Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1–Dependent Pathway in Multiple Myeloma

¹Department of Medical Oncology, ²Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, ³Center for Applied Cancer Science, and ⁴Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School; ⁵Center for Multiple Myeloma, Massachussetts General Hospital and Harvard Medical School, Boston, Massachussetts; ⁶Division of Biostatistics, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville, Maryland; ⁷Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas; ⁸San Raffaele Scientific Institute, Milan, Italy; and ⁹National Center for Tumor Diseases (NCT)/University of Heidelberg, Heidelberg, Germany

^* To whom correspondence should be addressed. E-mail: klaus_podar{at}dfci.harvard.edu.

	Abstract

Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1 (Hif-1) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1 and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1–dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1 as a novel molecular target in MM and add another facet to anti-MM drug activity. [Cancer Res 2009;69(12):5082–90]

Key Words: c-Myc, Hif-1, multiple myeloma, angiogenesis, bortezomib, enzastaurin, lenalidomide, adaphostin