Trial Information

Childhood Cancer and Plexiform Neurofibroma Tissue Microarray for Molecular Target Screening and Clinical Drug Development

Background: Cancer drug discovery is now focused on identifying molecularly targeted drugs
that are more selective and specific for proteins and signaling pathways that are directly
involved in tumorigenesis. This new paradigm alters the approach to clinical drug
development for childhood cancers because the emphasis is on therapeutic targets present in
common epithelially-derived adult cancers, which have a different pathogenesis. The
pharmaceutical industry is unlikely to undertake target discovery programs for low incidence
cancers, such as childhood cancers. Therefore, a more pragmatic approach to the development
of molecularly targeted drugs in children is required.

Objective: Construct a childhood cancer tissue microarrays (TMA) for screening and selecting
the most appropriate molecularly targeted agents for clinical development in childhood
cancers.

Eligibility: Ten to twenty representative specimens (paraffin blocks) for each of 25
histologically distinct pediatric solid tumors or plexiform neurofibromas will be collected.

Design: Using a robotic arrayer, three 0.6 mm cores from each tissue block will be donated
into one of 3 recipient paraffin TMA blocks (CNS tumors, sarcomas, embryonal tumors).
Standard immunohistochemical techniques will be applied to 5 micro m sections from the TMA
block using validated antibodies directed against specific protein targets of interest. If
greater than 8 to 20 tumors from each specific histological type of cancer are positive,
there is a 95% probability that the true proportion of positive specimens exceeds 20%. The
results of the TMA target assessment will guide in the selection of molecularly targeted
drugs for pediatric phase I clinical trials in the POB and Pediatric Phase I/Pilot
Consortium and the selection of candidate tumors for activity testing in phase II clinical
trials. If clinical responses are observed in phase I or II trials in tumor types that
express the target on the TMA, we will return to the original paraffin blocks and perform
Laser Capture Microdissection and produce reverse-phase lysate protein microarrays to assess
the activation state of targeted signaling pathways and investigate the role of the target
protein in tumorigenesis of the responsive childhood cancers.