Andreas G. Bader

Bio: Andreas G. Bader is an academic researcher from Scripps Research Institute. The author has contributed to research in topics: Cancer & microRNA. The author has an hindex of 32, co-authored 59 publications receiving 9805 citations. Previous affiliations of Andreas G. Bader include University of Texas MD Anderson Cancer Center & Woodward, Inc..

The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44

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.

Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic

Abstract: Mutations in genes that encode components of the phosphatidyl-inositol 3-kinase (PI3-kinase) signaling pathway are common in human cancer. The recent discovery of nonrandom somatic mutations in the PIK3CA gene of many human tumors suggests an oncogenic role for the mutated enzyme. We have determined the growth-regulatory and signaling properties of the three most frequently observed PI3-kinase mutations: E542K, E545K, and H1047R. Expressed in chicken embryo fibroblasts, all three mutants induce oncogenic transformation with high efficiency. This transforming ability is correlated with elevated catalytic activity in in vitro kinase assays. The mutant-transformed cells show constitutive phosphorylation of Akt, of p70 S6 kinase, and of the 4E-binding protein 1. Phosphorylation of S6 kinase and of 4E-binding protein 1 is regulated by the target of rapamycin (TOR) kinase and affects rates of protein synthesis. The inhibitor of TOR, rapamycin, strongly interferes with cellular transformation induced by the PI3-kinase mutants, suggesting that the TOR and its downstream targets are essential components of the transformation process. The oncogenic transforming activity makes the mutated PI3-kinase proteins promising targets for small molecule inhibitors that could be developed into effective and highly specific anticancer drugs.

Oncogenic PI3K deregulates transcription and translation.

Abstract: There have long been indications of a role for PI3K (phosphatidylinositol 3-kinase) in cancer pathogenesis. Experimental data document a requirement for deregulation of both transcription and translation in PI3K-mediated oncogenic transformation. The recent discoveries of cancer-specific mutations in PIK3CA, the gene that encodes the catalytic subunit p110α of PI3K, have heightened the interest in the oncogenic potential of this lipid kinase and have made p110α an ideal drug target.

miR-34 - a microRNA replacement therapy is headed to the clinic.

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.

Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34

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.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Abstract: Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.

Causes and consequences of microRNA dysregulation in cancer

Abstract: Over the past several years it has become clear that alterations in the expression of microRNA (miRNA) genes contribute to the pathogenesis of most — if not all — human malignancies. These alterations can be caused by various mechanisms, including deletions, amplifications or mutations involving miRNA loci, epigenetic silencing or the dysregulation of transcription factors that target specific miRNAs. Because malignant cells show dependence on the dysregulated expression of miRNA genes, which in turn control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumour suppressor genes, these small RNAs provide important opportunities for the development of future miRNA-based therapies.