A new initiative on precision medicine Collins, Francis S; Varmus, Harold
The New England journal of medicine,
02/2015, Letnik:
372, Številka:
9
Journal Article
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President Obama has announced a research initiative that aims to accelerate progress toward a new era of precision medicine, with a near-term focus on cancers and a longer-term aim to generate ...knowledge applicable to the whole range of health and disease.
New Era in Cancer Research Varmus, Harold
Science (American Association for the Advancement of Science),
05/2006, Letnik:
312, Številka:
5777
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For many years, discoveries about the genetic determinants of cancer appeared to be having only minor effects on efforts to control the disease in the clinic. Following advances made over the past ...decade, however, a description of cancer in molecular terms seems increasingly likely to improve the ways in which human cancers are detected, classified, monitored, and (especially) treated. Achieving the medical promise of this new era in cancer research will require a deeper understanding of the biology of cancer and imaginative application of new knowledge in the clinic, as well as political, social, and cultural changes.
Wnt genes and components of Wnt signalling pathways have been implicated in a wide spectrum of important biological phenomena, ranging from early organismal development to cell behaviours to several ...diseases, especially cancers. Emergence of the field of Wnt signalling can be largely traced back to the discovery of the first mammalian Wnt gene in 1982. In this essay, we mark the thirtieth anniversary of that discovery by describing some of the critical scientific developments that led to the flowering of this field of research.
Celebrating more than 30 years of Wnt research, Roel Nusse and Harold Varmus share some personal thoughts on the past and the future of this intensely studied field.
Toward a Shared Vision for Cancer Genomic Data Grossman, Robert L; Heath, Allison P; Ferretti, Vincent ...
The New England journal of medicine,
2016-Sep-22, Letnik:
375, Številka:
12
Journal Article
Insurance for broad genomic tests in oncology Eisenberg, Rebecca; Varmus, Harold
Science (American Association for the Advancement of Science),
12/2017, Letnik:
358, Številka:
6367
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Insurance coverage should precede rather than follow clinical validation of broad genomic testing in oncology
Tests based on DNA sequencing methods are redefining diagnostic categories in oncology ...and providing a rational basis for the development and use of new cancer therapies, especially the many drugs targeted against mutant proteins that drive malignant growth (
1
). The medical and economic value of identifying specific genetic abnormalities in cancers has been established by the evidence-based use of targeted drugs and immunotherapies in cancer patients (see the figure for an example). For some cancer therapies, the U.S. Food and Drug Administration (FDA)–approved label calls for the use of a companion diagnostic test for the presence or absence of certain genetic changes before initiating treatment. Most recently, the FDA approved the use of the immunotherapeutic pembrolizumab for treatment of tumors that show a defect in DNA repair called microsatellite instability, irrespective of the tissue of origin; although an FDA-approved test for microsatellite instability is not yet available, many clinical laboratories are using assays for the relevant biomarkers (
2
).
Harold Varmus has made pioneering contributions to our understanding of cancer as a genetic disease. The discovery of the cellular origin of retroviral oncogenes earned him and his long-term ...collaborator, Michael Bishop, the Lasker Prize for Basic Medical Sciences in 1982 and the Nobel Prize in Physiology and Medicine in 1989. Throughout his career, Varmus has held several leadership roles that shaped science policy in the US and worldwide, and he has been an outspoken advocate for open science. In this interview, he talks (among other things) about the factors that shaped his early career choices, the thrill of scientific discovery, and the importance of including diverse populations in genomic studies of cancer and other diseases.
Rescuing US biomedical research from its systemic flaws Albertsa, Bruce; Kirschner, Marc W.; Tilghman, Shirley ...
Proceedings of the National Academy of Sciences - PNAS,
04/2014, Letnik:
111, Številka:
16
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The long-held but erroneous assumption of never-ending rapid growth in biomedical science has created an unsustainable hypercompetitive system that is discouraging even the most outstanding ...prospective students from entering our profession—and making it difficult for seasoned investigators to produce their best work. This is a recipe for long-term decline, and the problems cannot be solved with simplistic approaches. Instead, it is time to confront the dangers at hand and rethink some fundamental features of the US biomedical research ecosystem.
Bromodomain and extra terminal domain (BET) proteins function as epigenetic signaling factors that associate with acetylated histones and facilitate transcription of target genes. Inhibitors ...targeting the activity of BET proteins have shown potent antiproliferative effects in hematological cancers through the suppression of c-MYC and downstream target genes. However, as the epigenetic landscape of a cell varies drastically depending on lineage, transcriptional coactivators such as BETs would be expected to have different targets in cancers derived from different cells of origin, and this may influence the activity and mechanism of action of BET inhibitors. To test this hypothesis, we treated a panel of lung adenocarcinoma (LAC) cell lines with the BET inhibitor JQ1 and found that a subset is acutely susceptible to BET inhibition. In contrast to blood tumors, we show that LAC cells are inhibited by JQ1 through a mechanism independent of c-MYC down-regulation. Through gene expression profiling, we discovered that the oncogenic transcription factor FOSL1 and its targets are suppressed by JQ1 in a dose-dependant manner. Knockdown of BRD4 also decreased FOSL1 levels, and inhibition of FOSL1 phenocopied the effects of JQ1 treatment suggesting that loss of this transcription factor may be partly responsible for the cytotoxic effects of BET inhibition in LAC cells, although ectopic expression of FOSL1 alone did not rescue the phenotype. Together, these findings suggest that BET inhibitors may be useful in solid tumors and that cell-lineage-specific differences in transcriptional targets of BETs may influence the activity of inhibitors of these proteins in different cancer types.
Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) ...and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive.
We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug.
Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.
Synthetic lethality results when mutant KRAS and EGFR proteins are co-expressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for mutual exclusivity of
and
mutations. We ...have now defined the biochemical events responsible for the toxic effects by combining pharmacological and genetic approaches and to show that signaling through extracellular signal-regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes in the RAS pathway must restrain the activity of ERK1/2 to avoid toxicities and enable tumor growth. A dual specificity phosphatase, DUSP6, that negatively regulates phosphorylation of (P)-ERK is up-regulated in EGFR- or KRAS-mutant LUAD, potentially protecting cells with mutations in the RAS signaling pathway, a proposal supported by experiments with
-specific siRNA and an inhibitory drug. Targeting DUSP6 or other negative regulators might offer a treatment strategy for certain cancers by inducing the toxic effects of RAS-mediated signaling.
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