PubMed · 15170449
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Timothy J Yeatman. 2004. A renaissance for SRC.. https://doi.org/10.1038/nrc1366
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
Innovative hypothesis-driven clinical trials have achieved major successes over the past several decades in treating children and adolescents with cancer. DNA-damaging cytotoxic agents have cured children with cancer. While the mission is not yet accomplished, chemotherapy has been validated. None of these drugs were designed specifically for a pediatric disease. Continued progress will require new strategies. Now being tested for adult cancers, these strategies include gene therapy, immunotherapy, cancer prevention, and signal transduction inhibitor (STI) therapy. Of these, the most promising is STI therapy, also known as molecular therapeutics or targeted therapy. For this therapy to succeed, components of signal transduction (i.e., candidate drug targets) must be identified, the targets relevant to cancers, and the drugs available for trial. Because STI therapy is biologically driven and because therapy will be tailored depending on the molecular profile of a specific patient's tumor, clinical pediatric oncologists will need to acquire greater understanding of signaling pathways and their therapeutic relevance. With examples drawn from pediatric oncology, the critical steps in the pre-clinical development of targeted therapy are reviewed here.
BACKGROUND: Prostatic neuroendocrine (NE) cells are intraglandular hybrid epithelial-neural-endocrine cells that express and secrete numerous hormones and neuropeptides, which presumably regulate growth, differentiation, and secretory activity of the prostatic epithelium. This specialized cell type appears to differentiate from a common basal/precursor/stem cell that also gives rise to the secretory epithelium. In order to elucidate mechanisms of NE-differentiation the effects of type 1 (alpha, beta) and type 2 (gamma) interferons (IFNs) on human prostate basal cells (PrECs) were evaluated. METHODS AND RESULTS: Application of alpha/beta IFN increased the expression of the cell-cycle inhibitor p21(CIP1) and inhibited DNA synthesis, while only IFN-gamma led to increased apoptosis, cell-cycle inhibitor p27(KIP1) upregulation, and differentiation of PrECs into NE-like cells. In vitro differentiated NE-like cells expressed the glycolytic enzyme neuron-specific enolase (NSE) and chromogranin A (CgA), known markers of NE-cells in vivo in the prostate. These NE-like cells also changed cytokeratin (CK) expression patterns by upregulating CK 8/18, predominantly found in terminally-differentiated secretory luminal/NE epithelial cells. CONCLUSIONS: IFN-gamma produced locally in the prostate by basal cells and, under proinflammatory conditions, by infiltrating lymphocytes could support NE cell differentiation and play a role in NE differentiation processes of tumor cells in hormone-refractory prostate cancer.