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Review Article

New agents in cancer clinical trials

Oncogene volume 19, pages 6687–6692 (2000)Cite this article

The 26S proteasome is the universal multi-catalytic protease, responsible for the bulk of protein turnover in all cells (Peters et al., 1998; Ciechanover, 1998; Lee and Goldberg, 1998; Spataro et al., 1998). Researchers at Millennium have developed a selective inhibitor of the chymotryptic activity which is sufficient to block cellular proteolysis. PS-341, a dipeptide boronic acid binds reversibly to the active site threonine residue, in a competitive fashion (Adams et al., 1998). In cell culture proteasome inhibition initially leads to G2-M arrest when studied between 4–8 h. Longer exposures (>16 h) result in apoptoic death (Adams et al., 1999). Extensive testing of PS-341 in a large number of tumor cell lines revealed it to be a potent inhibitor of cell growth and induction of apoptosis at low nanomolar concentrations. When compared with untransformed cells, PS-341 (and other proteasome inhibitors) demonstrated selective killing of tumor cells (Adams et al., 1999). The mechanisms of action necessarily involve the stabilization of hundreds to thousands of proteins including short lived regulatory molecules which drive the cell cycle, tumor suppressors and growth factors. All of these actions conspire to confound cellular signals for growth, lead to a profound stress response, and induce apoptosis. It is tempting to speculate, although hard data is still required to support the hypothesis, that tumor cells, which have defective DNA repair and checkpoint machinery are more susceptible to the effects of proteasome inhibition, thus providing the basis for a therapeutic index (Orlowski et al., 1998). Further work using PS-341 in cell culture experiments has demonstrated that it is a potent inhibitor of the activation of NF-κB, a transcription factor which has recently been implicated in tumor cell survival (Beg and Baltimore 1996; Van Antwerp et al., 1996; Wang et al., 1996). This is achieved through the stabilization of the inhibitor protein IκB thereby preventing nuclear translocation of the active transcription factor. PS-341 has also been shown to bypass Bcl-2 cytoprotection (Herrmann et al., 1998). Encouraged by cellular experiments, several murine and human tumor xenograft models were studied revealing potent growth inhibition (Adams et al., 1999). DNA damaging agents which activate NF-κB, when combined with PS-341, have led to regression of tumors in animals. Following extensive pre-clinical experimentation to demonstrate that proteasome blockade is tolerated to 80% inhibition, PS-341 entered clinical trials and its activity was monitored using an ex vivo enzyme bioassay (Millennium Pharmaceuticals, Inc., Proteasome Inhibitor, PS-341, IND# 56,515, submission to the FDA, July 1998). The results to date are most encouraging. The drug is remarkably well tolerated, with few of the common toxicities observed with approved chemotherapy agents, such as myelosuppression and alopecia. The drug inhibits its biological target, the proteasome, and this pharmacodynamic endpoint has been used to guide the escalation of dose. PS-341 has shown promising biological activity in both hematological and solid tumor malignancies, although it is too early to assess the full clinical impact of these early observations. Phase II monotherapy studies will begin shortly and Phase I studies in combination with standard chemotherapy agents have just begun.

The benzoquinone ansamycin geldanamycin analog, bearing a 17-allyl amino moiety is currently in Phase I Clinical Trials at the National Cancer Institute (Neckers et al., 1999). 17-AAG is a member of a larger class of related antibiotic natural products. It was thought originally to be a non-specific kinase inhibitor. Its molecular mechanism has recently been redefined where it has been shown that geldanamycin binds to the chaperone protein Hsp90 (Hickey et al., 1989). The co-crystal structure revealed that the binding site is a hydrophobic pocket which is normally associated with interactions of denatured protein substrates (Stebbins et al., 1997). This pocket also bears strong homology with ATP binding motifs present in bacterial DNA gyrase, suggesting a role for ATP binding of Hsp90. Further biochemical and genetic studies have shown that immobilized geldanamycin bound the glycine-rich N-terminal domain requiring ATP (Grenert et al., 1997). Taken together, the data point to ATP/geldanamycin interactions which regulate the conformation of Hsp90 chaperone complexes with numerous protein substrates, depending on whether the nucleotide is in the triphosphate or hydrolyzed diphosphate mode–a molecular switch.

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    Julian Adams & Peter J Elliott

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Adams, J., Elliott, P. New agents in cancer clinical trials. Oncogene 19, 6687–6692 (2000). https://doi.org/10.1038/sj.onc.1204088

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