Genes & Cancer

Our medical research library holds 6 studies published in Genes & Cancer (2010–2017). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 6 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Impact Journals LLC
• Published: 2010 to the present, United States
• Language: English
• ISSN: 1947-6019 (print), 1947-6027 (electronic)
• Its record in the NLM Catalog

2010s

• Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma. N. Sobhani, S.P. Corona, F. Zanconati, et al. 2017;8(3-4):495-496. PubMed · Publisher · Free full text

  Abstract

  Malignant Mesothelioma (MM) is a rare and aggressive form of tumour that affects the lining of the internal organs for which current treatments have not been proven to be very effective. P16INK4A tumour suppressor encoding CDKN2A gene is often downregulated in MM. This protein is a cyclin dependent kinase 4 and 6 inhibitor, that normally phosphorylates RB1, which has to be un-phosphorylated in order to block cell-cycle at G1 in normal cells. Adding CDK inhibitor molecules to MM in pre-clinical studies has been proven to restore the normal function of p16INK4A, blocking thereby MM cell cycle at G1. Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted.

• Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines. O. Melaiu, C. Catalano, C. De Santi, et al. 2017;8(1-2):438-452. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy. The identification of novel therapeutic targets is needed to improve its poor prognosis. Following a review of literature and a screening of specimens we found that platelet-derived growth factor receptor beta (PDGFRB) is over-expressed, but not somatically mutated, in MPM tissues. We aimed to ascertain whether PDGFRB is a MPM-cancer driver gene. The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25). Met5A cells were used as non-malignant mesothelial cell line. PDGFRB-silencing caused a decrease in the proliferation rate, and a reduced colony formation capacity, as well as an increase of the share of cells in sub-G1 and in G2 phase, and increased apoptotic rate of MPM cell lines. Loss of migration ability was also observed. Similar, or even further enhanced, results were obtained with crenolanib. Imatinib showed the least effective activity on the phenotype. In conclusion, our study highlights PDGFRB as target with a clear role in MPM tumorigenesis and provided a rationale to explore further the efficacy of crenolanib in MPM patients, with promising results.

• Switching off malignant mesothelioma: exploiting the hypoxic microenvironment. N. Nabavi, K.L. Bennewith, A. Churg, et al. 2016;7(11-12):340-354. Review PubMed · Publisher · Free full text

  Abstract

  Malignant mesotheliomas are aggressive, asbestos-related cancers with poor patient prognosis, typically arising in the mesothelial surfaces of tissues in pleural and peritoneal cavity. The relative unspecific symptoms of mesotheliomas, misdiagnoses, and lack of precise targeted therapies call for a more critical assessment of this disease. In the present review, we categorize commonly identified genomic aberrations of mesotheliomas into their canonical pathways and discuss targeting these pathways in the context of tumor hypoxia, a hallmark of cancer known to render solid tumors more resistant to radiation and most chemo-therapy. We then explore the concept that the intrinsic hypoxic microenvironment of mesotheliomas can be Achilles' heel for targeted, multimodal therapeutic intervention.

• Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma. B.A. Jacobson, E.Z. Chen, S. Tang, et al. 2015;6(3-4):144-52. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is a devastating disease with a poor prognosis for which there is a clear need for more successful therapeutic approaches. Triptolide, a diterpenoid triepoxide, is a highly effective agent against several cancer types in animal models. Owing to triptolide's poor solubility in water, a water-soluble analog, minnelide, was synthesized. Minnelide is a prodrug of triptolide and is activated by exposure to phosphatases that are found in all body tissues, including blood. Mesothelioma cells were treated in vitro with minnelide or its parent compound, triptolide. Minnelide and triptolide were both found to significantly reduce mesothelioma cell viability and induce apoptosis. The level of Hsp70, a protein that promotes cancer cell survival, was measured in mesothelioma cells before and after treatment with triptolide. Hsp70 levels were decreased in a dose-dependent manner. In addition, triptolide sensitized cells to gemcitabine and pemetrexed as measured by cell viability. Mice bearing mesothelioma flank tumors were treated with daily injections (28 d) of minnelide or saline solution and xenograft tumor growth recorded. Mice displayed significantly reduced tumor burden. These findings support the clinical evaluation of minnelide therapy for mesothelioma.

• A Phosphotyrosine Proteomic Screen Identifies Multiple Tyrosine Kinase Signaling Pathways Aberrantly Activated in Malignant Mesothelioma. C.W. Menges, Y. Chen, B.T. Mossman, et al. 2010;1(5):493-505. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a highly aggressive cancer that is refractory to all current chemotherapeutic regimens. Therefore, uncovering new rational therapeutic targets is imperative in the field. Tyrosine kinase signaling pathways are aberrantly activated in many human cancers and are currently being targeted for chemotherapeutic intervention. Thus, we sought to identify tyrosine kinases hyperactivated in MM. An unbiased phosphotyrosine proteomic screen was employed to identify tyrosine kinases activated in human MM cell lines. From this screen, we have identified novel signaling molecules, such as JAK1, STAT1, cortactin (CTTN), FER, p130Cas (BCAR1), SRC and FYN as tyrosine phosphorylated in human MM cell lines. Additionally, STAT1 and SRC family kinases (SFK) were confirmed to be active in primary MM specimens. We also confirmed that known signal transduction pathways previously implicated in MM, such as EGFR and MET signaling axes, are co-activated in the majority of human MM specimens and cell lines tested. EGFR, MET, and SFK appear to be co-activated in a significant proportion of MM cell lines, and dual inhibition of these kinases was demonstrated to be more efficacious for inhibiting MM cell viability and downstream effector signaling than inhibition of a single tyrosine kinase. Consequently, these data suggest that TKI mono-therapy may not represent an efficacious strategy for the treatment of MM, due to multiple tyrosine kinases potentially signaling redundantly to cellular pathways involved in tumor cell survival and proliferation.

• Tissue Tropism of SV40 Transformation of Human Cells: Role of the Viral Regulatory Region and of Cellular Oncogenes. L. Zhang, F. Qi, G. Gaudino, et al. 2010;1(10):1008-20. PubMed · Publisher · Free full text

  Abstract

  SV40 has been detected prevalently in a limited panel of human tumors: mesothelioma, bone and brain tumors, and lymphoma. These are the same tumor types that are specifically induced by SV40 when injected into hamsters, a finding that has raised concerns about the possible pathogenic role of SV40 in humans. Two different SV40 isolates differing in the number of 72-bp elements in the virus regulatory region, archetypal SV40 (1ESV40), which contains one 72 bp, and nonarchetypal SV40 (wtSV40), which contains two 72 bp, have been detected in human tumors. 1ESV40 has been prevalently detected in brain tumors, with wtSV40 prevalently in mesothelioma. The apparent different cell tropism could be related to the virus (i.e., possibly to the number of 72-bp elements) and to different expression of cellular genes, known to play a critical role in SV40-mediated transformation of human cells, such as Notch-1 and c-Met. To test for possible differences in tissue tropism, we infected primary human mesothelial cells (HM) and primary human astrocytes (Ast) with 1ESV40 and with wtSV40 from 2 different SV40 strains, 776 and Baylor. All viruses transformed astrocytes; only wtSV40 transformed HM. Intracellular signaling of c-Met and Notch-1 was differently induced by these 2 viruses in HM and Ast. Differences in Notch-1 expression and signaling (i.e., downstream effectors, c-Myc, HEY-1, HES-1, and HEY-L) appeared to influence SV40-mediated transformation of primary astrocytes and mesothelial cells. Our results provide a biological rationale to the observation that 1ESV40 is prevalently detected in brain tumors and wtSV40 in mesotheliomas.

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