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Last Updated: 3/18/2009
| Ryan Miller, MD, PhD
Assistant Professor |  |
Clinical Interests
Surgical neuropathology
Research Interests
Cancer, an acquired disease of somatic genetic/epigenetic alterations and dysregulated protein expression, is currently classified by morphological criteria and treated empirically on a tissue-of-origin basis with toxic chemotherapy drugs. Major efforts are currently underway to develop a molecular classification of cancer on the mRNA and DNA levels by systematically quantifying (profiling) gene expression and copy number in tumor lysates using high-throughput genomics technologies. But tumors are both morphologically (composed of different cell types) and molecularly (different alterations in subpopulations of tumor cells) heterogeneous and it is widely thought that this heterogeneity ultimately leads to treatment resistance and patient mortality. With advances in microscopy, computer-enhanced image analysis, and tissue microarrays, genomic abnormalities and protein expression can now be profiled in-situ without destroying tissue morphology and the spatial relationships among different constituent cell types. Such spatial in-situ proteomics data will complement existing genomic techniques and aid discovery of
1. Protein-level effects of genetic/epigenetic abnormalities and transcript profiles
2. Dysregulated molecular pathways in individual tumor cell subpopulations
3. Novel tumor subtypes and diagnostic tests to aid in their detection
4. The impact of morphological and molecular heterogeneity on tumor biology and drug efficacy
Knowledge gained through in-situ proteomics may ultimately permit oncologists to more effectively individualize therapy with drugs targeted to the specific dysregulated proteins present in an individual patient's tumor.
My laboratory focuses on gliomas, a morphologically and molecularly heterogeneous group of brain tumors with potentially dismal patient outcomes for which few effective drugs are available. The paradigms of personalized chemotherapy for solid tumors, namely Herceptin/trastuzumab and Her-2/neu (ErbB-2) testing in breast cancer as well as Gleevec/imatinib and c-kit testing in gastrointestinal stromal tumors (GIST), serve as scientific blueprints for our approach to coordinated drug-diagnostic biomarker co-development with the following goals (summarized in Fig. 1):
1. Development of a molecular classification of human gliomas. Tumors will be profiled using high-throughput assays on tissue microarrays, including quantitative fluorescence immunohistochemistry (Q-IHC, Camp, et al. Nature Med 8(11):1323 Nov 2002) and fluorescence in-situ hybridization (FISH).
2. Molecular characterization of genetically engineered murine (GEM) models of gliomas and comparison to their human counterparts with the above techniques
3. Investigation of the molecular mechanisms of drug sensitivity and resistance in vitro and in GEM murine models to identify promising drug candidates for application to the above molecularly-defined tumor subtypes in human clinical trials
Recent Accomplishments and Honors
2007 Member, Glioblastoma Disease Working Group, The Cancer Genome Atlas (TCGA) Project, National Cancer Institute
2007 American Association of Neuropathologists Moore Award
2007 American Association of Neuropathologists Merit Award
2006 American Society of Clinical Oncology Merit Award
2006 National Cancer Institute Postdoctoral Fellowship. Cancer Biology Training Program, Washington University Department of Pathology and Immunology
2005 American Association of Neuropathologists Merit Award
2001 Postdoctoral Career Enhancement Award. UAB Office of Postdoctoral Education
2000 American Brain Tumor Association Lucien J. Rubenstein Award for Outstanding Brain Tumor Research. UAB Division of Neurosurgery
Training
Washington University School of Medicine, St. Louis, Missouri
Barnes-Jewish Hospital
Neuropathology Fellowship, June 2006
American Board of Pathology, eligible
Washington University School of Medicine, St. Louis, Missouri
Barnes-Jewish Hospital
Anatomic Pathology Residency, June 2004
American Board of Pathology, eligible
University of Alabama School of Medicine (UASOM), Birmingham, Alabama
Doctor of Medicine (MD), June 2002
Medical Scientist Training (MD/PhD) Program
University of Alabama at Birmingham (UAB), Birmingham, Alabama
Doctor of Philosophy (PhD), June 1999
Department of Pathology, Division of Cellular and Molecular Pathology
Vanderbilt University, Nashville, Tennessee
Bachelor of Arts, Summa Cum Laude, May 1992
Phi Beta Kappa, Honors in the College of Arts & Science
Majors: Chemistry and Mathematics
Publications
Perry A, Miller CR, Gujrati M, Scheithauer BW, Zambrano SC, Jost SC, Raghavan R, Qian J, Cochran EJ, Huse JT, Holland EC, Burger PC, Rosenblum MK. Malignant gliomas with primitive neuroectodermal tumor-like components: A clinicopathologic and genetic study of 53 cases. Brain Pathol 2008. Epub ahead of print. PMID: 18452568
Goodgame B, Viswanathan A, Miller CR, Gao F, Meyers B, Battafarano RJ, Patterson A, Cooper J, Guthrie TJ, Bradley J, Pillot G, Govindan R. A clinical model to estimate recurrence risk in resected stage I non-small cell lung cancer. Am J Clin Oncol 31(1):22 Feb 2008. Miller CR and Perry A. Glioblastoma: Morphological and molecular genetic
diversity. Archives of Pathology and Laboratory Medicine. 131(3):397-406. Mar 2007. Review article.
Lim WT, Zhang WH, Miller CR, Watters JW, Gao F, Viswanathan A, Govindan R, McLeod HL. PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer. Oncol Rep. 17(4):853-7 Apr 2007.
Miller CR and McLeod HL. Pharmacogenomics of cancer chemotherapy-related
toxicity. Journal of Supportive Oncology. 5(1):9 Jan 2007. Review article.
Yuan L, Siegel M, Choi K, Khosla C, Miller CR, Jackson EN, Piwnica-Worms D,
Rich KM. Tissue transglutaminase 2 inhibitor, KCC009, disrupts fibronectin
assembly in the extracellular matrix and sensitizes orthotopic glioblastomas
to chemotherapy. Oncogene. 26(18):2563 Apr 2007.
Miller CR, Dunham C, Scheithauer B, Perry A. Significance of necrosis in
grading of oligodendroglial neoplasms: A clinicopathological and genetic
study of 1093 high-grade gliomas. Journal of Clinical Oncology.
24(34):5419 Dec 2006.
Conrad CA, Miller CR, Ji Y, Gumin J, Gomez-Manzano C, Bharara S, McMurray
JS, Lang FF, Wong F, Sawaya R, Yung WKA, Fueyo J. Δ24-hyCD adenovirus
suppresses glioma growth in vivo by combining oncolysis and
chemosensitization. Cancer Gene Therapy 12(3):284 Mar 2005.
Miller CR, Williams CR, Buchsbaum DJ, Gillespie GY. Intratumoral
5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy
is effective for experimental human glioblastomas. Cancer Research
62(3):773 Feb 2002.
E-mail: rmiller@med.unc.edu
Telephone: 966-4333
FAX: 966-6718
Address: 919 Brinkhous-Bullitt Chapel Hill, NC 27599
