Screening Technologies Branch

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

The main interest of the Tumor Hypoxia Laboratory is the discovery and development of pharmacological and molecular strategies targeting hypoxia-inducible factor-1 (HIF-1) for cancer therapy. Hypoxia is a common feature of solid tumors and HIF-1 is a critical transcription factor for the response of mammalian cells to oxygen deprivation. Preclinical and clinical studies have demonstrated that HIF-1 plays a critical role in angiogenesis and tumor progression. Therefore, HIF-1 is an attractive molecular target for development of cancer therapeutics and anti-angiogenic drugs. We have identified and described a number of HIF-1 inhibitors by using a cell-based luciferase reporter high throughput screen.

A second effort of the Tumor Hypoxia Laboratory is the translation of findings generated in the laboratory to clinical trials. Development of small molecule inhibitors of HIF-1 requires validation of target inhibition in preclinical models and early clinical trials. Efforts are devoted to the identification and characterization of tissue and imaging endpoints that can be used to validateHIF-1 inhibition and to the design of phase I-II clinical trials aimed at testing the effects of HIF-1 inhibition in cancer patients.

Interactive possibilities and available reagents include: human cancer cell lines expressing the luciferase reporter gene under control of hypoxia responsive promoters; small molecule inhibitors of HIF-1.

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 and Head of the Tumor Hypoxia Laboratory of the Developmental Therapeutics Program at the NCI-Frederick. Dr. Melillo is Associate Editor of Cancer Research and Journal of Molecular Medicine and is a member of the Editorial Board of Molecular Cancer Therapeutics and Cell Cycle. His current research interests are the discovery and development of novel therapeutic strategies targeting hypoxic cell signaling and the translation of laboratory finding to early clinical trials.

Recent Publications

NCBI PubMed listing of publications by Giovanni Melillo

1. Terzuoli E., Puppo M., Rapisarda A., Uranhchimag B., Cao L, Burger A. M., Ziche M., Melillo G.: Aminoflavone, a ligand of the aryl hydroarbon receptor (AhR), inhibits HIF-1α expression in an AhR-independent fashion. Cancer Res. 70(17):6837-48, 2010

2. Terzuoli E., Donnini S., Giachetti A., Iniguez M. A., Fresno M., Melillo G.*, Ziche M.*: Inhibition of HIF-1α by digydroxyphenylethanol, a product from olive oil, blocks mPGES-1/VEGF expression and reduces tumor angiogenesis. Clin. Cancer Res. 16(16):4207-16, 2010 (*corresponding authors)

3. Rapisarda A., Hollingshead M., Uranchimeg B., Bonomi C. A., Borgel S. D., Carter J. P., Gehrs B., Raffeld M., Kinders R. J., Parchment R., Anver M. R., Shoemaker R. H., Melillo G.: Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol. Cancer Ther. 8(7):1867-77, 2009

4. Onnis B., Rapisarda A., Melillo G.: Development of HIF-1 Inhibitors for Cancer Therapy. J. Cell. Mol. Med. 13(9A): 2780-2786, 2009

5. Rapisarda A. and Melillo G. Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist. Updat. 12(3):74-80, 2009

6. Kummar S., Gutierrez M., Gardner E. R., Chen X., Figg W. D., Zajac-Kaye M., Chen M., Steinberg S. M., Muir C. A., Yancey M. A., Horneffer Y. R., Juwara L., Melillo G., Ivy S. P., Merino M., Neckers L., Treeg P. S., Conley B. A., Giaccone G., Doroshow J. H., Murgo A. J.: Phase I Trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur. J. Cancer. 46(2):340-7, 2010

7. Trisciuoglio D., Uranchimeg B., Cardellina J. H., II, Meragelman T., Matsunaga S., Fusetani N., Del Bufalo D., Shoemaker R. H., and Melillo G.: Induction of apoptosis in human cancer cells by Candidaspongiolide, a novel sponge polyketide. Journal of the National Cancer Institute , 100(17):1233-46, 2008

8. Calvani M., Trisciuoglio D., Bergamaschi C., Shoemaker R. H., and Melillo G.: Differential involvement of VEGF in the survival of hypoxic colon cancer cells. Cancer Res. . 68(1):285-91, 2008

9. Melillo G.: Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 26(2): 341-52, 2007

10. Kummar S., Gutierrez M., Gardner E. R., Donovan E., Hwang K., Chung E. J., Lee M. J., Maynard K., Kalnitskiy M., Chen A., Melillo G., Ryan Q. C., Conley B., Figg W. D., Trepel J. B., Zwiebel J., Doroshow J. H., Murgo A. J.: Phase I Trial of MS-275, a Histone Deacetylase Inhibitor, Administered Weekly in Refractory Solid Tumors and Lymphoid Malignancies. Clin. Cancer Res. 13(18):5411-5417, 2007

11. Creighton-Gutteridge M., Cardellina J. H., Stephen A. G., Rapisarda A., Uranchimeg B., Hite K., Denny W.A., Shoemaker R. H., and Melillo G.: Cell-type specific, topoisomerase II-dependent inhibition of HIF-1α protein accumulation by NSC 644221. Clin. Cancer Res. 13(3): 1010-1018, 2007

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

13. 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

14. Rapisarda A., Zalek J., Hollingshead M., Braunschweig T., Uranchimeg B., Bonomi C. A., Borgel S. D., Carter J. P., Hewitt S. M., Shoemaker R. H., 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

15. 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

16. 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(*corresponding authors)