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Donald M. Miller, M.D., Ph.D.

by Wittliff,James L. last modified Dec 07, 2009 12:19 PM

Director, Brown Cancer Center, Professor of Medicine and of Biochemistry

Miller

Email Donald Miller
Phone Number: 502-562-4585 (Office)
Fax Number: 502-562-4368
Address: Brown Cancer Center
M.D. 1973, Duke University
Ph. D. 1972, Duke University

 

 

 

Additional Appointments:

  • Director, James Graham Brown Cancer Center, Associate Vice President for Health Affairs,  School of Medicine
  • Professor, Internal Medicine and Pharmacology,  School of Medicine
  • James Graham Brown Professor of Oncology, School of Medicine

 

 

Investigators:

 

Research Interests:

Dr. Miller's laboratory has a longstanding interest in modulation of gene expression as a potential anticancer therapy. During the past decade, his group has characterized the growth inhibitory activity of a set of four-stranded quadruplex-forming oligonucleotides that bind to nucleolin. These unique oligonucleotides inhibit growth of a variety of cancer cell types, but appear to have no effect on nontransformed cells.  One of these oligonucleotides (AS1411) has been studied in a Phase I clinical trial at the Brown Cancer Center and has been shown to have significant clinical activity, with no toxicity.  AS1411 is now being tested in multicenter Phase II trials in acute myelogenous leukemia and renal cell carcinoma.  Dr. Miller's group is currently characterizing the growth inhibitory activity of natrually occurring, genomic quadruplex-forming sequences which they have shown to be growth inhibitory.

 

In addition to the work with G-rich oligonucleotides, Dr. Miller's laboratory is studying the regulation of alpha-enolase, a glycolytic pathway enzyme. His group discovered an alternative translation product of alpha-enolase (MBP-1) which binds to the c-myc promoter and functions as a tumor suppressor.  MBP-1, which is translated from alpha-enolase mRNA, does not have enolase activity and does not form homodimers.  Alpha-enolase on the other hand, does not have growth inhibitory characteristics, forms homodimers and does not bind the c-myc promoter.  Alpha-enolase/MBP-1 expression appears to play an important role in the HIF-1α signaling pathway.  Dr. Miller’s group has shown that MBP-1 is intimately involved in the cellular response to hypoxia and hypoglycemia.  This unique system represents an interesting intersection between the pathways of energy metabolism and growth regulation.

 

 

Selected Publications:

  1. Lane, A.N., Fan, Teresa W-M, Higashi, Richard, Tan Jianlian, Bousamra, Michael, Miller, D.M.: Clinical Cancer Metabolomics; Analysis of Cancer Cell Metabolism in Human Patients; In Press.
  2. Lane AN, Fan TW, Higashi RM, Tan J, Bousamra M, Miller DM; Prospects for clinical cancer metabolomics using stable isotope tracers. Exp. Mol. Pathol. 86 (3):165-173, 2009
  3. Bates PJ, Laber DA, Miller DM, Thomas SD, Trent JO; Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.  Exp. Mol. Pathol. 86 (3):151-164, 2009.
  4. Desai PC, Jaglal MV, Ghim SJ, Miller DM, Farghaly H, Jenson AB; Human Papillomavirus in metastatic squamous carcinomas from unknown primaries: A retrospective 7 year study.  Exp. Mol. Pathol. 2009, 87(2):94-98.
  5. Fan, TW, Higashi RM, Bousamra, M, Kloecker, G, Miller, DM; Metabolic Profiling Identifies Lung Cancer Responsiveness to Erlotinib. Exp. Mol. Pathol, 2009, 87(1):83-86.
  6. Fan TW, Lane AN, Higashi RM, Farag MA, Gao H, Bousamra M, Miller DM. Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM). Mol. Cancer 2009 8:41.
  7. Rasku MA, Clem AL, Telang S, Taft B, Gettings K, Gragg H, Cramer D, Lear SC, McMasters KM, Miller DM, Chesney J. Transient T cell depletion causes regression to melanoma metastases. J Transl Med. 2008 Mar 11;6(1):12
  8. Sedoris, KC, Thomas, SD, Miller, DM.  c-myc promoter binding protein regulates the cellular response to an altered glucose concentration.  Biochemistry 2007 Jul 24;46(29):8659-68.
  9. Stewart DA, Xu X, Thomas SD, Miller DM: Acridine-modified, clamp-forming antisense oligonucleotides synergize with cisplatin to inhibit c-myc expression and B16-F0 tumor progression.  Nucleic Acids Research, 2002 Jun 1;30(11):2565-74.
  10. Dapic V, Bates PJ, Trent JO, Rodger A, Thomas SD, Miller DM: Antiproliferative activity of G-quartet-forming oligonucleotides with backbone and sugar modifications.  Biochemistry.  2002 Mar 19; 41(11):3676-85.
  11. Xu X, Hamhouyia F, Thomas SD, Burke TJ, Girvan AC, McGregor WG, Trent JO, Miller DM, Bates, PJ: Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides. J Biol Chem. 276:43221-30, 2001.
  12. Stewart DA, Thomas SD, Mayfield CA, Miller DM; Psoralen-modified clamp-forming antisense oligonucleotides reduce cellular c-Myc protein expression and B16-F0 proliferation.  Nucleic Acids Res. 2001 29(19):4052-61.
  13. Subramanian A, Miller DM: Structural analysis of alpha-enolase.  Mapping the functional domains involved in down-regulation of the c-myc protooncogene.  J Biol Chem. 275-5958-65, 2000.
  14. Bates, P.J., Kahlon, J.B., Thomas, S.D., Trent, J.O., Miller, D.M.:  Antiproliferative activity in G-rich oligonucleotides correlates with protein binding.  J Biol  Chem. 274:26369-77, 1999.

 

Patents & Licenses:

  • U.S. Patent 7,541,150 Methods for the diagnosis of cancer by determining the neoplastic status of a cell by probing the cell plasma membrane for the presence of nucleolin are provided, as are kits to carry out such tests.   Issued June 2, 2009.
  • U.S. Patent 7,357,928  Methods for the treatment of tumors and cancer by exploiting the surface expression of the usually nuclear-localized protein, nucleolin.  Issued April 15, 2008.
  • U.S. Patent 7,314,926 Antiproliferative activity of g-rich oligonucleotides and method of using same to bind to nucleolin.  Issued January 1, 2008.

 

 

 

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