tbuckley/cabot-search huggingface dataset:
Meta-analysis of the predictive and prognostic value of erlotinib-related biomarkers in phase III, placebo-controlled trials in non-small cell lung cancer (NSCLC): Recommendations of the BioLOGUE advisors.
Authors: D. Soulieres, J. Wolf, F. A. Shepherd, F. Cappuzzo, P. A. Bunn, R. S. Herbst, F. R. Hirsch, K. M. Kerr, T. Mitsudomi, M. S. Tsao, C. Yang, F. C. Richardson, B. Klughammer, B. Wacker, D. Sternberg, A. M. Davies
Journal: Journal of Clinical Oncology (2011)

7533 Background: The BioLOGUE (Biomarkers Lung Oncology Group Understanding Erlotinib) advisors carried out a meta-analysis using two phase III, placebo-controlled trials of erlotinib to determine the clinical utility of four tumor-based biomarkers (BMs) in the post-first line setting: EGFR protein expression (immunohistochemistry [IHC]); EGFR copy number (fluorescent in-situ hybridization [FISH]); EGFR activating mutations; and KRAS mutations. Methods: Patient-based data from BR.21 and SATURN were pooled to carry out univariate and multivariate analyses of PFS and OS, with or without clinical factors, which differentiated between predictive and prognostic effects. Stepwise variable selection was used to identify any confounding relationships between BMs, clinical factors and outcome. Full methodology will be presented. Results: Results of the pooled meta-analysis for each BM are shown in the table: X indicates a predictive effect for outcome with erlotinib, Y+ and Y- indicate a positive or negative prognostic effect, respectively, and x or y indicate a trend, i.e. 0.05 < p ≤0.10. Conclusions: Based on these analyses, EGFR IHC, EGFR FISH and KRAS mutations should not be used to positively or negatively select patients for erlotinib after first-line chemotherapy. EGFR mutation testing, while of value in the first-line setting, should not be used to positively or negatively select patients for maintenance/second-line erlotinib. PFS OS Cox model terms EGFR IHC EGFR FISH EGFR mut KRAS mut EGFR IHC EGFR FISH EGFR mut KRAS mut BM only Y+ p=0.0210 HR=1.19 X p=0.0442 X p=0.0480 Y- p=0.0004 HR=1.43 – – Y+ p < 0.0001 HR=0.53 Y-p=0.0349 HR=1.27 BM and patient chars Y+ p=0.0122 HR=1.21 x p=0.0540 X p=0.0293 Y- p=0.0021 HR=1.37 y+ p=0.0669 HR=1.17 – Y+ p=0.0054 HR=0.65 Y- p=0.0931 HR=1.21 BM and other BMs Y+ p=0.0171 HR=1.20 – x p=0.0614 Y- p=0.0010 HR=1.40 – – Y+ p < 0.0001 HR=0.54 y- p=0.0810 HR=1.22 BM and other BMs and patient chars Y+ p=0.0050 HR=1.24 – X p=0.0371 Y- p=0.0030 HR=1.36 y+ p=0.0835 HR=1.26 – Y+ p=0.0049 HR=0.64 y- p=0.0803 HR=1.22
515. Oncolytic Adenovirus Armed with Cytokines Enhances CAR-T Cell Efficacy in Pancreatic Tumor Model
Authors: Keisuke Watanabe, John Scholler, Sonia Guedan, Shannon E. McGettigan, Yanping Luo, Siri Tähtinen, Suvi Parviainen, Riikka Havunen, Mikko Siurala, Akseli Hemminki, Carl H. June
Journal: Molecular Therapy (2016)

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has shown significant efficacy in hematological malignancies, however, the efficacy against solid tumors remains limited. Immunosuppression caused by tumor microenvironment or poor infiltration of transferred T cells can restrict T cell efficacy. We propose that oncolytic Adenovirus (O-Ad) armed with cytokines improves the efficacy of adoptive T cell therapy by modulating the tumor environment. Aim: Here we aimed to study if O-Ad armed with cytokines can 1) cause direct lysis of pancreatic cancer cells, 2) enhance killing by CAR-T cells. 3) enhance infiltration and persistence of CAR-T cells in the context of solid tumors. Methods: We targeted pancreatic tumor cell lines by mesothelin specific CAR-T cells (SS1-BBz CAR-T) in combination with O-Ad; Adv-5/3-d24-IL2 or Adv-5/3-d24-TNF-IL2, which consist of an adenovirus serotype 5 nucleic acid backbone, a serotype 5/3 chimeric fiber knob, a 24-bp deletion (d24) in the Rb binding constant region 2 of E1 promoter, an E2F tumor specific promoter and cytokines (interleukin 2 or tumor necrosis factor alpha or both). Results: Pancreatic tumor cell lines used in this study; ASPC1, BXPC3, Capan2 expressed the Adv-serotype 3 receptor, DSG2. We also confirmed that O-Ad does not have adverse effects on T cell viability and proliferation even at high titer (1,000vp/cell) in an in vitro assay. To look at the efficacy of the O-Ad and CAR-T combination, we performed a killing assay. O-Ad clearly enhanced killing by CAR-T cells in luciferase based assay. We also used xCELLigence real time cell analyzer (RTCA) for kinetic analysis of killing. In combination with O-Ad, more rapid killing kinetics by CAR-T cells were observed especially in lower E:T ratio. To look at the impact of the combination in vivo, subcutaneous ASPC1-CBG-GFP in NSG mice were treated with CAR-T alone or in combination with intra-tumoral injection of O-Ad. O-Ad showed significant synergy with CAR-T in luciferase based photon assay. And higher number of T cells was observed in spleen in the O-Ad armed with IL2 combination group. Conclusions: These results suggest that combination therapy of O-Ad armed with cytokine(s) and CAR-T cells is effective against solid tumors by enhancing T cell activity.
Abstract 2263: Mitochondrial ATAD3A combines with GRP78 to regulate the stability of the WASF3 metastasis-promoting gene
Authors: yong teng, xiaoou ren, John Cowell
Journal: Cancer Research (2015)

Abstract ATAD3A is an integral mitochondrial membrane protein with unknown function, although we now show that high-level expression is associated with poor survival in breast cancer patients. Using a mass spectrometry approach we have demonstrated that ATAD3A interacts with the WASF3 metastasis promoting protein. Knockdown of ATAD3A leads to decreased WASF3 protein levels in breast and colon cancer cells. Silencing ATAD3A also results in loss of both cell anchorage-independent growth and invasion and suppression of tumor growth and metastasis in vivo using NSG immuno-compromised mice. HSP70 is responsible for stabilizing WASF3 in the cytoplasm, but inactivation of HSP70 does not lead to loss of WASF3 stability at the mitochondrial membrane, where presumably it is protected through its interaction with ATAD3A. In response to endoplasmic reticulum stress, increases in the GRP78 protein level leads to increased WASF3 protein levels. We also show that ATAD3A was present in a WASF3-GRP78 complex and suppression of GRP78 led to destabilization of WASF3 at the mitochondrial membrane, which was ATAD3A dependent. Furthermore, ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability. It appears, therefore, that stabilization of WASF3 function occurs through its interaction with ATAD3A and GRP78, which may provide a bridge between the endoplasmic reticulum and mitochondria, allowing communication between the two organelles. These findings also suggest that pharmacologic inhibition of ATAD3A could be an effective therapeutic strategy to treat human cancer. Citation Format: yong teng, xiaoou ren, John Cowell. Mitochondrial ATAD3A combines with GRP78 to regulate the stability of the WASF3 metastasis-promoting gene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2263. doi:10.1158/1538-7445.AM2015-2263
Mobilization of Hematopoietic Stem Cells by a Bendamustine-Containing Regimen in Hodgkin's Lymphoma
Authors: Antonella Anastasia, Alessandro Pulsoni, Alessandro Re, Francesco Merli, Carmelo Carlo-Stella, Cristina Gabutti, Luca Castagna, Giorgia Annechini, Anna Marina Liberati, Ercole Brusamolino, Armando Santoro
Journal: Blood (2012)
Clinical applications of a next-generation sequencing panel in non-small cell lung cancer
Authors: E. Rijavec, C. Genova, G. Barletta, F. Biello, C. Maggioni, M.G. Dal Bello, A. Truini, S. Coco, I. Vanni, A. Alama, F. Grossi
Journal: Annals of Oncology (2015)
327. Oncolytic Virus Therapy Using Recombinant HSV-1 for Nonseminoma Germ Cell Tumors
Authors: Shigenori Kakutani, Hiroshi Fukuhara, Satoru Taguchi, Yuta Takeshima, Yukio Homma, Yasushi Ino, Tomoki Todo
Journal: Molecular Therapy (2015)

Oncolytic herpes simplex viruses type 1 (HSV-1) have been shown promising for treating a variety of tumor. G47Δ is a third-generation oncolytic HSV-1 that has triple mutations in the gamma34.5, alpha47 and ICP6 genes, and the first recombinant HSV-1 tried clinically in Japan. Clinical trials using G47Δ are currently ongoing in patients with glioblastoma, olfactory neuroblastoma or castration resistant prostate cancer. Preclinical studies have shown that G47Δ is also effective in many other types of cancer including breast cancer, schwannoma, renal carcinoma, and urothelial carcinoma. The purpose of this study was to investigate whether oncolytic HSV-1 can also be applied for treating testicular cancer. Testicular cancer is relatively rare, accounting for approximately 1% of male neoplasms and comprising morphologically diverse group of tumors, 90-95% of which are germ cell tumors (GCTs). GCTs are broadly classified as seminoma and non-seminoma (NSGCT). With the increase in early diagnosis and the development of cisplatin-based chemotherapy, a long-term survival can be expected for most GCT patients even with the initial presence of metastases. However, a group of NSGCT patients show resistance to chemotherapy and the five-year survival rate of such group is less than 50%, so clearly a new therapeutic approach is necessary for those patients. In this study, two recombinant HSV-1 were used. T-01 and T-mfIL12 are oncolytic HSV-1 with an empty cassette or the CMV promoter-driven murine interleukin 12 gene inserted into the backbone of G47Δ. Human NSGCT cell lines NTERA-2, Tera-1 and ITO-II, and a mouse NSGCT cell line F9 were used for in vitro evaluation. NTERA-2 and F9 were susceptible to T-01 at an MOI of 0.1: The percentages of surviving cells were less than11% at day 3. Cytopathic activities of T-mfIL12 were comparable to T-01. Athymic mice bearing established subcutaneous NTERA-2 tumors and immunocompetent mice bearing established subcutaneous F9 tumors were used for in vivo evaluation. When inoculated intraneoplastically, T-01 (4 × 10^4, 2 × 10^5 or 1 × 10^6 pfu) caused a significant inhibition of tumor growth compared with mock even at the lowest dose in the NTERA-2 model. In the F9 model, T-mfIL12 (4 × 10^4 pfu) caused a significant inhibition of tumor growth compared with T-01. Moreover, the combination of T-01 (4 × 10^4 pfu) with cisplatin (0.05mg per mouse injected intraperitoneally) was more efficacious than T-01 alone or cisplatin alone in the NTERA-2 model. These data suggest that oncolytic virus therapy using recombinant HSV-1 might be a useful strategy for treating NSGCT.
High Throughput Digital Quantification of Genomic Copy Number Alterations in Multiple Myeloma
Authors: Shashikant Kulkarni, Nathan Elliott, Mark Fiala, Jacob Paasch, Michael H. Tomasson, Keith E. Stockerl-Goldstein, John F. DiPersio, Gary Geiss, Ravi Vij, Vishwanathan Hucthagowder
Journal: Blood (2011)
Abstract 4458: The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo
Authors: Jens Kuebler, Stefanie Kirschner, Linda Hartmann, Grit Welzel, Maren Engelhardt, Carsten Herskind, Marlon R. Veldwijk, Christian Schultz, Manuela Felix, Gerhard Glatting, Patrick Maier, Frederik Wenz, Marc A. Brockmann, Frank A. Giordano
Journal: Cancer Research (2015)

Abstract Background: Patients with actively replicating human immunodeficiency virus (HIV) are highly radiosensitive and exhibit adverse reactions even at low irradiation doses. A major underlying cause is high intra- and extracellular levels of a virus-encoded peptide termed viral protein R (Vpr). As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined whether it may be utilized as a drug in the treatment of glioblastoma multiforme (GBM). Methods: Four glioblastoma-derived cell lines with and without lentivirus-mediated Methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2-6 Gy) or to combinations. Caspase assays were employed to detect apoptosis. Colony formation assays were used to analyse clonogenic survival. Dose escalation was performed using n = 12 NOD/SCID/γc−/− (NSG) mice in a classical 3+3 manner. This strain was also used as an orthotopic implant model of glioma using luciferase-expressing U87 cells (n = 18). Continuous Vpr administration was achieved using osmotic pumps, irradiation (3×5 Gy) was performed using a small-animal irradiation device and intracerebral tumor growth was monitored using repetitive contrast-enhanced micro CT scans. Results: Vpr showed high rates of acute toxicities with a LD50 of 4.0±1.1 μM for U251 and a LD50 of 15.7±7.5 μM for U87 cells. Caspase assays revealed Vpr-induced apoptosis in U251 but not in U87 cells. Vpr also efficiently inhibited clonogenic survival both in U251 and U87 cells and showed additive effects with irradiation. In contrast to TMZ, Vpr acted independently of the MGMT expression status. Dose escalation in mice (n = 12) was feasible and resulted in no evident renal or liver toxicity. Similar to irradiation with 3 × 5 Gy (n = 8), Vpr treatment of orthotopically implanted NSG mice (n = 5) delayed tumor growth and significantly (p = 0.041; log-rank test) prolonged overall survival compared to untreated animals (n = 5). Conclusion: The HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM. Citation Format: Jens Kuebler, Stefanie Kirschner, Linda Hartmann, Grit Welzel, Maren Engelhardt, Carsten Herskind, Marlon R. Veldwijk, Christian Schultz, Manuela Felix, Gerhard Glatting, Patrick Maier, Frederik Wenz, Marc A. Brockmann, Frank A. Giordano. The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4458. doi:10.1158/1538-7445.AM2015-4458
Abstract 2495: STING agonists formulated into cancer vaccines (STINGVAX) can cure established tumor resistant to immune checkpoint blockade by activating NK cells
Authors: Young Kim, Drew Pardoll, Juan Fu, Tom Dubensky
Journal: Cancer Research (2015)

Abstract Stimulator of Interferon Genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides, activating TBK-1/IRF-3, NF-κB, and STAT6 signaling pathways to induce robust type I interferons and proinflammatory cytokines. Cyclic dinucleotide ligands were formulated with GM-CSF-producing cellular cancer vaccines - termed STINGVAX - that demonstrated potent in vivo anti-tumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and non-canonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge structure conferred significantly enhanced therapeutic anti-tumor efficacy in multiple aggressive therapeutic models of established cancer in mice. Anti-tumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8+ T cells. Tumors from STINGVAX treated mice demonstrated dramatic PD-L1 upregulation, which was associated with tumor infiltrating CD8+IFNγ+ T-cells. When combined with PD-1 blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone. We found that the STINGVAX's anti-tumor efficacy is NK cell dependent, and demonstrated that CDN are potent activators of IFNg in NK cells. Citation Format: Young Kim, Drew Pardoll, Juan Fu, Tom Dubensky. STING agonists formulated into cancer vaccines (STINGVAX) can cure established tumor resistant to immune checkpoint blockade by activating NK cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2495. doi:10.1158/1538-7445.AM2015-2495
567. Enhanced Efficiency of CRISPR-Mediated Gene Knock-Out in Primary Human T-Cells
Authors: Kamila S. Gwiazda, Alexandra Grier, Jaya Sahni, Michelle Krutein, Andrew M. Scharenberg
Journal: Molecular Therapy (2015)

RNA-guided endonuclease (RGEN) technology has great promise for enabling efficient editing of essentially any target genomic locus. Here, we have evaluated application of S. pyogenes Cas9 for gene editing in primary human T-cells using mRNA-mediated delivery of a first generation spCas9 and adeno-associated virus (AAV) to drive guide RNA expression. We find that spCas9-mediated editing using this approach can achieve targeted gene disruption rates at the TCRa locus of up to 30%. Furthermore, evaluation of the dose response of editing efficiency at different Cas9 mRNA doses and over a range of AAV MOI suggests that editing efficiency is limited primarily by AAV-driven guide RNA expression. Evaluation of several approaches to achieve higher editing efficiencies led to the development of a novel method capable of achieving up to 90% TCRa disruption at reduced AAV MOI in selected cell populations. These results suggest that a Cas9-mRNA/AAV-guide approach can be applied to effectively disrupt multiple individual genes in primary human T-cells, and highlight an innovate method through which CRISPR/Cas9 technology may be applied with enhanced efficiency.
Abstract 922: Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer
Authors: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Jochen Gaedcke, Michael Ghadimi, Matthias Gaida, Thomas Ried, Nader Hannah, H. Richard Alexander, S. Perwez Hussain
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Aberrant macrophage migration inhibitory factor (MIF) expression is associated with disease aggressiveness and increased MIF in PDAC predicts poor patient survival. Here we show that MIF-induced disease aggressiveness and poor survival in PDAC involves the inhibition of the nuclear receptor subfamily group c member 2 (NR3C2). Tumors with aberrant high levels of MIF (MIF-high) showed an increased expression of mir-301b and a decrease in NR3C2 expression as compared to the tumors with a lower level of MIF (MIF-low) in PDAC cases and a negative correlation existed between MIF and NR3C2 expressions in these tumors. Furthermore, patients with an increase in mir-301b or decrease in NR3C2 expression had a significantly shorter survival than other patients. MIF overexpression and knockdown confirmed that MIF up-regulates miR-301b, which then binds to the 3′UTR of NR3C2 and markedly decreases its expression. Moreover, MIF-overexpressing orthotopic tumor xenografts showed an increase in mir-301b and a decrease in NR3C2 expressions. MIF-induced regulation of mir-301b and NR3C2 functionally involved the PI3Kinase/Akt pathway. Examination of the tumor suppressor mechanism of NR3C2 revealed that it inhibits proliferation, colony formation, migration and invasion, and enhances sensitivity to chemotherapeutic drug gemcitabine in pancreatic cancer cells. Furthermore, NR3C2 knock down enhanced epithelial-to-mesenchymal transition. These data identify a novel MIF-induced signaling pathway targeting NR3C2, leading to increased disease aggressiveness and poor outcome in PDAC. We identified a MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor of PDAC, NR3C2, involving miR-301b. The inhibition of NR3C2 enhanced disease aggressiveness and predicted to poor survival, as shown by our survival analysis. Therapies that target the MIF-miR-301b-NR3C2 axis may improve disease outcome in pancreatic cancer. Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Jochen Gaedcke, Michael Ghadimi, Matthias Gaida, Thomas Ried, Nader Hannah, H. Richard Alexander, S. Perwez Hussain. Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 922. doi:10.1158/1538-7445.AM2015-922
Abstract 2438: Identification of the mitochondrial binding site on the amino-terminal end of hexokinase II
Authors: Nadezda Bryan, Michelle M. Hwang, Kevin P. Raisch
Journal: Cancer Research (2015)

Abstract Hexokinase II is responsible for the first step in the glycolysis pathway. Hexokinase II adds a phosphate onto the glucose molecule so it can proceed down the pathway to give the cancer cell energy for its continuous growth. Tumor cells overexpress the hexokinase II enzyme. In fact, it is the overexpression of the hexokinase II enzyme that makes the diagnosis of cancer possible when imaged by positron emission tomography (PET). Hexokinase II binds to the voltage-dependent anion channel (VDAC) on the mitochondrial membrane and when it is attached to the mitochondrial membrane it is blocking a major pathway for cell death. Thus, hexokinase II is responsible for two characteristics of cancer cells, rapid tumor growth and difficulty to kill. Therefore the overall goal of our laboratory is to identify novel compounds with the ability to displace or translocate hexokinase II from the mitochondrial membrane to the cytoplasm. To attain our goal, we propose to use the crystal structure of hexokinase II to create a molecular model of the enzyme. However the amino acids responsible for binding to VDAC are not known. Therefore, we made a series of truncations and point mutations to identify the binding site to VDAC. Truncations of the first 10 and 20 amino acids indicated that important amino acids for binding were located within the first 10 amino acids. We made a series of single, double and triple point mutations within the first 10 amino acids. Immunofluorescence and immunoblot data has confirmed that mutating the fifth amino acid from histidine to proline completely abolished binding to the mitochondrial membrane. To prepare hexokinase II for crystallization, we have cloned the enzyme downstream of a thrombin cleavage site and His-tag. We were able to purify hexokinase II using a cobalt column, then eluting hexokinase II using thrombin to cleave at the thrombin cleavage site. Purified hexokinase II is isolated after removal of the thrombin using Protein A beads. After the crystal structure of hexokinase II is obtained, we will use the University of Florida Structure-based Molecular Docking Core facility to identify compounds predicted to fit into the VDAC binding site. The compounds will be characterized to validate a mechanism-of-action of translocating hexokinase II from the mitochondrial membrane to the cytoplasm, blocking glycolysis and decreasing ATP synthesis. The positive compounds will be analyzed to determine the best strategy for moving our studies closer to clinical application in cancer patients. Citation Format: Nadezda Bryan, Michelle M. Hwang, Kevin P. Raisch. Identification of the mitochondrial binding site on the amino-terminal end of hexokinase II. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2438. doi:10.1158/1538-7445.AM2015-2438