Grisham R.N.,Sloan Kettering Cancer Center |
Grisham R.N.,Cornell College |
Sylvester B.E.,Sloan Kettering Cancer Center |
Won H.,Sloan Kettering Cancer Center |
And 25 more authors.
Journal of Clinical Oncology | Year: 2015
Purpose No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. Patients and Methods Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed. Results Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitorâ€"based combination therapy. Conclusion Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Abdel-Wahab O.,Leukemia Service |
Abdel-Wahab O.,New York Medical College |
Klimek V.M.,Leukemia Service |
Klimek V.M.,New York Medical College |
And 21 more authors.
Cancer Discovery | Year: 2014
Vemurafenib, a RAF inhibitor, extends survival in patients with BRAFV600-mutant melanoma but activates extracellular signal-regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAFV600K-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP-ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma. Significance: We show that in a patient with simultaneous RAS-mutant leukemia and BRAF-mutant melanoma, intermittent RAF inhibitor therapy induced a near-complete melanoma response, and addition of a MEK inhibitor prevented RAF inhibitor-induced activation of the RAS-mutant leukemia. Intermittent therapy may permit greater pathway inhibition with less toxicity, avoid chronic relief of pathway feedback, and have enhanced effectiveness compared with chronic administration. © 2014 American Association for Cancer Research.
Berney D.M.,Queen Mary, University of London |
Berney D.M.,Center for Molecular Oncology |
Algaba F.,Autonomous University of Barcelona |
Comperat E.,Hopital La Pitie Salpetriere |
And 6 more authors.
Virchows Archiv | Year: 2014
It is not known how uropathologists currently report histopathological features of prostate biopsies such as core length, tumor extent, perineural invasion, and non-tumor-associated features such as inflammation and hyperplasia in needle biopsies. A web-based survey was distributed among 661 members of the European Network of Uropathology. Complete replies were received from 266 pathologists in 22 European countries. Total core lengths were reported by 64 %. The numbers of cores positive for cancer was given by 79 %. Linear cancer extent was reported by 81 %, most often given in millimeters for each core (53 %) followed by the estimation of percentage of cancer in each core (40 %). A gap of benign tissue between separate cancer foci in a single core would always be subtracted by 48 % and by 63 % if cancer foci were minute and widely separated. Perineural invasion was reported by 97 %. Fat invasion by tumor was interpreted as extraprostatic extension by 81 %. Chronic and active/acute inflammation was always reported by 32 and 56 % but only if pronounced by 54 and 39 %, respectively. While most (79 %) would never diagnose benign prostatic hyperplasia on needle biopsy, 21 % would attempt to make this diagnosis. Reporting practices for prostate biopsies are variable among European pathologists. The great variation in some methodologies used suggests a need for further international consensus, in order for retrospective data to be comparable between different institutions. © 2014 Springer-Verlag.
Di Cara F.,University of Alberta |
Maile T.M.,Genentech |
Parsons B.D.,University of Alberta |
Magico A.,University of Alberta |
And 3 more authors.
Cell Death and Differentiation | Year: 2015
Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. © 2015 Macmillan Publishers Limited.
Zhang J.,University of Houston |
Fujimoto J.,University of Houston |
Zhang J.,Anderson University, South Carolina |
Wedge D.C.,Wellcome Trust Sanger Institute |
And 23 more authors.
Science | Year: 2014
Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied.We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. © 2014 by the American Association for the Advancement of Science; all rights reserved.
Keenan S.W.,Saint Louis University |
Hill C.A.,Saint Louis University |
Kandoth C.,Center for Molecular Oncology |
Buck L.T.,University of Toronto |
Warren D.E.,Saint Louis University
PLoS ONE | Year: 2015
Painted turtles are the most anoxia-tolerant tetrapods known, capable of surviving without oxygen for more than four months at 3°C and 30 hours at 20°C. To investigate the transcriptomic basis of this ability, we used RNA-seq to quantify mRNA expression in the painted turtle ventricle and telencephalon after 24 hours of anoxia at 19°C. Reads were obtained from 22,174 different genes, 13,236 of which were compared statistically between treatments for each tissue. Total tissue RNA contents decreased by 16% in telencephalon and 53% in ventricle. The telencephalon and ventricle showed ≥2x expression (increased expression) in 19 and 23 genes, respectively, while only four genes in ventricle showed ≥0.5x changes (decreased expression). When treatment effects were compared between anoxic and normoxic conditions in the two tissue types, 31 genes were increased (≥ 2x change) and 2 were decreased (≥0.5x change). Most of the effected genes were immediate early genes and transcription factors that regulate cellular growth and development; changes that would seem to promote transcriptional, translational, and metabolic arrest. No genes related to ion channels, synaptic transmission, cardiac contractility or excitation-contraction coupling changed. The generalized expression pattern in telencephalon and across tissues, but not in ventricle, correlated with the predicted metabolic cost of transcription, with the shortest genes and those with the fewest exons showing the largest increases in expression. Copyright: © 2015 Keenan et al.
PubMed | Queen Mary, University of London and Center for Molecular Oncology
Type: Journal Article | Journal: Human molecular genetics | Year: 2015
The male hormone androgen, working through the androgen receptor (AR), plays a major role in physiological process and disease development. Previous studies of AR mainly focus on its transcriptional activity. Here, we found that androgen-induced TMPRSS2 and ERG gene proximity is mediated by AR control of DNA replication rather than gene transcription. We demonstrate that, in both AR transactivation-positive and -negative prostate cells, androgen regulates DNA replication and androgen-induced gene proximity relies on both DNA replication-licensing and actual DNA replication activity. Androgen stimulation advances DNA replication timing of certain genomic regions, which may potentially increase gene proximity through sharing the same replication factory at a similar time. Therefore, we have revealed novel mechanisms of AR biological function, which will stimulate new research directions.