Targeting Protein Synthesis Control for Cancer Therapy

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Molecular mechanisms of translation control in cancer

The central mission of research in our laboratory is to unravel the molecular basis of growth and proliferation control in cancer. The emphasis is on mechanisms of protein synthesis control via signal transduction to the translation initiation apparatus.


Fig 1: Major signal transduction pathways converging on protein synthesis machinery

Key biological properties of malignancy, e.g. unhinged cell cycle control, metabolic/hypoxic stress resistance, improper apoptotic/survival regulation, involve translation control.

Areas under investigation include:
• Mitogen-activated protein kinase (MAPK) signals to the translation initiation helicase complex and their role in translation initiation control
• MAPK signal convergence on Mnk and its role in oncogenesis
• Translation control of mitosis
• The translation control response to stress/pro-inflammatory cytokine signals
• The functional effects of signal transduction to the central scaffold and ribosome adaptor of the translation apparatus, the eukaryotic initiation factor 4G

Our basic mechanistic studies support clinical translational investigations of new strategies to combat cancer. These focus on primary CNS malignancies, but will be expanded to non-CNS cancers.

Oncolytic virotherapy of primary CNS tumors

All viruses depend on the host cell protein synthesis apparatus for biosynthesis of viral polypeptides. At the same time, they must restrict expression of host proteins involved in anti-viral defenses. To cope with this dilemma, viruses evolved with sophisticated strategies to hijack host cell protein synthesis machinery for their purposes. We engineered the translation interference strategy of poliovirus to generate non-pathogenic, oncolytic recombinants with selective cytotoxicity in malignant cells. Tumor-specific cytotoxicity of such virus recombinants depends on anomalous protein synthesis regulation in cancer cells.

PVS-RIPO, the prototype oncolytic poliovirus recombinant, was FDA approved under an Investigator-initiated Investigational New Drug application (IND no. 14,735). Clinical trials in patients with glioblastoma multiforme are currently recruiting patients (clinicaltrials.gov trial no. NCT01491893).
 

Fig. 2: glioma xenograft regression and scar formation upon intratumoral PVS-RIPO infusion

The empirical rationale for targeting cancer with oncolytic polioviruses is based on a) ectopic expression of the poliovirus receptor Necl5/CD155 in almost all cancers; b) tumor-specific cell killing by PVS-RIPO due to constitutively active MAPK signals to protein synthesis machinery; c) a host inflammatory response to viral tumor cell killing (see below).

Areas under investigation include:
• The mechanism of cell type-specific viral translation in neoplastic cells
• The mechanism of viral, cap-independent translation initiation
• The role of Necl5/CD155 in tumor targeting by PVS-RIPO
• The mechanism of cell death induced by PVS-RIPO and the role or cytotoxic viral proteases
• Targeting non-CNS cancers, such as pancreatic or prostate carcinomas, with PVS-RIPO

Our goals are to understand how abnormal protein synthesis regulation in cancer can best be targeted for therapy, e.g. with oncolytic poliovirus recombinants.  

Oncolytic viral immunotherapy

Intratumoral infusion of oncolytic viruses, e.g. PVS-RIPO, induces complex inflammatory responses that are likely involved in clinical efficacy. Therefore, we are investigating the immunologic effects associated with oncolytic virus treatment with PVS-RIPO. These include correlative studies in clinical trials as well as basic mechanistic investigations in animal models and in vitro. These are due to activation of innate antiviral defenses, cytokine responses, and host inflammatory responses to tumor cell lysis and the release of proteolytically digested tumor antigens.
 

Fig. 3: the innate immune response to RNA viruses

Areas under investigation include:
• The mechanism of Mda5 activation by poliovirus
• The role of immune effector cells in PVS-RIPO oncolytic virotherapy
• Humoral anti-viral and anti-tumor responses to PVS-RIPO oncolytic virotherapy
• PVS-RIPO infection/activation of macrophages and dendritic cells and its role in oncolytic immunotherapy
• PVS-RIPO synergism with inhibitors of the Jak/Stat signaling pathway

The goal of these studies is a mechanistic understanding of the viral and host-related events that contribute to clinical efficacy of oncolytic virotherapy in cancer patients.

Mechanisms of microRNA (miRNA)-mediated gene repression

miRNAs repress gene expression by recruiting the RISC complex to mRNAs. RISC works through associations with translation factors, e.g. the poly(A)-binding protein and its binding partner eIF4G. We are investigating basic mechanisms of miR-mediated gene regulation.

Areas under investigation include:
• The role of PABP-eIF4G in miRNA-mediated translation repression and template degradation
• miRNA interference with translation initiation mechanisms
• Template/translation mechanism-specific miRNA effects
• p38 MAPK depletion by miR-124/8 in the brain and its role in brain physiology
• The role of miRNA-mediated p38 MAPK depletion in the control of neuro-inflammation and in the pathogenesis in chronic degenerative CNS disease

Our objective is a mechanistic understanding of the involvement of translation machinery in miRNA-mediated translation repression.
Contact Information

Lab Director

Matthias Gromeier, MD
Associate Professor of Surgery
Duke University Medical Center
Box 3020
Durham, NC 27710

Phone: 919-668-6205
Fax: 919-681-4991
E-mail: grome001@mc.duke.edu

Current Lab Members

  • Mikhail Dobrikov, PhD
  • Elena Dobrikova, PhD
  • Sarah Lawson, PhD candidate
  • Michael Brown, PhD candidate
  • Jordan Swearingen, undergraduate
  • David Lung, undergraduate

Representative Publications

  • Gromeier M, Lachmann S, Rosenfeld M, Gutin PH, Wimmer E (2000) Nonpathogenic intergeneric poliovirus recombinants for the treatment of glioma. Proc Natl Acad Sci USA 97:6803-8. PMCID: PMC18745
  • Dufresne A, Gromeier M (2004) Non-polio enteroviruses with respiratory tropism cause poliomyelitis in intercellular adhesion molecule-1 transgenic mice. Proc Natl Acad Sci USA 101:13636-41. PMCID: PMC518806
  • Merrill MK, Gromeier M (2006) The dsRNA binding protein 76:NF45 heterodimer inhibits translation initiation at the rhinovirus type 2 internal ribosome entry site. J Virol 80:6936-42. PMCID: PMC1489066
  • Kaiser C, Dobrikova E, Bradrick SS, Shveygert M, Herbert JT, Gromeier M (2008) Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo. RNA 14:2170-82. PMCID: PMC2553731
  • Dobrikova E, Broadt T, Poiley-Nelson J, Yang X, Soman G, Gromeier M (2008) Recombinant oncolytic poliovirus eliminates glioma in vivo without genetic adaptation to a pathogenic phenotype. Mol Ther 16:1865-72. PMCID: PMC2856473.
  • Walters RW, Bradrick SS, Gromeier M (2010) Poly(A)-binding protein modulates mRNA susceptibility to cap-dependent miRNA-mediated repression. RNA 16:239-50. PMCID: PMC2802033
  • Shveygert M, Kaiser C, Bradrick SS, Gromeier M (2010) Regulation of Mnk1 interaction with eIF4G by MAPK signal transduction. Mol Cell Biol 30:5160-7. PMCID: PMC2953056
  • Dobrikov M, Dobrikova E, Shveygert M, Gromeier M (2011) Phosphorylation of eIF4G1 by PKC regulates eIF4G1 binding to Mnk1. Mol Cell Biol 31:2947-59. PMCID: PMC3133411
  • Lawson SK, Dobrikova EY, Shveygert M, Gromeier M (2013) p38- MAPK depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neurons. Mol Cell Biol 33:127-35. PMID: 23109423 [PubMed - in process]
  • Dobrikov MI, Dobrikova EY, Gromeier M (2013) Dynamic regulation of the translation initiation helicase complex by mitogenic signal transduction to eIF4G. Mol Cell Biol, epub ahead of print. PMID: 23263986 [PubMed - as supplied by publisher]