DEPARTMENT OF PATHOLOGY

Frank Furnari, Ph.D.

Mana M. Parast, M.D., Ph.D.

  • Professor
  • Ph.D. - University of North Carolina-Chapel Hill

Research Interests

The formation of human tumors is a complex process involving the accumulation of genetic lesions in genes that normally regulate cell proliferation, differentiation and cell death. For glioblastoma (GBM), the most frequent CNS tumor in adults, these genetic lesions occur in a relatively defined order and include loss of heterozygosity for chromosome 17p, mutation of the p53 gene, overexpression of the platelet derived growth factor receptor (PDGFA receptor), allelic losses of chromosome 22q, 13q (inclusive of the RB1 locus), and 19q, deletion of the interferon alpha and beta and INK4a and 4b loci on chromosome 9p, losses of heterozygosity for chromosome 10 for which the phosphatase and tensin (PTEN) homology gene, located at 10q23.3 is a frequent target, and gene amplification of EGFR.

Data from many studies, including the recent Cancer Genome Atlas (TCGA) initiative of the NCI, show that both PTEN mutation and EGFR amplification/mutation are the most frequent of the genetic lesions found in GBMs.  The focus of my research group is to investigate the role of these two genetic lesions in the genesis of GBM and how they cooperate to promote therapeutic resistance commonly associated with this tumor type. Specifically, 1) how expression of a mutant form of EGFR (ΔEGFR) potentiates tumor heterogeneity and hence aggressiveness; 2) the role of this receptor in driving tumor maintenance; 3) how modulators of the PTEN/PI3K signaling axis influence the effectiveness of receptor-directed therapeutics; and, 4) deciphering parameters that regulate sensitivity to therapeutics directed at ΔEGFR, are projects actively pursued. 

Representative Publications

  1. Okumura, K., Zhao, M., DePinho, R.A., Furnari, F.B., Cavenee, W.K. Cellular Transformation by the MSP58 Oncogene is Inhibited by its Physical Interaction with the PTEN Tumor Suppressor. PNAS 102: 2703-2706, 2005.
  2. Okumura, K., Zhao, M., DePinho, R.A., Furnari, F.B., Cavenee, W.K. Cellular Transformation by the MSP58 Oncogene is Inhibited by its Physical Interaction with the PTEN Tumor Suppressor. PNAS 102: 2703-2706, 2005.
  3. Okumura, K., Mendoza, M., Bachoo, R. M., DePinho, R. A., Cavenee, W. K., Furnari, F. B. PCAF regulates the PI3-kinase signaling pathway by acetylating PTEN. JBC, 281: 26562-26568, 2006 (paper of the week).
  4. Johns, T. G., Perera R. M., Vernes, S. C., Vitali A. A., Cao, D. X., Cavenee, W. K., Scott, A. M., Furnari F. B. The Efficacy of EGFR-Specific Antibodies Against Glioma Xenografts is Influenced by Receptor Levels, Activation Status and Heterodimerization. Clinical Cancer Research, 13: 1911-1925, 2007 (cover of issue).
  5. Huang, P. H., Mukasa, A., Bonavia, R., Flynn, R. A., Zachary E. Brewer Z. E., Cavenee, W. K., Furnari, F. B*, White, F. M.* Quantitative Analysis of EGFRvIII Cellular Signaling Networks Reveals a Novel Combinatorial Therapeutic Strategy for Glioblastoma. PNAS 104: 12867-12872, 2007 (* co-corresponding authors).
  6. Lu, K., Zhu, S., Cvrljevic, S., Huang, T., Sarkaria, S., Akhavan, D., Dang, J., Dinca, E., Plaisier, S., Oderberg, I., Lee, Y., Chen, Z., Caldwell, J., Xie, Y., Loo, J., Seligson, D., Chakravarti, A., Lee, F., Weinmann, R., Cloughesy, T., Nelson, S., Bergers, G., Graeber, T., Furnari, F., James, C.D., Cavenee, W., Johns, T., and Mischel, P. Fyn and Src are Effectors of Oncogenic EGFR Signaling in Glioblastoma Patients. Cancer Res., 17: 6889-6898, 2009.
  7. Nitta, M., Kozono, D., Kennedy, R., Stommel, J., Ng, K., Zinn, P.O., Kushwaha, D., Kesari, S., Furnari, F., Hoadley, K.A., Chin, L., Depinho, R.A., Cavenee, W.K., D'Andrea, A., Chen, C.C. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy. PLoS One, 5: May, 2010.
  8. Mukasa, A., Wykosky, J., Ligon, K. L., Chin, L., Cavenee, W. K., Furnari, F. Mutant EGFR is Required for Maintenance of Glioma Growth In Vivo, and Its Ablation Leads to Escape from Receptor Dependence. PNAS. 107: 2616-2621, 2010.
  9. Inda, M. Bonavia, R., Sah, D. W. Y., Mukasa, A., Narita, Y., Johns, T. G., Bachoo, R., Hadwiger P., Tan, P., DePinho, R. A., Cavenee, W., ¬ and Furnari, F. Tumor Heterogeneity is an Active Process Maintained by a Mutant EGFR-induced Cytokine Circuit in Glioblastoma. Genes & Development, 24: 1731-45, 2010.
  10. Chumbalkar, V., Latha, K., Hwang, Y.H., Maywald, R., Hawley, L., Sawaya, R., Diao, L., Baggerly, K., Cavenee, W.K., Furnari, F.B., Bogler, O. Analysis of phosphotyrosine signaling in glioblastoma identifies STAT5 as a novel downstream target of ∆EGFR. J. of Proteome Res, 10: 1343-52, 2011.
  11. Wang, Y., Huang, J. W., Li, M., Cavenee, W. K., Mitchell, P. S., Zhou, X., Tewari, M., Furnari, F. B., Taniguchi, T. MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression. Mol cancer Res, In Press.
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