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.-American Association for Cancer Research
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#1 Bio-Marker Identifies Patients Who Benefit From Targeted Drugs
Many patients are treated not only with a "targeted" therapy drug but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
Findings presented at the 41st Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden, April 18, 2007, concluded that "functional profiling" with cell culture assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity of Iressa, Tarceva, Sutent, Nexavar, and Avastin in primary cultures of "fresh" human tumors).
Cell Culture Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.
There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell culture assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).
"Funtional profiling" measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, "functional profiling" is measuring them through the surrogate of measuring if the cell is alive or dead.
The "funtional profiling" technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This type of bio-marker testing could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007