Cancer cells want to live forever.

"Inhibition of apoptosis is a hallmark of cancer," Jean Viallet, vice president of clinical development at Montreal-based Gemin X Biotechnologies Inc., told BioWorld Today. "It is a core characteristic of the cancer state, and one that has not been successfully targeted to date."

Viallet and his colleagues at Gemin X hope to exploit that hallmark. The company announced last week that it has initiated Phase I trials with its bcl-2 inhibitor, GX15-070, for the treatment of solid tumors. The trial is being conducted at Georgetown University.

Apoptosis can be induced through two pathways: mitochondrial-based apoptosis plays a role in cancer, while receptor mediation is the induction method of choice for cellular suicide in inflammation and immunity.

Apoptosis: Fun For The Whole Protein Family

The bcl-2 family is an extended one. Among a number of other members, it includes two pro-apoptotic proteins, known as bax and bak, and two anti-apoptotic proteins, known as bcl-2 and bcl-xl. Pro-and anti-apoptotic proteins usually are bound to each other, with the net effect of inhibiting apoptosis.

Mitochondria are sensitive to a variety of cellular stressors. When those stressors exceed a certain threshold level, cellular machinery is activated that leads to an increased permeability of the mitochondrial membrane, the activation of caspases and, ultimately, cellular suicide.

In cancerous cells, the anti-apoptotic bcl-2 is overexpressed. Since mitochondrial apoptosis is induced via a threshold mechanism, that overexpression tips the scales against apoptosis, allowing the cells to resist apoptotic signals; the excess bcl-2 protein binds and neutralizes the bax and bak. That is where Gemin X has focused its efforts.

"Our drug prevents this binding, thus freeing members of the pro-apoptotic family to do their work," Viallet said.

Specifically, the compounds inhibit the interaction between bcl-2 and its counterparts, bax and bak. GX15-070 binds to a conserved feature of the bcl-2 family. "In the cancerous state, it's common to observe multiple [bcl-2] family members being overexpressed, so blocking only one has limited effects," Viallet said.

So Far, Rough Clinical Path

It should be noted that the first therapeutic aimed at inhibiting bcl-2 in the clinic has not paid off to date for its developer, Genta Inc., of Berkeley Heights, N.J. Earlier this week, the company reported that despite its drug Genasense meeting the primary endpoint in a Phase III chronic lymphocytic leukemia (CLL) trial, it missed key secondary endpoints, prompting Aventis to end its marketing partnership for the drug. Genasense is an antisense RNA inhibitor of bcl-2 synthesis. (See BioWorld Today, Nov. 10, 2004.)

Genta spokeswoman Joy Schmitt told BioWorld Today that Genasense is the subject of more than 20 clinical trials in a variety of cancers, and the results of a late-stage trial for Genasense in myeloma will be presented at the annual meeting of the American Society of Hematology (ASH) in December.

It was the second late-stage clinical failure for Genasense, which had missed its primary endpoint in a 2003 Phase III trial for the treatment of advanced melanoma. In May, an advisory panel recommended against its approval to the FDA, prompting Genta to withdraw its new drug application. (See BioWorld Today, May 4, 2004, and May 17, 2004.)

Viallet said that there are reasons that Gemin X's compound should be able to avoid failure. Most importantly, by targeting a conserved domain and protein-protein interaction rather than one specific protein, per se, GX15-070 takes aim at the whole bcl-2 family and thus should not be foiled as easily by redundantly overexpressed family members. Another reason is the use of a small-molecule blocker, which he said has "fundamentally different pharmacokinetics," as well as better penetration compared to antisense RNA.

While there are no clinical results as yet, there already is one piece of encouraging biological data from the trial. During apoptosis, a specific type of DNA fragment, known as oligonucleosome DNA fragments, are produced by caspases. Those fragments have a specific size, which makes them straightforward to detect; they are being monitored as part of the trial.

"It is too early to be able to comment about clinical response," Viallet said. "But in the days following drug administration, we saw about a 30-fold increase in circulating oligonucleosome DNA fragments, indicating apoptosis has been triggered."

In addition to the solid-tumor study, Gemin X also plans to initiate a second trial to test its compound in CLL.

"In CLL, overexpression of bcl proteins is universal and has been linked to the behavior of the tumor," Viallet said. "It is to CLL what the Philadelphia chromosome is to [chronic myelogenous leukemia]."

So far, at least, those results appear encouraging. Viallet said that in ex vivo tests, 80 percent to 90 percent of cultured cells from CLL patients have been responsive to GX15-070.