Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance.

The lactate transporter /monocarboxylate transporter 1 (MCT1) plays a central role in tumor cell energy homeostasis. In a cell-based screen, we identified a novel class of MCT1 inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246 cancer cell lines and show that hematopoietic tumor cells, in particular diffuse large B-cell lymphoma cell lines, and subsets of solid tumor models are particularly sensitive to MCT1 inhibition.

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo.

Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs.

Effect of oncogene activating mutations and kinase inhibitors on amino acid metabolism of human isogenic breast cancer cells.

We investigated the changes in amino acid (AA) metabolism induced in MCF10A, a human mammary epithelial cell line, by the sequential knock-in of K-Ras and PI3K mutant oncogenes. Differentially regulated genes associated to AA pathways were identified on comparing gene expression patterns in the isogenic cell lines. Additionally, we monitored the changes in the levels of AAs and transcripts in the cell lines treated with kinase inhibitors (REGO: a multi-kinase inhibitor, PI3K-i: a PI3K inhibitor, and MEK-i: a MEK inhibitor).

Isogenic human mammary epithelial cell lines: novel tools for target identification and validation. Comprehensive characterization of an isogenic human mammary epithelial cell model provides evidence for epithelial-mesenchymal transition.

Tumorigenesis is a multi-step process involving several consecutive genetic alterations resulting in loss of genomic stability and deregulated signal transduction pathways. To study these deregulated processes in vitro, typically established cancer cell lines derived from primary tumors, ascites, or from metastases are used. However, these cancer cell lines reflect only late stages of the tumorigenic process.

Specific PET imaging of xC- transporter activity using a ¹⁸F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism.

Purpose: (18)F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable ¹⁸F-labeled glutamate analogue for PET imaging of tumors.

Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets.

The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor-derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients.

Protein-structure-based prediction of animal model suitability for pharmacodynamic studies of subtype-selective estrogens.

Subtype-selective estrogens are of increasing importance as tools used to unravel physiological roles of the estrogen receptors, ERalpha and ERbeta, in various species. Although human ERalpha and ERbeta differ by only two amino acids within the binding pockets, we and others recently succeeded in generating subtype-selective agonists. We have proposed that the selectivity of the steroidal compounds 16alpha-lactone-estradiol (16alpha-LE(2), hERalpha selective) and 8beta-vinyl-estradiol (8beta-VE(2), hERbeta selective) is based on the interaction of certain substituents of these compounds with essentially one amino acid in the respective ER binding pockets.

LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain.

Human leucine-rich repeat kinase 1 (LRRK1) is a multi-domain protein of unknown function belonging to the ROCO family of complex proteins. Here, we report the molecular characterization of human LRRK1 and show, for the first time, that LRRK1 is both a functional protein kinase and a GDP/GTP-binding protein. Binding of GTP to LRRK1 is specific, requires the GTPase-like Roc domain, and leads to a stimulation of LRRK1 kinase activity.