Novel therapeutic strategies related to Hypoxia inducible factor-1 (HIF-1).

Current interests of the DTP-Tumor Hypoxia Laboratory include the development of pharmacological and molecular strategies targeting hypoxia-inducible factor-1 (HIF-1) activity. In vitro and in vivo studies support a role for the HIF-1 in angiogenesis and tumor progression. Therefore, HIF-1 is a novel molecular target for development of cancer therapeutics and anti-angiogenic drugs. To identify novel HIF-1 inhibitors we are developing a screening system based on a luciferase reporter assay.

A second interest of the laboratory is to identify and characterize novel hypoxia and HIF-1-inducible genes and to study the molecular mechanisms by which hypoxia promotes gene expression in the tumor microenvironment. To fully elucidate the gene expression profile under hypoxic conditions we are using the microarray technique. We are interested in studying hypoxic induction of novel genes in normal cells infiltrating the tumor (i.e. human monocytes) as well as in cancer cell lines.

Interactive possibilities and available reagents include: hypoxia-inducible reporter gene vectors.

Credentials

Dr. Giovanni Melillo obtained his medical doctor degree from the University of Naples, Italy in 1981. He had his residency and fellowship in Medical Oncology at the National Tumor Institute in Naples. In 1991 he was awarded a CNR-NATO international fellowship and he joined the Laboratory of Molecular Immunoregulation at the NCI-FCRDC as a visiting scientist. He then joined the Laboratory of Experimental Immunology at the NCI-FCRDC where he characterized the role of a hypoxia-responsive element in the promoter of the inducible nitric oxide synthase gene. In July 1996 he became a Clinical associate at the Clinical Oncology Program of the NCI in Bethesda where he became interested in the role of hypoxia-induced angiogenesis in tumor progression. In July 1999 he became a Senior Investigator with the DTP-Tumor Hypoxia Laboratory at the NCI-Frederick. His current interests are to develop novel therapeutic strategies to target hypoxia inducible factor-1 (HIF-1) activity and to identify and characterize novel hypoxia and HIF-1-inducible genes.

Recent Publications

1. Melillo G.: Inhibiting HIF-1 for cancer therapy. Molecular Cancer Research 4(9):601-605, 2006

2. Calvani M., Rapisarda A., Uranchimeg B., Shoemaker R.H., and Melillo G.: Hypoxic induction of a HIF-1a-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. BLOOD 107:2705-2712, 2006

3. Kong D., Park E.J., Stephen A.G., Calvani M., Cardellina J.H., Monks A., Fisher R.J., Shoemaker R.H., and Melillo G.: Echinomycin, a small molecule inhibitor of HIF-1 DNA binding activity. Cancer Res. 65:9047-9055, 2005

4. Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J, Figg WD, Hwang K, Chung EJ, Murgo A, Melillo G, Elsayed Y, Monga M, Kalnitskiy M, Zwiebel J, Sausville EA: Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma. J. Clin. Oncol. 23(17):3912-22, 2005

5. Melillo G: HIF-1: a Target for Cancer, Ischemia and Inflammation. Too good to be true? Cell Cycle 3:154-155, 2004

6. Rapisarda A., Uranchimeg B., Sordet O., Pommier Y., Shoemaker R.H., and Melillo G.: Topoisomerase I mediated inhibition of Hypoxia Inducible Factor-1 (HIF-1): mechanism and therapeutic implications. Cancer Res. 64: 1475-1482, 2004

7. Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, and Melillo G.: Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res. 64: 6845-6848, 2004

8. Schioppa T., Uranchimeg B., Saccani A., Biswas S.K., Rapisarda A., Bernasconi S., Saccani S., Nebuloni M., Vago L., Mantovani A., Melillo G., and Sica A.: Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 198: 1391-1402, 2003

9. Rapisarda A., Uranchimeg B., Scudiero D.A., Selby M., Sausville E.A., Shoemaker R.H., and Melillo G.: Identification of Small Molecule Inhibitors of Hypoxia Inducible Factor 1 (HIF-1) Transcriptional Activation Pathway. Cancer Res. 62: 4316-4324, 2002