Lessons from the Cancer Genome

Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Cell (Impact Factor: 32.24). 03/2013; 153(1):17-37. DOI: 10.1016/j.cell.2013.03.002
Source: PubMed


Systematic studies of the cancer genome have exploded in recent years. These studies have revealed scores of new cancer genes, including many in processes not previously known to be causal targets in cancer. The genes affect cell signaling, chromatin, and epigenomic regulation; RNA splicing; protein homeostasis; metabolism; and lineage maturation. Still, cancer genomics is in its infancy. Much work remains to complete the mutational catalog in primary tumors and across the natural history of cancer, to connect recurrent genomic alterations to altered pathways and acquired cellular vulnerabilities, and to use this information to guide the development and application of therapies.

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    • "Recent large-scale genomic analyses have led to the identification of ''actionable'' driver genes of specific cancers that are therapeutically accessible, including oncogene and non-oncogene dependencies (Al-Lazikani et al., 2012; Garraway and Lander, 2013; Luo et al., 2009; Rubio-Perez et al., 2015). However , the accurate and efficient identification of drugs and drug combinations that inhibit such drivers within specific tumor contexts represents a major challenge, particularly for transcriptional regulators that, in general, are pharmacologically inaccessible . "
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    ABSTRACT: Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy. Validation of mouse and human prostate cancer models confirmed the specificity and synergy of a predicted drug combination to abrogate FOXM1/CENPF activity and inhibit tumorigenicity. Network-based analysis of treatment signatures from GEM models identified treatment-responsive genes in human prostate cancer that are potential biomarkers of patient response. More generally, this approach allows systematic identification of drugs that inhibit tumor dependencies, thereby improving the utility of GEM models for prioritizing drugs for clinical evaluation.
    Cell Reports 09/2015; 12(12). DOI:10.1016/j.celrep.2015.08.051 · 8.36 Impact Factor
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    • "Genomic instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many human cancers (Hanahan and Weinberg, 2011; Garraway and Lander, 2013). In prostate cancer, structural genomic rearrangements, including translocations (e.g., TMPRSS2-ERG) and copy number aberrations (e.g., 8q gain, 10q23/PTEN loss) are a key mechanism driving tumorigenesis (Visakorpi et al., 1995; Cher et al., 1996; Tomlins et al., 2005; Zhao et al., 2005; Liu et al., 2006; Demichelis et al., 2009; Beroukhim et al., 2010). "
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    ABSTRACT: Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.09207.001 · 9.32 Impact Factor
    • "Several studies using human and mouse tumour cells have suggested that not all tumour cells have the potential to migrate, invade, circulate and colonise to form metastatic foci (Garraway and Lander, 2013; Vogelstein et al., 2013; Kreso and Dick, 2014). A seemingly uniform tumour tissue contains numerous genetically and epigenetically heterogeneous cells. "
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    ABSTRACT: Metastases are associated with a poor prognosis for canine mammary gland tumours (CMGTs). Metastatic and non-metastatic clones were isolated previously from a single malignant CMGT cell line. The difference in metastatic potential between the two cell lines was hypothesised to be associated with distinct cellular signalling. The aim of this study was to screen for compounds that specifically target metastatic cells in order to improve CMGT therapeutic outcomes. The two clonal cell lines were characterised by transcriptome analysis and their sensitivity to a library of 291 different compounds was compared. The metastatic clone exhibited elevated expression of molecules associated with degradation of the extracellular matrix, epithelial-mesenchymal transition and cancer stem cell phenotype. This was confirmed using a matrigel invasion assay and by assessment of aldehyde dehydrogenase activity. The mitochondrial respiratory chain complex inhibitors (MRCIs; rotenone, antimycin and oligomycin) significantly inhibited the growth of the metastatic clone. Although MRCIs similarly depleted mitochondrial ATP in both clones, the subsequent cellular response was different, with toxicity to the metastatic clone being independent of AMP-activated protein kinase activity. The results of this study suggest a potential utility of MRCIs as anti-tumour agents against metastatic CMGTs. Further studies are needed to investigate the clinical utility of MRCIs and to determine the association between MRCI sensitivity and malignancy. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Veterinary Journal 04/2015; 205(2). DOI:10.1016/j.tvjl.2015.04.025 · 1.76 Impact Factor
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