Experimental Cancer Pharmaceuticals under Trial

SAN FRANCISCO - Advances in drug development have enabled scientists to attack new and unconventional cancer targets, leading to better treatments for cancer patients with fewer unwanted side effects. The following items highlight the early results from two experimental therapeutics, currently involved in Phase I or II trials, which are being presented today at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

A potent and selective inhibitor of the mitotic kinesin CENP-E (GSK923295A) demonstrates a novel mechanism of inhibiting tumor cell proliferation and shows activity against a broad panel of human tumor cell lines in vitro: Abstract A 111.

A first-in-class, targeted investigational therapy specifically designed to inhibit a single protein that functions only during cell division shows potent activity in a broad range of cancer cell lines, say researchers from GlaxoSmithKline. Because the compound is so specifically targeted, it may help reduce some of the more common toxic side effects of chemotherapy, they say.

The experimental drug, GSK923295A, inhibits the mitotic kinesin centromere-associated protein E (CENP-E), which is required during mitosis, the process by which a cell duplicates its genetic information in order to generate two, identical, daughter cells. The resulting mitotic arrest can lead to apoptosis, or cell death. A characteristic of CENP-E inhibition is the presence of misaligned or lagging chromosomes within cells attempting to replicate.

“Investigators were able to observe lagging chromosomes in most tumor cells treated with GSK923295A. These effects are rarely observed in untreated cells,” said the study’s lead investigator, David Sutton, B.Sc., associate director of biology, within the Oncology division of GlaxoSmithKline in Collegeville, Pa. GlaxoSmithKline funded the study.

Although CENP-E is expressed in all dividing cells, GSK923925A is more likely to affect rapidly dividing cancer cells, Sutton says. Furthermore, because of the very low expression of CENP-E in non-dividing cells such as neurons, GSK923295A may not cause the peripheral nerve damage often seen with chemotherapy treatments such as taxanes and vinca alkaloids, which also inhibit mitosis, he says.

Studies conducted in animal models have shown complete tumor regression in some cancer types, says Sutton. In preclinical tests conducted in 214 solid and 85 hematological tumor cell lines, sensitivity to GSK923295A was seen in 16 out of 17 breast tumor cell lines, 20 out of 25 colon cancer lines, 24 out of 26 lung cancer lines, 11 out of 11 ovarian cancer lines, and six out of six prostate cancer lines, he says. Additionally, laboratory analysis suggests that anti-tumor activity might be achieved with minimal suppression of the bone marrow, which could reduce the typical myelosuppression (reduction in production of blood cells) seen with chemotherapy treatment, he says.

“It is a big leap from doing laboratory experiments to understanding what will happen in patients, but we think it is very encouraging that this first-in-class drug candidate shows both broad activity and the potential for enhanced tolerability in preclinical studies,” Sutton said. GSK923295A, a small molecule drug given intravenously, is now being evaluated in a Phase I clinical trial in patients with advanced solid tumors. It was discovered and optimized by GSK, in partnership with Cytokinetics Inc.

Phase I pharmacokinetic study of ECO-4601, a novel bifunctional targeting agent: Abstract B 119.

Researchers report positive results from a Phase I/II clinical trial of a novel anti-cancer drug which offers two modes of action. In 26 patients with advanced solid tumors, treatment with ECO-4601 is safe and well tolerated, including at doses yielding plasma concentrations above the expected therapeutic threshold, says Pierre Falardeau, Ph.D., chief operating officer at Thallion Pharmaceuticals in Montreal, Canada. Thallion has produced and tested ECO-4601 in association with the Segal Cancer Centre of McGill University.

Falardeau says that ECO-4601 has a unique mechanism of action comprising two distinct activities. It inhibits the RAS/MAPK intracellular signaling pathway, which is mutated in many cancer types, and which is the target of several approved cancer drugs such as Erbitux, Avastin, Tarceva, Nexavar, and Sutent. “However, unlike these drugs, our preclinical experiments suggest that ECO-4601 acts at a unique point within the pathway, specifically at the level of RAS itself,” Falardeau said.

As a target for inhibition, RAS presented researchers with a chance to affect the signaling pathway with less fear that loops in the pathway will compensate for its loss. “Because RAS sits at a crossroad of multiple signaling pathways, targeting RAS may avoid some of the redundancies inherent in intracellular signaling,” Falardeau said.

The agent also binds to the peripheral benzodiazepine receptor (PBR), which is over-expressed in multiple cancers. This intracellular PBR binding may allow the drug to accumulate within tumor cells, providing a more efficient way to inhibit the RAS/MAPK signaling pathway. “In other words, ECO-4601 may preferentially target and accumulate within tumor cells because of the over-expression of the PBR,” Falardeau said.

In addition to its safety, the researchers also found that, while blood concentrations of the drug increased linearly along with an increase in dosage, at the end of the treatment’s two-week infusion, ECO-4601 was cleared from the blood relatively quickly. “Therefore, there is unlikely to be drug accumulation from cycle to cycle. This is important as the drug is intended to be used chronically and if a drug accumulates, side effects and toxicities may develop,” Falardeau said. The anti-tumor activity of ECO-461 is further maximized by continuous infusion, he explains.

The researchers say that of seven patients who completed three cycles of drug treatment in the dose escalation portion of the trial, six demonstrated stable disease, which Falardeau suggests is a preliminary sign of efficacy. “These data, together with extensive non-clinical data and the data presented at this conference, support the continued development of ECO-4601 for the treatment of cancer,” said Falardeau.