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Wei E.Y.,Human Oncology and Pathogenesis Program | Hsieh J.J.,Sloan Kettering Cancer Center
Nature Reviews Urology | Year: 2015

Intratumoural heterogeneity in clear cell renal cell carcinoma (ccRCC) complicates identification and validation of biomarkers and thwarts attempts to improve precision medicine. Efforts to depict intratumoural heterogeneity and to pinpoint strategies for disease control resulted in the creation of the trunk-branch model of mutational cancer evolution, which emphasizes targeting trunk mutations. However, most patients with ccRCC receiving current therapeutics that target these mutations, such as inhibitors of vascular endothelial growth factors, eventually develop resistance. A novel paradigm might improve depiction of cancer evolution and advise therapeutic selection: the river model is based on findings from multiregion sequencing in samples from exceptional responders to mTOR inhibitors. The accumulating data on genotypic and phenotypic convergence in renal cell carcinoma and other malignancies can be used to examine how a mutable river model might best describe clinically significant phenotype-convergent events that could guide effective cancer control. This model originates from studying exceptional responders and its generalizability awaits validation. © 2015 Macmillan Publishers Limited. All rights reserved. Source

Gild M.L.,Human Oncology and Pathogenesis Program | Landa I.,Human Oncology and Pathogenesis Program | Ryder M.,Human Oncology and Pathogenesis Program | Ghossein R.A.,Sloan Kettering Cancer Center | And 2 more authors.
Endocrine-Related Cancer | Year: 2013

Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1, and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC2 kinase inhibitor, also resulted in marked growth suppression to levels similar to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells and provide a rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations. © 2013 Society for Endocrinology. Source

Sanborn J.Z.,LLC Five3 Genomics | Sanborn J.Z.,University of California at Santa Cruz | Salama S.R.,University of California at Santa Cruz | Salama S.R.,Howard Hughes Medical Institute | And 8 more authors.
Cancer Research | Year: 2013

DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. © 2013 American Association for Cancer Research. Source

Betts B.C.,Sloan Kettering Institute for Cancer Research | Betts B.C.,Sloan Kettering Cancer Center | Betts B.C.,New York Medical College | Abdel-Wahab O.,New York Medical College | And 8 more authors.
Blood | Year: 2011

Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2-mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4 + Tregs to CD8 +CD25 + effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell-stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment. © 2011 by The American Society of Hematology. Source

Callahan M.K.,Sloan Kettering Cancer Center | Callahan M.K.,New York Medical College | Rampal R.,Sloan Kettering Cancer Center | Rampal R.,New York Medical College | And 19 more authors.
New England Journal of Medicine | Year: 2012

Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E-mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E-mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors. We report the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib. Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal. Copyright © 2012 Massachusetts Medical Society. Source

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