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• W4300523887 abstract "Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz, et al. Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci U S A 2013;110:16580–5.Platforms to detect and isolate circulating tumor cells (CTC) mark early systemic disease, monitor response, and may enable molecular characterization of metastatic disease. For patients without metastases (M0), tools are needed to determine those in whom metastases will develop. However, the limited numbers of CTCs, and the 1–10 mL volumes of blood used for their detection, have hampered reliability and reproducibility. Fischer and colleagues address these issues, using leukapheresis (LA), a clinical method to isolate mononuclear cells from large volumes of blood. LA efficiently detected cytokeratin-positive CTCs (>91% in breast cancer), recovering enough material to analyze somatic copy number variation (SCNV) as well. LA-based CTC enumeration and genomic characterization in M0 patients were also prognostic, as patients whose CTCs displayed >10 SCNVs, analyzed both retrospectively and prospectively, were prone to early metastatic relapse. Analysis of large volumes of blood enabled accurate estimation of CTC frequency in patients, ranging from ∼2 × 103 to ∼8 × 104, as compared with studies using smaller volumes, which estimated 104 to 106 CTCs. This study applies a common clinical method to the CTC field and provides a model for clinical application and diagnosis.Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013; 19:1264–72.Tumor-associated macrophages (TAM) are abundant in cancers, including glioblastoma multiforme, and growing interest has been expressed in their therapeutic targeting. Pyonteck and colleagues used an inhibitor of the colony stimulating factor-1 receptor (CSF-1R), essential for cell survival, to modulate microglia and macrophages in glioma. Using BLZ945, a brain-penetrant CSF-1R inhibitor, and a platelet-derived growth factor (PDGF)-B driven murine model for glioma, the authors were able to specifically target microglia and macrophages, resulting in improved survival and delayed tumor progression. BLZ945 reduced tumor size even when given late in tumor development, and tumors treated with this agent had decreased proliferation and increased apoptosis. The glioma model driven by PDGF-B most closely recapitulates human proneural glioblastoma, characterized by alterations in PDGFRA signaling. Focusing their human studies only on proneural models, the investigators found that BLZ945 inhibited orthotopic tumor growth of human proneural tumor spheres and cell lines. To understand the antitumor activity of BLZ945, they examined the quantitative and qualitative aspects of the TAM response. An interesting finding was that CSF-1R inhibition in tumors did not change the total number of brain microglia and macrophages despite a clear decrease in cell number under normal conditions. In vitro, BLZ945-mediated killing of bone marrow–derived macrophages (BMDM) could be prevented by incubation with glioma conditioned media, suggesting that glioma cells secrete TAM survival factors. Using a combination of cell selection and proteomics the authors identified GM-CSF and IFN-γ as sufficient to confer survival to BLZ945-treated BMDMs. Although BLZ945 did not change the TAM number it altered the TAM phenotype. BMDMs treated with BLZ945 had decreased expression of characteristic M2 activation phenotype markers and increased glioma phagocytosis. Interestingly, human proneural glioblastoma, but not other glioblastoma subtypes, enriched for the gene expression signature of the CSF-1R inhibited mouse TAMs, had longer median survival. These data suggest that CSF-1R inhibition can induce molecular alterations associated with a survival benefit in human glioblastoma. Modulating TAM phenotype to promote tumor killing may be an important therapeutic strategy in glioblastoma.Zhou B, Su L, Hu S, Hu W, Yip M LR, Wu J, et al. A small molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. Cancer Res; Published OnlineFirst September 26, 2013; doi:10.1158/0008-5472.CAN-13-1094.Ribonucleotide reductase (RNR) plays a central role in DNA synthesis, growth, metastasis, and drug resistance in cancer and is an attractive target for therapy. Available clinical RNR inhibitors have several shortcomings, including short half-life, drug resistance, and iron chelation. This study developed novel RNR inhibitors that overcame some of these drawbacks. A novel ligand-binding pocket on the RNR small subunit near the C-terminal tail was proposed and experimentally verified, and a small molecule targeting this pocket identified. Following lead optimization, Zhou and colleagues developed COH29 as a potent inhibitor of RNR enzymes. COH29 not only inhibited proliferation of several ovarian and leukemia cell lines but also aided in overcoming hydroxyurea and gemcitabine resistance. Interestingly, COH29 did not affect normal fibroblast and endothelial cells, specifically inhibiting proliferation of cancer cells. These in vitro activities translated to reduced tumor growth in vivo in a xenograft mouse model as well. These findings shed light on the potential of COH29 as an example of a new class of RNR inhibitors that target a wide variety of human cancers.Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013;45:1127–33.The Cancer Genome Atlas collects and profiles thousands of tumors from multiple tumor types to develop an atlas of molecular alterations. The data demonstrate intra-cancer heterogeneity and cross-cancer similarity, presenting both a clinical challenge and an opportunity to design treatment protocols based on the shared genomic traits of different histiotypes. Ciriello and colleagues developed an algorithmic approach that is independent of tissue of origin by integrating genomic data from ∼3,000 tumors representing 12 tumor types. The first major subdivision of data, integrated somatic copy number variation, somatic mutations from whole-exome sequencing, and gene DNA methylation events, identified 479 candidate functional alterations (116 copy number gains, 151 copy number losses, 199 recurrently mutated, and 13 epigenetically silenced genes). Interestingly, the overall characteristic events were predominantly somatic mutations in one class and copy number alterations in the other class, with a striking inverse relationship. The only notable exception was TP53 mutations, strongly enriched in the copy number class. The first partition of the “mutation class” had alterations in distinct oncogenic pathways, with PI3K–AKT signaling in one subclass and APC, TP53, and KRAS mutations most prominent in the second subclass. Recurrent hotspot mutations in chromatin modifiers ARID1A and CTCF were also identified in the mutation class. Most of the recurrent mutations identified were found to characterize tissue-independent tumor subsets, though tumor type-specific mutational events such as EGFR amplification in glioblastoma multiforme were identified. The second major class was dominated by recurrent copy number changes and TP53 mutations. Similar cross-cancer similarities were identified, in which genomic alterations were shared by subsets of tumors of different origin, or genomic differences seemed to converge on the same pathway (e.g., RB-mediated cell-cycle control via either loss of CDKN2A or gain of CCND1). A major subclass of tumors was characterized by recurrent gains and losses on chromosome 8, including amplification of the MYC locus. An interesting subclass had recurrent amplification and overexpression of Aurora kinase A across multiple cancer types. The investigators reveal cross-cancer targetable alterations that set the stage for designing tissue-independent treatment strategies based on likely functional events.Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun 2013;4:2126.Anglesio MW, Wiegand KC, Melnyk N, Chow C, Salamanca C, Prentice LM, et al. Type-specific cell line models for type-specific ovarian cancer research. PLoS One 2013;8:e72162.“Ovarian” cancer represents at least five distinct diseases—low-grade serous, mucinous, endometrioid, clear cell, and high-grade serous (the most common and lethal)—defined by their genomic profile and biomarkers rather than growth and spread within the ovary and peritoneal cavity. This concept is widely accepted and has major clinical implications, as each of these diseases requires different approaches to treatment. However, the ambiguous nature of many commonly used human ovarian cancer cell lines is hampering research. Many ovarian cancer cell line models were established before our current understanding of these diseases and are not properly annotated. In the post-genome era it is important that human cancer cell lines represent the well-characterized subtypes of the cancers we study. Two recent articles document important contributions to ovarian cancer research by defining those cell lines that are representative of high-grade serous and clear cell ovarian cancer. Domcke and colleagues compared molecular profiles of ovarian cancer cell lines from the Cancer Cell Line Encyclopedia and 47 high-grade serous tumor samples from The Cancer Genome Atlas. High-grade serous cancers are characterized by TP53 mutations, mutations in BRCA1 and BRCA2 and other genes associated with homologous recombination repair, and a wide range of copy number variations. Although 12 of these cell lines were defined as “likely high-grade serous,” commonly used lines such as SKOV3, A2780, and IGROV-1 did not have any molecular characteristics of high-grade serous cancer. Moreover, the 12 cell lines that most closely resembled high-grade serous cancer were only used in 1% of all publications featuring human ovarian cancer cell lines. In the second article, Anglesio and colleagues describe their use of a panel of biomarkers and molecular features to investigate 32 commonly used and in-house derived ovarian carcinoma cell lines, with the intention of defining those cell lines representative of clear cell carcinoma of the ovary, a disease defined by mutations in ARID1A and PIK3CA that is thought to arise from a rare progression of endometriosis. Using their panel of biomarkers and molecular features they were able to reclassify the ovarian cancer cell lines into type-specific categories. They confirmed cell lines such as TOV21G and JHOC-5 to be characteristic of clear cell carcinoma but, in agreement with Domcke and colleagues, they questioned the use of SKOV3 and A2780 as models of high-grade serous cancers. These stories demonstrate the power of genomics to identify the most relevant models that best represent the studied human disease.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described." @default.
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• W4300523887 date "2013-10-31" @default.
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• W4300523887 title "Highlights from Recent Cancer Literature" @default.
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