This application requests support for a promising young investigator in Neurofibromatosis Type 1 (NF1). The candidate's long-term career goal is to oversee an academic research lab aimed at delineating a molecular model of tumor progression in NF1, guiding therapeutic strategies. The training objectives of this proposal are to provide: 1) contemporary training in bioinformatics, statistics, and research ethics, 2) experience handling large amounts of gene expression microarray data, 3) sufficient preliminary data to develop an independent research program, 4) contacts and collaborations with other investigators in the fields of Neurofibromatosis, Pharmacogenomics, and Translational Neuroscience. The mentors, Dr. Nancy Ratner and Dr. Bruce Aronow, have carefully designed a career development plan including courses, research, and participation in scientific meetings. Dr. Ratner's expertise in Neurofibromatosis, Dr. Aronow's expertise in Bioinformatics, and the interdisciplinary environment of the Cincinnati Children's Hospital Research Foundation will provide the candidate with an exceptional environment to achieve these goals. The research objective of this proposal is to test the hypothesis that global gene expression analysis of tumor cells by microarray technology identifies therapeutic targets for malignant peripheral nerve sheath tumors (MPNST). MPNST is an aggressive cancer with poor prognosis that occurs at a high frequency and mortality in patients with NF1. Preliminary comparison of gene expression profiles of 2 sporadic and 6 NF1-associated MPNST cell lines to 7 normal Schwann cell samples and a panel of 45 primary MPNST samples resulted in the identification of a molecular signature for malignant transformation of Schwann cells. One gene consistently overexpressed in MPNST samples, TWIST, is a transcription factor that can cause tumor cell chemo-resistance. Another gene, matrix metalloproteinase 1 (MMP1), can cause tumor cell invasion and was dramatically overexpressed in a subset of MPNST. Specific research aims of this proposal are to: 1) confirm the 67 gene MPNST expression signature, and identify additional gene signatures, characteristic of subsets of MPNST; 2) test the hypothesis that TWIST contributes to MPNST chemo-resistance; 3) test the hypothesis that MMP1 contributes to MPNST invasion and 4) test the hypothesis that an effective therapeutic agent would normalize gene expression in MPNST cell lines, a pilot pharmacogenomics study.
| Miller, S J; Lan, Z D; Hardiman, A et al. (2010) Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene 29:368-79 |
| Hummel, Trent R; Jessen, Walter J; Miller, Shyra J et al. (2010) Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin. Clin Cancer Res 16:5048-57 |
| Miller, Shyra J; Jessen, Walter J; Mehta, Tapan et al. (2009) Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene. EMBO Mol Med 1:236-48 |
