E Antonio Chiocca

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

Are you E Antonio Chiocca?

Claim your profile

Publications (350)1814.6 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the challenge of implementing oncolytic viral therapy into mainstream clinical use, the obstacles of early clinical trials have outlined numerous areas requiring additional investigation. In particular, the role of innate and adaptive immunity has received significant attention in this context. It is increasingly clear that a one-sided approach of either immune suppression or robust immune cell activation is not the answer for clinical success. Rather, recent studies are increasingly demonstrating the delicate balance between both anti-viral immune suppression and immune mediated tumor killing. In this review we focus on aspects of innate immune cell activation following oncolytic viral infection and how this response has the potential of bridging to the broader goal of viral mediated immunotherapy. Copyright © 2015. Published by Elsevier B.V.
    Current Opinion in Virology 08/2015; 13. DOI:10.1016/j.coviro.2015.03.015 · 6.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score ≥ 70. Twenty-six percent of patients underwent gross total resection, 77 % received ≥ 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival.
    Journal of Neuro-Oncology 06/2015; DOI:10.1007/s11060-015-1820-3 · 2.79 Impact Factor
  • Agnieszka Bronisz, E Antonio Chiocca
    Nature medicine 05/2015; 21(5):426-7. DOI:10.1038/nm.3857 · 28.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We present a 59-year-old woman who noted an enlarging lump on her forehead 6months after a left frontotemporal craniotomy for tumor resection and chemoradiation of her primary glioblastoma multiforme (GBM). GBM is a highly aggressive intracranial neoplasm associated with the shortest survival time of any primary central nervous system malignancy. Extracranial metastasis is rare, especially without previous surgical disruption of the dura and calvarium, which has been postulated to cause seeding of the extracranial space with tumor cells. This patient's MRI revealed tumor recurrence for which she underwent repeat resection. Histopathology confirmed GBM with unmethylated O-6-methylguanine-DNA methyltransferase and wildtype isocitrate dehydrogenase 1 status, as well as tumor invasion through the bone and subdermal space. The genetic and molecular factors that predict extracranial invasion remain unclear and require further investigation. Emerging data on circulating tumor cells in GBM patients indicate that extraaxial metastasis may be part of the disease course in some, particularly in long term survivors. Furthermore, the proximity of calvarial and scalp lesions to previous surgical sites and the time course in which they emerge after surgery suggests that iatrogenic seeding may also play a role in metastasis. With heightened awareness of the phenomenon, surgical strategies such as watertight approximation of the dura, bone flap replacement, or changing surgical instruments once the intradural component is complete may prove useful to prevent seeding. Prophylactic craniospinal irradiation may also be an appropriate tool in patients at high risk for metastasis, although this population is difficult to identify. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 05/2015; DOI:10.1016/j.jocn.2015.03.018 · 1.32 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In aggressive, rapidly growing solid tumors such as glioblastoma multiforme (GBM), cancer cells face frequent dynamic changes in their microenvironment, including the availability of glucose and other nutrients. These challenges require that tumor cells have the ability to adapt in order to survive periods of nutrient/energy starvation. We have identified a reciprocal negative feedback loop mechanism in which the levels of microRNA-451 (miR-451) are negatively regulated through the phosphorylation and inactivation of its direct transcriptional activator OCT1 by 5' AMP-activated protein kinase (AMPK), which is activated by glucose depletion-induced metabolic stress. Conversely, in a glucose-rich environment, unrestrained expression of miR-451 suppresses AMPK pathway activity. These findings uncover miR-451 as a major effector of glucose-regulated AMPK signaling, allowing tumor cell adaptation to variations in nutrient availability in the tumor microenvironment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(6). DOI:10.1016/j.celrep.2015.04.016 · 7.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ). We conducted a retrospective analysis of patients ≥65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis. Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P<.001) and had worse baseline performance status (P<.001) than those receiving SRT. On multivariate analysis, older age (adjusted hazard ratio [AHR]: 1.06; 95% confidence interval [CI]: 1.01-1.10, P=.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P=.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P=.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P=.03; HRT: AHR: 3.92; 95% CI: 1.44-10.60, P=.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P=.82). With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall survival for HRT and SRT with concurrent TMZ among elderly patients, suggesting the need for a randomized trial to compare these regimens directly. Copyright © 2015 Elsevier Inc. All rights reserved.
    International journal of radiation oncology, biology, physics 04/2015; 92(2). DOI:10.1016/j.ijrobp.2015.01.017 · 4.18 Impact Factor
  • Source
    Richard Lee Price, Ennio Antonio Chiocca
    [Show abstract] [Hide abstract]
    ABSTRACT: The hypothesis that cytomegalovirus (CMV) modulates cancer is evolving. Originally discovered in glioblastoma in 2002, the number of cancers, where intratumoral CMV antigen is detected, has increased in recent years suggesting that CMV actively affects the pathobiology of certain tumors. These findings are controversial as several groups have also reported inability to replicate these results. Regardless, several clinical trials for glioblastoma are underway or have been completed that target intratumoral CMV with anti-viral drugs or immunotherapy. Therefore, a better understanding of the possible pathobiology of CMV in cancer needs to be ascertained. We have developed genetic, syngeneic, and orthotopic malignant glioma mouse models to study the role of CMV in cancer development and progression. These models recapitulate for the most part intratumoral CMV expression as seen in human tumors. Additionally, we discovered that CMV infection in Trp53(-/+) mice promotes pleomorphic rhabdomyosarcomas. These mouse models are not only a vehicle for studying pathobiology of the viral-tumor interaction but also a platform for developing and testing cancer therapeutics.
    Frontiers in Oncology 03/2015; 5:61. DOI:10.3389/fonc.2015.00061
  • Source
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
  • Kaith Almefty, E. Antonio Chiocca
    World Neurosurgery 02/2015; DOI:10.1016/j.wneu.2015.02.019 · 2.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion.
    Oncotarget 02/2015; · 6.63 Impact Factor
  • M Maher Hulou, E Antonio Chiocca
    Neurosurgical FOCUS 01/2015; 38(1):E8. DOI:10.3171/2014.10.FOCUS14719 · 2.14 Impact Factor
  • 8th International Conference on Oncolytic Virus Therapeutics; 12/2014
  • Source
    Hiroshi Nakashima, Tran Nguyen, William F Goins, Ennio Antonio Chiocca
    [Show abstract] [Hide abstract]
    ABSTRACT: The ubiquitin-like interferon (IFN)-stimulated gene 15 (ISG15), and its specific E1, E2 and E3 enzymes are transcriptionally induced by type I Interferons (IFNs). ISG15 conjugates newly synthesized proteins. ISG15 linkage to proteins appears to be an important downstream IFN-signaling event that discrimininates cellular and pathogenic proteins synthesized during IFN stimulation, from existing proteins. This eliminates potentially pathogenic proteins, as the cell attempts to return to normal homeostasis after IFN stressed conditions. However, the molecular events that occur in this process are not well known. Here, we show that the C-terminal LRLRGG of ISG15 interacts with the ubiquitin zinc finger (BUZ) domain of Histone Deacetylase 6 (HDAC6). Since HDAC6 is involved in the autophagic clearance of ubiquitinated (Ub) aggregates, during which SQSTM1/p62 plays a major role as a cargo adapter, we also were able to confirm that p62 binds to ISG15 protein and its conjugated proteins, upon forced expression. Both HDAC6 and p62 colocalize with ISG15 in an insoluble fraction of the cytosol and this colocalization was magnified by the proteasome inhibitor, MG132. In addition, ISG15 was degraded via the lysosome. Overexpression of ISG15, which leads to an increased conjugation level of the cellular proteome, enhanced autophagic degradation, independent of IFN signaling transduction. These results thus indicate that ISG15 conjugation marks proteins for interaction with HDAC6 and p62 upon forced stressful conditions, likely as a step towards autophagic clearance. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 11/2014; DOI:10.1074/jbc.M114.593871 · 4.60 Impact Factor
  • Wenya Linda Bi, E. Antonio Chiocca
    World Neurosurgery 11/2014; 82(5). DOI:10.1016/j.wneu.2014.04.070 · 2.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The complexity of glioblastoma multiforme (GBM) and its distinct pathophysiology belong to a unique brain microenvironment and its cellular interactions. Despite extensive evidence of a role for microRNAs in GBM cells, little is known about microRNA-dependent communication between different cellular compartments of the microenvironment that may contribute to the tumor phenotype. While the majority of microRNAs are found intracellularly, a significant number of microRNAs have been observed outside of cells, often encapsulated in secreted extracellular vesicles (EVs). The function of these circulating/secreted microRNAs has not been explored in the context of the brain tumor microenvironment. Establishing how microRNAs are involved in the regulation of oncogenic signaling networks between tumor cells and stroma is likely to add a needed additional layer of complexity to the tumor network, consisting of intercellular communication. More importantly, microRNA/EV signaling may provide an additional therapeutic target for this deadly disease.
    Neuro-Oncology 10/2014; 17(5). DOI:10.1093/neuonc/nou292 · 5.29 Impact Factor
  • Lee Adam Wheeler, E. Antonio Chiocca
    [Show abstract] [Hide abstract]
    ABSTRACT: This is a perspective related to the retrospective analysis by Grossman et al. related to RPA use to predict survivorship in subjects with sarcomas metastatic to the brain.
    World Neurosurgery 09/2014; 82(6). DOI:10.1016/j.wneu.2014.09.015 · 2.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation.
    Neuro-Oncology 09/2014; 16(11). DOI:10.1093/neuonc/nou212 · 5.29 Impact Factor
  • Hormuzdiyar H Dasenbrock, E Antonio Chiocca
    World Neurosurgery 08/2014; 83(4). DOI:10.1016/j.wneu.2014.08.049 · 2.42 Impact Factor

Publication Stats

10k Citations
1,814.60 Total Impact Points

Institutions

  • 2013–2015
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
    • University of Leeds
      Leeds, England, United Kingdom
  • 2012–2015
    • Brigham and Women's Hospital
      • Department of Neurosurgery
      Boston, Massachusetts, United States
    • Northwestern University
      • Department of Neurological Surgery
      Evanston, Illinois, United States
  • 1990–2015
    • Harvard Medical School
      • • Department of Neurology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1998–2014
    • Harvard University
      Cambridge, Massachusetts, United States
    • Università degli Studi di Genova
      Genova, Liguria, Italy
    • Cornell University
      Итак, New York, United States
  • 2004–2013
    • The Ohio State University
      • Department of Neurological Surgery
      Columbus, Ohio, United States
    • Okayama University
      • Department of Neurological Surgery
      Okayama, Okayama, Japan
  • 1994–2013
    • Massachusetts General Hospital
      • • Division of Surgical Oncology
      • • Department of Neurosurgery
      • • Molecular Neurobiology Laboratory
      • • Department of Surgery
      Boston, MA, United States
  • 2009
    • University of Pittsburgh
      • Department of Neurological Surgery
      Pittsburgh, PA, United States
  • 2007
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2005
    • St. Jude Children's Research Hospital
      Memphis, Tennessee, United States
  • 2003
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2001
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 1998–1999
    • Martin Luther University of Halle-Wittenberg
      Halle-on-the-Saale, Saxony-Anhalt, Germany