A sophisticated new chemical genetic screening strategy that serves as a tool for identifying anticancer compounds may significantly enhance the drug discovery process. Two research papers that describe using this exciting gene expression-based chemical genomic strategy to identify therapeutics for cancer phenotypes previously associated with a poor prognosis and to gain new insight into cancer biology are publishing online on September 28th, and in the October 2006 print issue of the journal Cancer Cell, published by Cell Press.
Dr. Todd R. Golub and colleagues, from the Dana-Farber Cancer Institute, the Broad Institute of MIT, and Harvard Medical School, identified compounds that inhibit androgen receptor (AR)-mediated signaling. AR signaling plays a critical role in the progression of prostate cancer, even in patients whose androgen level is dramatically reduced through androgen ablation therapy. Currently, there are very few clinically effective AR signaling inhibitors. By applying a gene expression signature-based screening approach, Dr. Golub's group was able to identify two chemical compounds derived from plants with a medicinal history, celastrol and gedunin, as potent inhibitors of AR signaling.
The researchers then used a computational tool they named the Connectivity Map to compare gene expression signatures evoked by these compounds with the gene expression signatures of drugs that had established biological activities. This comparison revealed that celastrol and gedunin inhibit heat-shock protein 90 (HSP90). HSP90 has been under intensive investigation as a target for cancer therapy in recent years. However, the structures of celastrol and gedunin and how they interact with HSP90 differ from currently known HSP90 inhibitors. Therefore, these structurally and mechanistically novel modulators of HSP90 open unique scientific and therapeutic avenues.
In a separate study, researchers, led by Scott A. Armstrong of Children's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, attempted to overcome glucocorticoid (GC) resistance in childhood acute lymphoblastic leukemia (ALL). Resistance to treatment with GC is a strong predictor of poor prognosis in ALL, but the precise explanation for sensitivity versus resistance to GC in ALL as well as how to overcome GC resistance is not clear. These researchers applied gene expression analysis to identify genetic signatures associated with GC-sensitive and GC-resistant ALL samples. They then used these genetic signatures to query a database derived from many biologically active compounds by using the Connectivity Map approach. This comparison revealed that the compound rapamycin is an agent capable of potentially reversing the GC resistance signature. The researchers further demonstrated that rapamycin modulates a signaling molecule linked to cell death and suggested that combination therapy with rapamycin and GC may be useful for treatment of ALL.
Results from these two studies demonstrate that the gene expression-based chemical genomic approach represents a strategy for identification of promising new therapies for cancer. "Chemical genomics has the potential to identify modulators of complex cancer phenotypes, predict their activities, and subsequently establish their mechanisms of actions with little prior knowledge about underlying mechanisms," offers Dr. Golub.
The researchers include Guo Wei of Dana Farber Cancer Institute and Harvard Medical School and The Broad Institute of Harvard University and Massachusetts Institute of Technology; David Twomey of Children's Hospital and Harvard Medical School and The Broad Institute of Harvard University and Massachusetts Institute of Technology; Justin Lamb of The Broad Institute of Harvard University and Massachusetts Institute of Technology; Krysta Schlis, Stephen E. Sallan, and Scott A. Armstrong of Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School; Jyoti Agarwal of Children's Hospital and Harvard Medical School; Ronald W. Stam, Monique L. den Boer, and Rob Pieters of Sophia Children's Hospital, Erasmus University Medical Center; Joseph T. Opferman of St. Jude Children's Research Hospital; and Todd R. Golub of Dana Farber Cancer Institute and Harvard Medical School, The Broad Institute of Harvard University and Massachusetts Institute of Technology, and Howard Hughes Medical Institute.
This work was supported by The Leukemia Lymphoma Society (S.A.A), Damon Runyon Cancer Research foundation (S.A.A)(G.W), and the National Cancer Institute (NCI grants K08 CA92551 and PO1 CA068484).
Hieronymus et al.: "Gene expression signature-based chemical genomic prediction identifies novel class of HSP90 pathway modulators." Publishing in Cancer Cell, Volume 10, Issue 4, October 2006. DOI 10.1016/j.ccr.2006.09.005.
Wei et al.: "Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL-1 and glucocorticoid resistance." Publishing in Cancer Cell, Volume 10, Issue 4, October 2006. DOI 10.1016/j.ccr.2006.09.006.