IDH mutations: new genetic signatures in cholangiocarcinoma and therapeutic implications.

Department of Medicine, Massachusetts General Hospital, Translational Research Laboratory, GRJ-1008A, 55 Fruit Street, Boston, MA 02114, USA. .
Expert Review of Anti-infective Therapy (Impact Factor: 3.06). 05/2012; 12(5):543-6. DOI: 10.1586/era.12.32
Source: PubMed
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcriptional regulation involves complex and interdependent interactions of noncoding and coding regions of the genome with proteins that interact and modify them. Genetic variation/mutation in coding and noncoding regions of the genome can drive aberrant transcription and disease. In spite of accounting for nearly 98% of the genome comparatively little is known about the contribution of noncoding DNA elements to disease. Genome-wide association studies of complex human diseases including cancer have revealed enrichment for variants in the noncoding genome. A striking finding of recent cancer genome re-sequencing efforts has been the previously underappreciated frequency of mutations in epigenetic modifiers across a wide range of cancer types. Taken together these results point to the importance of dysregulation in transcriptional regulatory control in genesis of cancer. Powered by recent technological advancements in functional genomic profiling, exploration of normal and transformed regulatory networks will provide novel insight into the initiation and progression of cancer and open new windows to future prognostic and diagnostic tools. For further resources related to this article, please visit the WIREs website. Conflict of interest: The author has declared no conflicts of interest for this article.
    Wiley Interdisciplinary Reviews Systems Biology and Medicine 11/2013; DOI:10.1002/wsbm.1250 · 3.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer. We isolated CD133+ cells from a spontaneous PDAC mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133+ cells in immune competent mice. Effect of Minnelide, a drug currently under Phase I clinical trial, was studied on the tumors derived from the CD133+ cells. Our study showed for the first time that CD133+ population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of pro-survival and pro-invasive proteins compared to the CD133- non-TIC population. Our study further showed that Minnelide, was very efficient in downregulating both CD133- and CD133+ population in the tumors, resulting in a 60% decrease in tumor volume compared to the untreated ones. As Minnelide is currently under Phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy.
    Clinical Cancer Research 03/2014; 20(9). DOI:10.1158/1078-0432.CCR-13-2947 · 8.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an "oncometabolite" by inhibiting a class of α-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation.
    Cancer Discovery 06/2013; 3(7). DOI:10.1158/2159-8290.CD-13-0083 · 15.93 Impact Factor

Full-text (2 Sources)

Available from
Jul 31, 2014