Molecular Pathology and Biologic Behavior of Tumors
Howard Colman, M.D., Ph.D.
Understanding the molecular pathology of a tumor and how that influences its biologic behavior is crucial for developing novel treatment approaches. My research focuses on identifying molecular mechanisms that regulate tumor phenotype, differentiation state and clinical behavior in gliomas. By analyzing alterations in DNA copy number and gene expression in glioblastoma tumors, we have identified specific molecular alterations that define tumor subtypes with different biological and clinical behavior.
Dr. Colman serves as co-leader of project 3 in the Brain Cancer SPORE. Project 3 is developing a molecular biomarker panel to identify patients who, based on the molecular profiles of their tumors, are not likely to benefit from standard therapy. When findings are validated in a large ongoing clinical trial with over 800 patients, novel targets will be identified to develop new treatments for these resistant tumors.
Other studies have shown that loss of chromosome 10 can be associated with shorter survival time, and with global changes in gene expression across genes on many other chromosomes. We also found that the gene YKL-40 (also known as CHI3L1 or human cartilage glycoprotein-39) was highly associated with chromosome 10 status, and that increased expression of YKL-40 was associated with worse survival.
In a study of a large set of tumors, increased YKL-40 expression in glioblastoma was associated with increased resistance to radiotherapy, shorter time to progression and worse overall survival. YKL-40 remained an independent prognostic factor in multivariate analysis after adjustment for age.
In addition to defining molecular subtypes of glioblastoma, gene expression array studies also suggest that these molecular subtypes were associated with different patterns of cellular differentiation. Tumors from patients who survived longest had differentiation markers associated with neural cells (including stem cells, astrocytes, oligodendrocytes and neurons) while tumors with worse prognosis were associated with increased expression of extracellular matrix and mesenchymal genes.
Additional studies are ongoing to identify individual transcription factors and developmental mechanisms that regulate these differences in differentiation state. Techniques such as array-comparative genomic hybridization and array-based gene expression profiles, used in combination, enable the identification of clinically relevant and robust molecular classes of tumors. Furthermore, they point to candidate genes and mechanisms that underlie the biologic and clinical behavior of these aggressive tumors, and thus could serve as novel therapeutic targets.
Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG, 2nd, Buckner JC, James CD, Aldape K. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 25: 2288-2294, 2007.
Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression and resemble stages in neurogenesis. Cancer Cell 9: 157-173, 2006.
Colman H, Giannini C, Huang L, Gonzalez J, Hess K, Bruner J, Fuller G, Langford L, Pelloski C, Aaron J, Burger P, Aldape K. Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol 30: 657-664, 2006.
Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, Chang S, Barker FG, 3rd, Fuller GN, Aldape KD. Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res 12: 3935-3941, 2006.
Colman H, Berkey BA, Maor MH, Groves MD, Schultz CJ, Vermeulen S, Nelson DF, Mehta MP, Yung WK. Phase II Radiation Therapy Oncology Group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: results of RTOG 9710. Int J Radiat Oncol Biol Phys 66: 818-824, 2006.
Pelloski CE, Mahajan A, Maor M, Chang EL, Woo S, Gilbert M, Colman H, Yang H, Ledoux A, Blair H, Passe S, Jenkins RB, Aldape KD. YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma. Clin Cancer Res 11: 3326-3334, 2005.
McDonald JM, See SJ, Tremont IW, Colman H, Gilbert MR, Groves M, Burger PC, Louis DN, Giannini C, Fuller G, Passe S, Blair H, Jenkins RB, Yang H, Ledoux A, Aaron J, Tipnis U, Zhang W, Hess K, Aldape K. The prognostic impact of histology and 1p/19q status in anaplastic oligodendroglial tumors. Cancer 104: 1468-1477, 2005.
Nigro JM, Misra A, Zhang L, Smirnov I, Colman H, Griffin C, Ozburn N, Chen M, Pan E, Koul D, Yung WK, Feuerstein BG, Aldape KD. Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Research 65: 1678-1686, 2005.