citation Format: Brian C. Miller, Marc H. Wadsworth, Kevin Bi, Travis K. Hughes, Robert Manguso, Arlene H. Sharpe, Alex K. Shalek, Nicholas Haining. Dissecting mechanisms of anti-PD-1 therapy with massively parallel single-cell RNA-sequencing [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 3027. doi:10.1158/1538-7445.AM2017-3027
Abstract 4597: A novel immuno-oncology approach: targeting cell-surface mesothelin with a fusion construct containing human granzyme B
Authors: Lawrence H. Cheung, Rasheed Tijani, Nasir Khan, Claire Thuning-Roberson, Michael G. Rosenblum
Journal: Cancer Research (2017)

Abstract Immunological approaches to target tumors have gained considerable traction recently because of excellent clinical results. In addition, targeted treatment with antibody-drug conjugates (ADCs) can also be effective in achieving regression of solid tumors. The challenge for ADCs continues to be efficacy, stability of the construct and development of resistance. We have developed a unique fusion protein composed of 1) a novel human single-domain antibody (SD1) that uniquely targets Region III of the mesothelin glycoprotein and 2) an engineered version of the human serine protease Granzyme B (GrB). Mesothelin is highly expressed in aggressive cancers such as malignant mesothelioma, pancreatic and ovarian cancers, and NSCLC. Granzyme B generates an intense, irreversible pro-apoptotic effect through direct cleavage of caspases, release of cytochrome C from mitochrondria, and cleavage of nuclear matrix. Previous ADCs targeting mesothelin have faced the drawbacks of toxic payloads, formation of neutralizing antibodies, and competition with the serum protein MUC16/CA125. SD1-GrB represents a new class of completely human immunotoxins containing a payload with a unique mechanism of action. Additionally, because of its unique binding properties, SD1 does not compete with circulating CA125 and is not subject to cleavage. The SD1-GrB construct was designed as a homodimer (~200kDa) containing an IgG Fc domain and was expressed using transient-transfection of HEK293E cells. The soluble SD1-GrB was isolated from conditioned media and purified to homogeneity as assessed by SDS-PAGE and Western. Enzymatic activity of the GrB component was assessed by IEPD and found to be similar to authentic, native GrB. Binding to mesothelin was confirmed by surface plasmon resonance. Additionally, binding to the human lung adenocarcinoma cell lines H460 and HCC1703 was demonstrated by ELISA. Initial cytotoxicity (IC50) of SD1-GrB against H460 and HCC1703 was in the 30 nM range. Assessment against a larger panel of cell lines is ongoing followed by in vivo efficacy in a human tumor xenograft model. Our preliminary evaluation of SD1-GrB ADC suggests this construct has a unique mechanism of action and is highly cytotoxic against target cells. This molecule appears to be an excellent candidate for further pre-clinical development as a therapeutic agent. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Lawrence H. Cheung, Rasheed Tijani, Nasir Khan, Claire Thuning-Roberson, Michael G. Rosenblum. A novel immuno-oncology approach: targeting cell-surface mesothelin with a fusion construct containing human granzyme B [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 4597. doi:10.1158/1538-7445.AM2017-4597