By David N. Leff
FT. LAUDERDALE, Fla. -- A three-way partnership of industry, academia and the National Cancer Institute (NCI) is mobilized to disarm the master enzyme that chops up proteins in the cell.
Harvard cell biologist Alfred Goldberg told the 1997 Miami Nature Biotechnology Winter Symposium here how proteasomes, instigated by a small polypeptide called ubiquitin, can break down proteins, and play a key double role in cancer and inflammatory diseases.
"Working like a bread-cutter or food-processor," Goldberg said, "proteasomes cut proteins at many sites."
Goldberg is co-founder of ProScript Inc., of Cambridge, Mass., and chairs the firm's scientific advisory board.
"The company," he told BioWorld Today, "is developing small molecules to inhibit proteasomes. The molecules that the NCI has approved for serious investigation are designed to inhibit the proteasome's active sites."
The theme of Goldberg's talk Sunday was, "Function of the proteasome in protein turnover and antigen presentation."
Goldberg explained that proteasomes are a major proteolytic complex, which constitutes one percent of the protein in the cell nucleus and cytosol. "It's the major site at which normal cellular proteins are degraded," he said, "so proteasomes play a role in the regulation of many pathways. They are also essential to generate peptides used in antigen presentation."
He pointed out that "in the breakdown of abnormal proteins, proteasomes serve as a cellular sanitation system.
"The process serves several functions," Goldberg added. "One is to break down the proteins all the way to amino acids. But some of the peptides this generates are pulled out of that pathway for antigen presentation to the immune system. The immune system regularly looks at small protein fragments. This process is activated by interferon, through changes in the proteasome."
It turns out that proteasome inhibitors are very potent anti-inflammatory agents.
"The activator of inflammatory responses," Goldberg said, "is NF*B (nuclear factor kappa B). This is the transcription factor involved in making most inflammatory cytokines, such as interleukin-1, tumor necrosis factor and adhesion molecules for white cells.
"These disease mediators," he continued, "are generated by transcription of genes in response to NF*B. When bacterial infection occurs, several events lead to its activation and movement into the nucleus. Proteasomes allow this activation to happen."
The ubiquitin-proteasome pathway trims NF*B and destroys its protein inhibitor, so that NF*B gets activated and inflammation arises. Hence the drive for proteasome inhibitors to combat inflammation.
"In many disease states," Goldberg observed, "the phenomenon of cachexia -- muscle wasting or failure to grow -- occurs, for example, in cases of AIDS or cancer, because of the excessive protein breakdown.
"This is a response that happens in starvation. When the body needs amino acids, it mobilizes them from muscle. And in these disease states, what has been a helpful reaction really gets out of control, leading to excessive destruction of muscle."
In another disease, cystic fibrosis, "the mutant form of the CFTR [cystic fibrosis transmembrane receptor] protein," Goldberg noted, "is rapidly degraded by the ubiquitin-protease pathway, and none of the protein channels make it to the cell surface."
He added, "A most promising therapeutic target for proteasome inhibitors is to kill tumor cells, because cell division requires the programmed destruction of regulatory proteins -- such as p53 and cyclins."
Therefore, NCI has given top priority to testing ProScript's proteasome inhibitor molecules for treating cancer, the company's CEO, Richard Bagley, told BioWorld Today. "The institute approached us," he said, "for some of our compounds, which it is intensively screening."
The firm is collaborating with Hoechst Marion-Roussel's (HMR) oncological group, in Cincinnatti, and with Nippon-Roche, in Tokyo. (See BioWorld Today, Oct. 8, 1996, p. 3, and Nov. 10, 1995, p. 1.)
It also is exploring the potential for a Cooperative Research and Development Agreement with NCI, said ProScript's chief financial officer, David Lubner.
In its own laboratory, the company is pursuing in vitro and in vivo preclinical studies of anti-cancer efficacy, in parallel with HMR.
"Early experiments," observed chief science officer Julian Adams, "show that our proteasome-inhibiting compounds can slow growth of both murine and human tumors -- prostate, colon, lung and melanoma -- in nude mice. We expect to file for an IND on treating lung cancer early next year." *