© 2007
Freund/OncoLab
Main Field(s) of Research
Primitive neuroectodermal brain tumors (PNET)
including medulloblastoma (PNET/MB) are the most common malignant
childhood brain tumors. Because of the high risk of leptomeningeal
dissemination, standard postoperative treatment for PNET includes not
only local radiotherapy, but also craniospinal radiotherapy and
chemotherapy. Such treatment causes long-term morbidity including
endocrine and growth disturbances, as well as neurocognitive
dysfunction, which is particularly severe in young children. To identify
molecular prognostic markers useful for routine disease risk
stratification of children with PNET/MB, we are prospectively analyzing
the expression of c-MYC, TrkC, and other candidates using quantitative
RT-PCR in a European multi-institution group effort. To understand the
role(s) of Trk receptor function in PNET, we are analyzing the effects
of neurotrophin addition and withdrawal on primary cultures of PNET and
human PNET cell lines expressing different levels of TrkC, and examine
radio-sensitivity and sensitivity to anti-tumor drugs. Ultimately,
better knowledge about the roles of neurotrophins, Trk receptors, and c-MYC
in PNET biology may lead to the development of individualized,
less-toxic treatment regimens that increase the quality of life for many
long-term survivors.
Central nervous system (CNS) atypical teratoid/rhabdoid tumors (ATT/RhT)
are among the pediatric malignant tumors with the worst prognosis and
fatal outcome. To date there are no explanations for their remarkable
resistance to cytostatic drugs and radiotherapy. The insulin-like growth
factor I receptor (IGF-IR) plays a critical role in cell survival,
proliferation, transformation and regulation of apoptosis. We expect our
efforts to modulate the function of IGF-IR in ATT/RhT to form the basis
of a better understanding of ATT/RhT biology and lead to novel
therapeutic strategies.
The Swiss
Pediatric Oncology Group (SPOG) Tumor Bank aims to create a national
basis for research into the molecular, genetic, immunological and other
characteristic features of children's tumors.
Our role in EET-Pipeline
Our role in the EET-Pipeline project focuses on the
functional and prognostic validation of target genes and pathways
identified as being common to various embryonal tumor entities, with
particular emphasis on medulloblastoma. Validation will be highly
focused to the field of cell cycle control, including Myc signaling
pathways, which are deregulated in most embryonal tumor entities. The
aim of this project is to investigate the distinct mechanisms of
activation of these common cell cycle regulatory pathways, identify
pathway components that best serve as reliable prognostic markers for
these diseases, identify broad-spectrum pathway components that can best
be targeted by therapeutic agents and establish a functional read-out
system for drugs targeting these pathway components.
We will
link this project with another project in the EET-Pipeline framework,
assessing a lipophilic quassinoid analog (NBT-272, NaPro BioTherapeutics,
Inc.) entered in FDA-required animal toxicity studies in 2004, that has
shown excellent activity against neuroblastoma cell lines and other
tumor types in vitro. We aim to improve the systematic use of
appropriate embryonal tumor cell line panels and xenograft models for
validation of the therapeutic relevance of NBT-272 and other novel drugs
with the final goal of selecting agents for clinical evaluation that
have an increased likelihood for clinical benefit.
Staff Member
Top 5 publications
1. Grotzer MA, Janss AJ, Fung K-M, Rorke LB, Sutton LN, Cnaan A, Zhao H, Biegel JA, Phillips PC, Lee VM-Y, Trojanowski JQ (2000) TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18:1027-1035
2. Grotzer MA, Eggert A, Zuzak TJ, Marwaha S, Wiewrodt BR, Ikegaki N, Brodeur GM, Phillips PC (2000) Resistance to TRAIL-induced apoptosis in PNET cells correlates with a loss of caspase-8. Oncogene 19: 4604-4610
3. Grotzer MA, Hogarty MD, Janss AJ, Liu X, Zhao H, Eggert A, Sutton LN, Rorke LB, Brodeur GM, Phillips PC (2001) MYC mRNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7: 2425-2433
4. Pingoud-Meier C, Lang D, Janss AJ, Rorke LB, Phillips PC, Shalaby T, Grotzer MA (2003) Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin Cancer Res 9: 6401-6409
5. Rutkowski S, von Bueren A, von Hoff K, Shalaby T, Hartmann W, Shalaby T, Deinlein F, Warmuth-Metz M, Soerensen N, Faldum A, Bode U, Mittler U, Urban C, Benesch M, Kortmann RD, Schlegel PG, Kuehl J, Pietsch T, Grotzer MA (2007) Prognostic relevance of clinical and biological risk factors in childhood medulloblastoma: results of patients treated in the prospective multicenter trial HIT'91 Clin Cancer Res 13: 2651-2657