Targeting the translational apparatus in MYCN-driven pediatric solid tumors

Summary

Principal Investigator: Justin Meyerowitz
Abstract: DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children, and the most aggressive molecular subgroups have poorly understood biology and no targeted therapies. These subgroups are characterized by increased levels of transcription factors MYCN or MYC, as well as independence from sonic hedgehog (SHH) signaling. We have recently developed a model of SHH-independent, murine NMYC-driven medulloblastoma in which high levels of NMYC protein drives oncogenesis. Previous data show that modulation of the translational apparatus downstream of the mammalian target of rapamycin (mTOR) is required for MYC-driven oncogenesis and that there is a synergistic relationship between MYC and the mTOR axis to promote tumor formation. mTOR signals through two primary outputs, rpS6 kinase (S6K) and the translation initiation factor eIF4E. A new class of clinical mTOR active site inhibitors disrupts signaling through both effectors, whereas the allosteric binder rapamycin disrupts only S6K. These mechanistically distinct activities have enormous therapeutic implications-in our medulloblastoma model, active site inhibitors of mTOR, but not rapamycin, demonstrate efficacy in vitro. Taken together, this supports the idea that signaling through S6K is dispensable, whereas eIF4E is required for MYC-driven oncogenesis. We hypothesize that MYCN cooperates with eIF4E downstream of mTOR signaling to induce proliferation of cerebellar neurospheres, and that mTOR kinase inhibition is a critical therapeutic strategy for SHH-independent medulloblastoma. We will investigate this hypothesis through the use of both pharmacological approaches and genetic approaches, the latter to eliminate the off-target effects of inhibitors, to validate the significace of mTOR active site inhibition as opposed to mTOR allosteric inhibition. First, we will determine how MYCN influences the translational apparatus (Aim 1). Using genetic approaches, we will separately evaluate the importance of S6K and eIF4E for MYCN-driven oncogenesis (Aim 2). Finally, we will use clinical inhibitors of mTOR to evaluate S6K (using allosteric inhibitors of mTOR) and eIF4E (using mTOR active site inhibitors) as potential therapeutic targets in both cell lines and our in vivo mouse models (Aim 3). Successful completion of these aims elucidates fundamental and targetable mechanisms underlying MYCN's role in the most aggressive subtypes of medulloblastoma.
Funding Period: 2013-01-01 - 2015-12-31
more information: NIH RePORT

Top Publications

  1. pmc The prenatal origins of cancer
    Glenn M Marshall
    Kids Cancer Centre, Sydney Children s Hospital, Randwick 2031, New South Wales, Australia and the Children s Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
    Nat Rev Cancer 14:277-89. 2014

Detail Information

Publications1

  1. pmc The prenatal origins of cancer
    Glenn M Marshall
    Kids Cancer Centre, Sydney Children s Hospital, Randwick 2031, New South Wales, Australia and the Children s Cancer Institute Australia for Medical Research, Lowy Cancer Centre, University of New South Wales, Randwick 2031, Australia
    Nat Rev Cancer 14:277-89. 2014
    ....

Research Grants30

  1. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013
    ..These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation. ..
  2. Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
    Timothy Gershon; Fiscal Year: 2013
    ..The mentorship, didactics, and research proposal along with the academic and research infrastructure provided by UNC will ensure the candidate's successful transition to an NIH-funded independent investigator. ..
  3. Overcoming resistance to BRAF(V600E) targeted therapies in melanoma
    David E Fisher; Fiscal Year: 2013
    ..abstract_text> ..
  4. Mycn and Medulloblastoma
    William A Weiss; Fiscal Year: 2013
    ..Aim 3. Use of PI3K inhibitors to address a role for Mycn and microRNA targets regulated by Mycn, in maintaining medulloblastoma angiogenesis in vivo. ..
  5. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  6. Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer
    Marina Pasca di Magliano; Fiscal Year: 2013
    ....
  7. Brain Enriched MicroRNA 128a and 9/9+: Impact on medulloblastoma pathogenesis
    Rajeev Vibhakar; Fiscal Year: 2013
    ..This study will help to understand their role in this devastating brain tumor of children and may enhance diagnosis and therapy in the future. ..
  8. Mechanisms of PPM1D in medulloblastoma tumorigenesis and invasion
    ROBERT CRAIG CASTELLINO; Fiscal Year: 2013
    ..Understanding the molecular mechanisms associated with WIP1 overexpression will ultimately lead to improved, less toxic therapeutic strategies and improved survival rates in children diagnosed with brain cancer. ..
  9. Hedgehog Pathway Blockade by Small-Molecule Gli Antagonists
    James K Chen; Fiscal Year: 2013
    ..These studies will determine how this compound blocks the Hedgehog pathway and evaluate its efficacy in mouse models of medulloblastoma, the most common pediatric brain tumor. ..