Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and accounts for more than 7% of childhood malignancies. Despite aggressive therapy, children with high risk neuroblastoma still fare poorly with less than half surviving the disease. The survivors also suffer long term side effects. More effective targeted therapy is urgently needed. Epidermal growth factor receptor (EGFR) has become a popular target for cancer therapy in recent years. EGFR inhibitors have been tested in children with refractory NB. Interestingly, partial response or stable disease was observed in 30 - 40% of these patients. Since EGFR mutations are biomarkers for response to anti-EGFR drugs, we screened for EGFR mutations in 62 primary NB tumors. We not only found that 32% expressed deletion mutations of EGFR, but were surprised to discover a novel EGFR extracellular deletion mutant, EGFR 768. Further studies in our laboratory found that EGFR 768 is constitutively active, confers sensitivity to the EGFR inhibitor, erlotinib, and enhances the growth as well as invasive potential of cancer cells. Based on these biological and biochemical properties of EGFR 768, we formulated the following hypothesis: EGFR 768 expression confers a significantly worse disease free survival in neuroblastoma patients. We plan to prove this hypothesis with the following specific aim.
Specific Aim : Determine if neuroblastoma that express EGFR 768 are more aggressive Using primary NB tumors accrued from patients who participated in the Children's Oncology Group neuroblastoma clinical trials, we will determine if NB that expressed EGFR?768 are more likely to be in the high risk group and therefore have a significantly worse 5 year disease free survival. There are two subaims.
Sub aim I : Production of a monoclonal EGFR 768 specific antibody. In this subaim, we will develop and validate an unique molecular diagnostic reagent to detect the EGFR?768 mutant protein on paraffin embedded tumor sections. The sensitivity and specificity of this antibody will be vigorously tested before using it for the outcome analysis.
Sub aim II : Survival analysis. In this subaim, we will perform clinical biological correlation to determine if EGFR?768 has prognostic value in NB. This project evaluates EGFR?768 as a prognostic biomarker for neuroblastoma. If successful, not only will a new neuroblastoma prognosticator be identified, but there is a potential for this mutant to be a new therapeutic target as well. Thus, the development of a EGFR?768 specific diagnostic reagent will allow for rapid identification of this mutant in clinical specimen and has the potential to advance personalized anti-EGFR therapy for neuroblastoma patients, thereby improving the outcome and minimizing the side effects of the current therapy.
Neuroblastoma is a common solid tumor of childhood. Despite aggressive therapy, children with high risk neuroblastoma do poorly. The survivors also suffered severe long term side effects. Thus, more precise treatments with less toxicity are urgently needed. Drugs targeting proteins called tyrosine kinases are becoming integral part of modern day cancer therapy. Increased amount and activities of tyrosine kinases are found in many human cancers. The expression of these kinases in cancers is sometimes associated with poor outcome. One tyrosine kinase called the epidermal growth factor receptor (EGFR) has been studied extensively for the past three decades and now become a focused target for drug development by many pharmaceutical companies. EGFR inhibitors have been in clinical trials for many adult cancers;they have also been tested in children with cancers, including neuroblastoma. Anecdotal cases reported potential efficacy of these drugs in a few neuroblastoma patients. Recently, alterations in the EGFR gene were shown to predict patients'response to EGFR inhibitors. For this reason, we searched for EGFR gene mutations in neuroblastoma and surprisingly found that some neuroblastoma express a novel EGFR mutant. In this proposal, we will develop a diagnostic agent to identify this EGFR mutant in tumor sections and investigate its prognostic significance in neuroblastoma. If successful, this project will identify a new prognostic marker for neuroblastoma and has the potential to advance personalized anti-EGFR therapy for neuroblastoma patients.
|Klinghammer, Konrad; Keller, James; George, Jonathan et al. (2018) A phosphoarray platform is capable of personalizing kinase inhibitor therapy in head and neck cancers. Int J Cancer 142:156-164|
|Keller, James; Nimnual, Anjaruwee S; Varghese, Mathew S et al. (2016) A Novel EGFR Extracellular Domain Mutant, EGFR?768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma. Mol Cancer Res 14:740-52|