The goals of the Nicolaides laboratory are:
1) To improve the outcome of children with brain tumors. While many children with brain tumors are cured, they are often left devastated as a result of aggressive cytotoxic chemotherapy, radiation, and surgery. Additionally, some tumor subtypes are incurable, regardless of therapy. I believe that biologically targeted therapy will allow us to cure children with previously incurable tumors, and, additionally, will allow us to decrease intensity of therapy for the rest of the children with brain tumors, resulting in decreased morbidity.
2) To identify and validate driving genetic alterations in pediatric brain tumors. Genetic characterization of pediatric brain tumors has significantly increased our understanding of the biology of these tumors. Unfortunately, it is often difficult to differentiate “driver” from “passenger” alterations in human cancers. Using gene knock-down experiments and small molecule inhibitors in in vitro and in vivo models of brain tumors, my lab is focused on validating targets in pediatric brain tumors and then moving these results rapidly into clinical trials.
Current Research Projects
RAS/RAF/MAP Kinase Pathway Blockade in Pediatric Astrocytomas
There has been a recent explosion in genetic evidence suggesting that alterations leading to activation of the MAP kinase pathway are common in pediatric astrocytomas. These include gain of function mutations in BRAF (BRAF-V600E, KIAA1549:BRAF fusions), PTPN11, CRAF, and loss of function mutations in NF1. Our lab uses pre-clinical models of BRAF-mutant astrocytomas to test signal transduction pathway inhibitors for potential efficacy and to understand the role of BRAF mutant proteins in tumor formation and maintenance.
EGFR Kinase Site Occupancy as a Biomarker for Efficacy in Cancer
The epidermal growth factor receptor (EGFR) is a proto-oncogene that is frequently over-expressed, amplified and/or mutated in many cancers. While EGFR tyrosine kinase inhibitors have proven clinical efficacy in lung cancers with hyperactive EGFR alleles, they show no efficacy against malignant glioma tumors that also harbor constitutively active EGFR variants. Our lab uses a fluorescent EGFR affinity probe to quantify EGFR kinase blockade in the presence of various inhibitors and tries to correlate this with efficacy against EGFR alleles.