By David N. Leff

Every time a rookie ball player gets signed up by a major league club, he becomes an instant celebrity on the sports pages — the bright new hope of the coming season.

It's a little bit the same with the anticancer research game. In the 1980s, the star hopefuls were cytokines; interleukin-2 and tumor necrosis factor in particular got top billing.

Then came the tumor suppressor factors, and their flip-side tumorigenic oncogenes, led by the front-running p53, ras and bcl2.

A buzzword of the early 1990s, big-time, was apoptosis — programmed cell suicide. And most recently, a nuclear transcription factor called NF-kB has climbed to the top of the charts.

All of the above players are out on the field in today's Science, dated Dec. 5, 1997. The article reporting their performance bears the title: "Requirement of NF-kB activation to suppress p-53-independent apoptosis induced by oncogenic Ras."

Molecular biologist Albert Baldwin Jr. is the paper's senior author. He teaches at the University of North Carolina's Lineberger Comprehensive Cancer Center, in Chapel Hill. "The non-mutated Ras protein," Baldwin told BioWorld Today, "controls normal proliferative responses in the body. So, if you have a wound that needs closing, Ras controls growth-factor responses, inducing healing cells to proliferate.

"Ras is used when it needs to be used," Baldwin went on, "and afterwards is shut off by normal regulatory mechanisms."

But if Ras is mutated, he explained, "mutations leave it stuck in the 'on' position, continuing to multiply cells indefinitely. Unless killed or removed, the tumor grows until the patient, or animal, dies. In fact," he added, "Ras is the most widely mutated oncogene, occurring in over 30 percent of all cancers."

When that Ras switches from normal to malignant growth control, its first instinct is to enlist the apoptosis pathway to kill off the unwanted cells as fast as they proliferate. But paradoxically, it then enlists the NF-kB nuclear factor, a natural, beneficial protein, which is programmed, among other tasks, to protect cells from untimely death. NF-kB attaches to the DNA inside the cell's nucleus, and turns other genes on and off.

However, when seduced by Ras, the NF-kB connives at frustrating apoptosis, so the transformed cells will turn tumor, and multiply out of control.

How Ras Subverts Cell Suicide Program

"This paper shows," Baldwin said, "that there really is a transformation-associated apoptosis, but that it's suppressed. Obviously, if you suppress that programmed death, the tumor cells never form; they can't grow out. And the way it's suppressed is by activating NFkB, so that's the bottom line here. It gives insight into a cellular response to an oncogene, and into how the oncogene overcomes that cellular response.

"Programmed cell death," he added, "is a natural defense against cancer. But NF-kB prevents cells in some tumor types from dying by this protective mechanism."

This finding puts that Ras-empowering nuclear factor squarely in the cross hairs of a therapeutic target, aimed at inhibiting NF-kB.

"We have gone into some late-stage tumors that are driven by Ras oncogenes," Baldwin recounted, "and have blocked NF-kB by the expression of I-kB (I for inhibitor), which we cloned in 1991 [see BioWorld Today, Oct. 16, 1995, p. 1]. Some tumors seem to die pretty well under those conditions," he observed, "but the majority don't."

"In those late-stage tumors, from which our in vitro tumor cell lines are derived, other anti-apoptotic, pro-cancer factors are also expressed, and whether or not you block NF-kB, the cells fail to undergo apoptosis.

"bcl2, for example," he continued, "is a widely known anti-apoptosis protein that's identified as an oncogene. And it's expressed in certain tumors."

Baldwin made the point that "We think the importance of this is in early tumorigenesis. And ras mutations, at least in some tumors, are an early event. For that tumor to survive, we think it needs the activation of NF-kB. So if we can sort through them, there will be some tumors that potentially can be treated just by blocking NF-kB. But we think they're going to be the minority."

Twin Strategies Are Chemotherapy, Chemoprevention

Ras oncogenes come in three persuasions, H, K and M. "They show different mutation frequencies at different tumors," Baldwin pointed out, "such that in pancreatic cancer, which is so aggressive and so deadly, it's the K Ras mutation that drives that tumor."

Chemotherapy, he noted, "initiates a tumor-cell-killing pathway, but it also activates NF-kB, which suppresses that chemotherapeutic effect. If," he observed, "we give chemotherapy and in parallel block NF-kB, we get a really dramatic antitumor response that occurs in virtually all cancerous cells."

His lab also studies chemoprevention, such as dietary blockers of NF-kB. "Flavonoids," he said, "as found in broccoli and cauliflower, are actually NF-kB inhibitors. So is resveratrol in red wine. And these chemopreventatives are particularly effective in the early stages of tumorigenesis."

Several pharmaceutical companies are developing NF-kB inhibitors. Among them is Signal Pharmaceuticals Inc., of San Diego. On Tuesday of this week, Signal's president and CEO, Alan Lewis, announced to the BancAmerica Robertson Stephens Conference in New York that it had signed a $59 million deal with Ares-Serono Group, of Geneva, Switzerland, to identify small-molecule inhibitors of the NF-kB gene regulation pathway. (See BioWorld Today, Dec. 3, 1997, p. 1.)

"Signal's scientific cofounder, Michael Karin, and we share a lot of data freely with each other," Baldwin told BioWorld Today. *