Agent In Cancer Models Research Articles

Integrated Approaches for the Use of Large Datasets to Identify Rational Therapies for the Treatment of Lung Cancers.

The benefit and burden of contemporary techniques for the molecular characterization of samples is the vast amount of data generated. In the era of “big data”, it has become imperative that we develop multi-disciplinary teams combining scientists, clinicians, and data analysts. In this review, we discuss a number of approaches developed by our University of Texas MD Anderson Lung Cancer Multidisciplinary Program to process and utilize such large datasets with the goal of identifying rational therapeutic options for biomarker-driven patient subsets. Large integrated datasets such as the The Cancer Genome Atlas (TCGA) for patient samples and the Cancer Cell Line Encyclopedia (CCLE) for tumor derived cell lines include genomic, transcriptomic, methylation, miRNA, and proteomic profiling alongside clinical data. To best use these datasets to address urgent questions such as whether we can define molecular subtypes of disease with specific therapeutic vulnerabilities, to quantify states such as epithelial-to-mesenchymal transition that are associated with resistance to treatment, or to identify potential therapeutic agents in models of cancer that are resistant to standard treatments required the development of tools for systematic, unbiased high-throughput analysis. Together, such tools, used in a multi-disciplinary environment, can be leveraged to identify novel treatments for molecularly defined subsets of cancer patients, which can be easily and rapidly translated from benchtop to bedside.

Use of GLV-1h68 for Vaccinia Virotherapy and Monitoring.

Herein we describe the use of the vaccinia virus strain GLV-1h68 as a theragnostic agent in cancer models. To date, GLV-1h68 has been used successfully in more than 50 xenograft tumor models. The recombinant vaccinia virus strain has been equipped with heterologous expression cassettes for a luciferase-fluorescent protein fusion gene, bacterial beta-galactosidase, as well as a bacterial glucuronidase. The methods to investigate and monitor GLV-1h68 mediated virotherapy, including optical imaging and biomarker analysis, will be presented in detail.

Abstract 2654: Human antibodies specific for oxidized macrophage migration inhibitory factor (oxMIF) synergize with chemotherapeutic agents in animal models of cancer

Abstract Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with pleiotropic biologic effects and is pathologically associated with several types of cancer. oxMIF is an immunological and conformational distinct isoform of MIF that can be mimicked in vitro by mild oxidation of recombinant MIF. Fully human monoclonal antibodies that specifically target oxMIF were shown to inhibit downstream signaling pathways associated with tumor proliferation and progression in vitro and in vivo. We assessed the potential of anti-oxMIF antibodies combined with standard chemotherapeutic agents on the proliferation of cancer cell lines in vitro and in vivo in xenograft models. In vitro, anti-oxMIF sensitization of the prostate cancer cell lines PC3 or LnCAP significantly reduced the half maximal effective concentration (EC50) of mitoxantrone by 30% and 40%, respectively. In the ovarian cancer cell lines A2780, EC50 of cisplatin was reduced by 70% after sensitization with anti-oxMIF. In vivo, mice bearing pancreatic cancer xenografts (COLO357, BxPC3 or MiaPaCa2) treated with anti-oxMIF in combination with gemcitabine had a strong survival advantage compared with mice treated with either monotherapy. This effect was accompanied by a decrease of tumor volumes up to 70% and an increase in the expression of caspase 3 in mice bearing COLO357 xenografts. In addition, combining gemcitabine with anti-oxMIF treatment normalized blood vessel density inside the tumors, decreased their permeability by 25%, and decreased tumor VEGF levels by 40%, whereas gemcitabine alone had the opposite effect. In mice bearing the ovarian human cancer cell line A2780 xenografts, combining anti-oxMIF antibodies with cisplatin led to a 45% reduction of tumor weights. Anti-oxMIF specific antibodies decreased proliferation, angiogenesis and inflammation inside tumor xenografts, but were not cytotoxic (no antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity). These experiments demonstrated synergistic effects between anti-oxMIF antibodies and cytotoxic chemotherapy. Combination treatments were superior to the corresponding monotherapies and led to a stronger inhibition of tumor growth and angiogenesis. A phase 1 clinical study of a novel human antibody that selectively targets oxMIF is currently ongoing in patients with solid malignancies (ClinicalTrials.gov identifier: NCT01765790). Citation Format: Patrice Douillard, Thorsten Hagemann, Michael Freissmuth, Michael Thiele, Alexander Schinagl, Dirk Völkel, Friedrich Scheiflinger, Randolf Kerschbaumer. Human antibodies specific for oxidized macrophage migration inhibitory factor (oxMIF) synergize with chemotherapeutic agents in animal models of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2654. doi:10.1158/1538-7445.AM2014-2654

818: Human antibodies specific for oxidized macrophage migration inhibitory factor (oxMIF) synergize with chemotherapeutic agents in animal models of cancer

818: Human antibodies specific for oxidized macrophage migration inhibitory factor (oxMIF) synergize with chemotherapeutic agents in animal models of cancer