Andreas G Bader

Mirna Therapeutics, Austin, Texas, United States

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Publications (44)328.94 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):2875-2875. DOI:10.1158/1538-7445.AM2015-2875 · 9.28 Impact Factor
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    Clinical Cancer Research 02/2015; 21(4 Supplement):B57-B57. DOI:10.1158/1557-3265.PMS14-B57 · 8.19 Impact Factor
  • Kevin Kelnar · Andreas G. Bader
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    ABSTRACT: MRX34 has recently entered the clinic as the first therapeutic product based on a microRNA (miRNA) mimic. In order to measure drug concentrations in vivo, a quantitation method is needed that exhibits high precision, accuracy and robustness. While most clinical applications for oligonucleotide therapeutics involve methods based on hybridization assays and liquid chromatography-tandem mass spectrometry, quantitative PCR (qPCR) is a less well described approach. Here, we present an RT, qPCR and analysis method to determine the tissue biodistribution of endogenous as well as a therapeutic, exogenous miRNA mimic therapeutic. Assay performance is demonstrated on multiple tissues from nonhuman primates dosed with MRX34.
    Methods in Molecular Biology: Gene Therapy of Solid Cancers, Edited by Wolfgang Walther and Ulrike Stein, 01/2015: chapter A qRT-PCR Method for Determining the Biodistribution Profile of a miR-34a Mimic: pages 125-133; Springer New York., ISBN: 978-1-4939-2727-2
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    ABSTRACT: Targeted cancer therapies, although often effective, have limited utility owing to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to repress multiple oncogenic pathways at once. Here we treated the aggressive Kras;p53 non-small cell lung cancer mouse model and demonstrated efficacy with a combination of two tumor-suppressive microRNAs (miRNAs). Systemic nanodelivery of miR-34 and let-7 suppressed tumor growth leading to survival advantage. This combinatorial miRNA therapeutic approach engages numerous components of tumor cell-addictive pathways and highlights the ability to deliver multiple miRNAs in a safe and effective manner to target lung tissue.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.282.
    Oncogene 09/2014; 34(27). DOI:10.1038/onc.2014.282 · 8.56 Impact Factor
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    ABSTRACT: The microRNA (miR) -200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial-mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future.Molecular Therapy (2014); doi:10.1038/mt.2014.79.
    Molecular Therapy 05/2014; 22(8). DOI:10.1038/mt.2014.79 · 6.43 Impact Factor
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    Jane Zhao · Kevin Kelnar · Andreas G Bader
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    ABSTRACT: Tyrosine kinase inhibitors directed against epidermal growth factor receptor (EGFR-TKI), such as erlotinib, are effective in a limited fraction of non-small cell lung cancer (NSCLC). However, the majority of NSCLC and other cancer types remain resistant. Therapeutic miRNA mimics modeled after endogenous tumor suppressor miRNAs inhibit tumor growth by repressing multiple oncogenes at once and, therefore, may be used to augment drug sensitivity. Here, we investigated the relationship of miR-34a and erlotinib and determined the therapeutic activity of the combination in NSCLC cells with primary and acquired erlotinib resistance. The drug combination was also tested in a panel of hepatocellular carcinoma cells (HCC), a cancer type known to be refractory to erlotinib. Using multiple analytical approaches, drug-induced inhibition of cancer cell proliferation was determined to reveal additive, antagonistic or synergistic effects. Our data show a strong synergistic interaction between erlotinib and miR-34a mimics in all cancer cells tested. Synergy was observed across a range of different dose levels and drug ratios, reducing IC50 dose requirements for erlotinib and miR-34a by up to 46-fold and 13-fold, respectively. Maximal synergy was detected at dosages that provide a high level of cancer cell inhibition beyond the one that is induced by the single agents alone and, thus, is of clinical relevance. The data suggest that a majority of NSCLC and other cancers previously not suited for erlotinib may prove sensitive to the drug when used in combination with a miR-34a-based therapy.
    PLoS ONE 02/2014; 9(2):e89105. DOI:10.1371/journal.pone.0089105 · 3.23 Impact Factor
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    ABSTRACT: MRX34, a microRNA (miRNA)-based therapy for cancer, has recently entered clinical trials as the first clinical candidate in its class. It is a liposomal nanoparticle loaded with a synthetic mimic of the tumor suppressor miRNA miR-34a as the active pharmaceutical ingredient. To understand the pharmacokinetic properties of the drug and to rationalize an optimal dosing regimen in the clinic, a method is needed to quantitatively detect the miRNA mimic. Here, we report the development and qualification of a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay in support of pharmacokinetic and toxicokinetic assessments in the non-human primate. Detection and quantification was performed on total ribonucleic acid (RNA) isolated from whole blood. The qualified range of the standard curve spans six orders of magnitude from 2.5 x 10-7 - 2.5 x 10-1 ng per reverse transcription (RT) reaction, corresponding to an estimated blood concentration of 6.2 x 10-5 - 6.2 x 101 ng/mL. Our results demonstrate that endogenous as well as the exogenous miR-34a can be accurately and precisely quantified. The assay was used to establish the pharmacokinetic profile of MRX34, showing a favorable residence time and exposure of the miRNA mimic in whole blood from non-human primates.
    Analytical Chemistry 01/2014; 86(3). DOI:10.1021/ac403044t · 5.83 Impact Factor
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    Andreas G Bader
    Cell cycle (Georgetown, Tex.) 12/2013; 13(3). DOI:10.4161/cc.27550 · 5.01 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):LB-250-LB-250. DOI:10.1158/1538-7445.AM2013-LB-250 · 9.28 Impact Factor
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    Jane Zhao · Paul Lammers · Chris J Torrance · Andreas G Bader
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    ABSTRACT: The tumor suppressor, microRNA-34 (miR-34), a transcriptional target of TP53, functions in a positive feedback loop to activate TP53. Although miR-34 can inhibit cancer cells carrying TP53 mutations, this feedback to TP53 may be a prerequisite for full miR-34 function and may restrict its therapeutic application to patients with intact TP53. To investigate the functional relationships between TP53 and miR-34, and that of other TP53-regulated miRNAs including miR-215/192, we have used a panel of isogenic cancer cell lines that differ only with respect to their endogenous TP53 status. miR-34-induced inhibition of cancer cell growth is the same in TP53-positive and TP53-negative cells. In contrast, miR-215/192 functions through TP53. In the absence of TP53, miR-34, but not miR-215/192, is sufficient to induce an upregulation of the cell cycle-dependent kinase inhibitor p21(CIP1/WAF1). We identify histone deacetylase 1 (HDAC1) as a direct target of miR-34 and demonstrate that repression of HDAC1 leads to an induction of p21(CIP1/WAF1) and mimics the miR-34 cellular phenotype. Depletion of p21(CIP1/WAF1) specifically interferes with the ability of miR-34 to inhibit cancer cell proliferation. The data suggest that miR-34 controls a tumor suppressor pathway previously reserved for TP53 and provides an attractive therapeutic strategy for cancer patients irrespective of TP53 status.Molecular Therapy (2013); doi:10.1038/mt.2013.148.
    Molecular Therapy 06/2013; 21(9). DOI:10.1038/mt.2013.148 · 6.43 Impact Factor
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    Andreas G Bader
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    ABSTRACT: MicroRNA-34 (miR-34) is a master regulator of tumor suppression. It is downregulated in numerous cancers and inhibits malignant growth by repressing genes involved in various oncogenic signaling pathways. Consequently, miR-34 antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. This broad anti-oncogenic activity holds the prospect of creating a new remedy that is effective against tumor heterogeneity. This review focuses on the molecular mechanisms of miR-34-mediated tumor suppression, pharmacologies in animal models of cancer, and a status update of a miR-34 therapy that may be among the first miRNA mimics to reach the clinic.
    Frontiers in Genetics 07/2012; 3:120. DOI:10.3389/fgene.2012.00120
  • V J Craig · A Tzankov · M Flori · CA Schmid · AG Bader · A Müller
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2012; 26(11). DOI:10.1038/leu.2012.110 · 9.38 Impact Factor
  • Cancer Research 04/2012; 72(8 Supplement):5636-5636. DOI:10.1158/1538-7445.AM2012-5636 · 9.28 Impact Factor
  • C. Daige · L. Priddy · K. Kelnar · J. Zhao · S. Dysart · A. Bader · D. Brown
    Molecular Cancer Therapeutics 11/2011; 10(Supplement 1):C142-C142. DOI:10.1158/1535-7163.TARG-11-C142 · 6.11 Impact Factor
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    A.G. Bader · D Brown · J Stoudemire · P Lammers
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    ABSTRACT: Despite substantial progress in understanding the cancer-signaling network, effective therapies remain scarce due to insufficient disruption of oncogenic pathways, drug resistance and drug-induced toxicity. This complexity of cancer defines an urgent goal for researchers and clinicians to develop novel therapeutic strategies. The discovery of microRNAs (miRNAs) provides new hope for accomplishing this task. Supported by solid evidence for a critical role in cancer and bolstered by a unique mechanism of action, miRNAs are likely to yield a new class of targeted therapeutics. In contrast to current cancer medicines, miRNA-based therapies function by subtle repression of gene expression on a yet large number of oncogenic factors and are, therefore, anticipated to be highly efficacious. After the completion of target validation for several candidates, the development of therapeutic miRNAs is now moving to a new stage that involves pharmacological drug delivery, preclinical toxicology and regulatory guidelines.
    Gene therapy 06/2011; 18(12):1121-6. DOI:10.1038/gt.2011.79 · 4.20 Impact Factor
  • Cancer Research 04/2011; 71(8 Supplement):1166-1166. DOI:10.1158/1538-7445.AM2011-1166 · 9.28 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are emerging as potential cancer therapeutics, but effective delivery mechanisms to tumor sites are a roadblock to utility. Here we show that systemically delivered, synthetic miRNA mimics in complex with a novel neutral lipid emulsion are preferentially targeted to lung tumors and show therapeutic benefit in mouse models of lung cancer. Therapeutic delivery was demonstrated using mimics of the tumor suppressors, microRNA-34a (miR-34a) and let-7, both of which are often down regulated or lost in lung cancer. Systemic treatment of a Kras-activated autochthonous mouse model of non-small cell lung cancer (NSCLC) led to a significant decrease in tumor burden. Specifically, mice treated with miR-34a displayed a 60% reduction in tumor area compared to mice treated with a miRNA control. Similar results were obtained with the let-7 mimic. These findings provide direct evidence that synthetic miRNA mimics can be systemically delivered to the mammalian lung and support the promise of miRNAs as a future targeted therapy for lung cancer.
    Molecular Therapy 03/2011; 19(6):1116-22. DOI:10.1038/mt.2011.48 · 6.43 Impact Factor
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    ABSTRACT: Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.
    Nature medicine 02/2011; 17(2):211-5. DOI:10.1038/nm.2284 · 28.05 Impact Factor
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    Andreas G Bader · David Brown · Matthew Winkler
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    ABSTRACT: MicroRNAs (miRNA), a class of natural RNA-interfering agents, have recently been identified as attractive targets for therapeutic intervention. The rationale for developing miRNA therapeutics is based on the premise that aberrantly expressed miRNAs play key roles in the development of human disease, and that correcting these miRNA deficiencies by either antagonizing or restoring miRNA function may provide a therapeutic benefit. Although miRNA antagonists are conceptually similar to other inhibitory therapies, restoring the function of a miRNA by miRNA replacement is a less well characterized approach. Here, we discuss the specific properties of miRNA replacement and review recent examples that explored the therapeutic delivery of miRNA mimics in animal models of cancer.
    Cancer Research 09/2010; 70(18):7027-30. DOI:10.1158/0008-5472.CAN-10-2010 · 9.28 Impact Factor
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    ABSTRACT: Tumor suppressor microRNAs (miRNA) provide a new opportunity to treat cancer. This approach, "miRNA replacement therapy," is based on the concept that the reintroduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Here, we describe the development of a therapeutic formulation using chemically synthesized miR-34a and a lipid-based delivery vehicle that blocks tumor growth in mouse models of non-small-cell lung cancer. This formulation is effective when administered locally or systemically. The antioncogenic effects are accompanied by an accumulation of miR-34a in the tumor tissue and downregulation of direct miR-34a targets. Intravenous delivery of formulated miR-34a does not induce an elevation of cytokines or liver and kidney enzymes in serum, suggesting that the formulation is well tolerated and does not induce an immune response. The data provide proof of concept for the systemic delivery of a synthetic tumor suppressor mimic, obviating obstacles associated with viral-based miRNA delivery and facilitating a rapid route for miRNA replacement therapy into the clinic.
    Cancer Research 07/2010; 70(14):5923-30. DOI:10.1158/0008-5472.CAN-10-0655 · 9.28 Impact Factor

Publication Stats

4k Citations
328.94 Total Impact Points

Institutions

  • 2009–2014
    • Mirna Therapeutics
      Austin, Texas, United States
  • 2008–2009
    • Asuragen
      Austin, Texas, United States
  • 2003–2008
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      لا هویا, California, United States
  • 2000–2001
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria