Klaus Früh, Ph.D.

2. Kaposi's Sarcoma Associated Herpesvirus (KSHV)
Molecular drug target identification for new, specific and less toxic cancer treatments will greatly benefit from functional genomics approaches to cancer cell biology. This strategy requires
a. a useful experimental model for a given cancer,
b. the global analysis of this model by functional genomics tools,
c. the validation of these results by interfering with the biochemical pathways identified by global analysis.
We apply such a strategy for drug target discovery for Kaposi's sarcoma (KS), the most common tumor in HIV-infected individuals. Strong epidemiological and experimental evidence links Kaposi's sarcoma-associated herpesvirus (KSHV) to KS. Dr. Ashlee Moses has established an in vitro culture system for KSHV that recapitulates several of the hallmarks of KS, most notably the development of spindle cells from endothelial cell precursors.

A preliminary global expression analysis of this system with DNA microarrays revealed cellular transcripts that change upon KSHV infection. Moreover, we demonstrated that some of these cellular gene products are essential for KSHV-replication or for spindle cell formation. Most notably, KSHV-induced upregulation of c-kit was found to be essential for spindle formation since this process could be blocked by inhibiting c-kit signaling with STI571.
Based on this proof-of-principle study, we are performing detailed DNA-microarray analysis studies of in vitro models for KS tumor development as well as KS tumor tissue. Using systematic data analysis tools we will identify cellular transcripts that are specifically induced by KSHV. These potential drug targets will be validated in our in vitro system in a series of biological assays. The expression or function of these gene targets will be inhibited by either small molecule inhibitors or antisense oligomers. Feasibility of this antisense approach has been validated with c-kit. Using this combined approach of global analysis and selected validation, we expect to identify a series of novel drug targets for KS. If successful, this study design could prove useful for a functional genomics approach to the molecular drug target discovery for other cancers as well.

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Download KSHV c-kit PDF from Journal of Virology, Aug. 2002, p. 8383-8399

Download Microarray Data

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KSHV

References