Professor Alex Adjei told the EORTC-NCI-AACR  Symposium on Molecular Targets and Cancer Therapeutics in Prague today (Wednesday 8 November) that the drug AZD6244 (ARRY-142886)  inhibited MEK1/2 – an enzyme that plays an important role in the Ras/Raf/MEK/ERK cell signalling pathway, which regulates cell proliferation and survival. Activation of this pathway has been implicated in a number of cancers, including lung, pancreatic, colon, melanoma and thyroid cancer.
“Laboratory studies have shown that AZD6244 has an effect on human tumours at nanomolar concentrations, and the first part of the phase I clinical trial has determined the maximum tolerated dose and the safety of the compound. Results from this second part of the trial demonstrate that a dose of 100mg of AZD6244 is well tolerated, produces a high incidence of long-lasting stable disease, and is associated with a profound inhibition of the cell signalling protein pERK and a reduction in cell proliferation – which indicates that the drug is working against the tumours,” said Prof Adjei, who was professor of oncology at the Mayo Clinic, Rochester, USA, before moving in October to be the senior vice-president for clinical research and chair of the Department of Medicine at the Roswell Park Cancer Institute, Buffalo, USA.
Prof Adjei and his colleagues at the Mayo Clinic, University of Colorado Health Sciences Center and Fox Chase Cancer Center recruited into the second part of the trial 34 patients with advanced cancers, including melanoma, breast, lung and colorectal cancers. Approximately 40% of the patients had melanoma. The researchers were particularly interested in this tumour type because a large proportion harbour B-Raf mutations, and tumours with these mutations may be highly sensitive to MEK inhibitors.
The patients were randomised to receive 100 or 200mg doses, twice a day for 28-day cycles. The larger dose proved to be too high for continuous dosing due to adverse side effects, but the smaller dose was well tolerated over a prolonged period.
The researchers tested biopsy tissue taken from the patients both before and after dosing. They found that the pERK protein was reduced by 77%. They also looked at another protein, Ki-67, which is used as a marker for cell proliferation. After dosing, there was a reduction in Ki-67 in nine out of 20 patients, and in five of those nine patients the reduction was at least 50% or more.
“We found that after 15 days of dosing, AZD6244 continued to inhibit pERK at times when concentrations of the drug in the blood were at their lowest levels between doses. At the lowest concentration, 400 nanograms of the compound per microlitre of plasma still corresponded to a 35-44% inhibition of pERK,” said Prof Adjei.
Overall, 39 of 57 patients completed at least one cycle of treatment with AZD6244. After completion of the second cycle, 19 (49%) had stable disease, and nine of these patients (six melanoma, one each of breast cancer, non-small cell lung cancer and medullary thyroid cancer) remained stable for five or more months (range, 5-14+ months; median, 6 months). Two patients, one with thyroid cancer and the other with melanoma, continue to receive treatment with AZD6244 after one year. Sixteen of the 20 patients with melanoma completed at least one cycle of treatment. Twelve had stable disease after completion of cycle two, with stable disease persisting for at least five months in six patients (range, 5 - 13+ months; median, 6.5 months).
Prof Adjei said: “This drug shows initial promising results. It appears to be able to target cancers with over-activation of MEK and associated cell signalling pathways in an efficient manner. Furthermore, it is easy to give to patients as it comes in an oral formulation that can be swallowed. As a result, a number of phase II clinical trials have been initiated in patients with melanoma, pancreatic, lung and colon cancers.”
EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].
AZD6244 (ARRY-142886), an MEK inhibitor, was invented by Array BioPharma and is being co-developed with AstraZeneca. Array BioPharma sponsored Prof Adjei’s study.
Emma Mason | alfa
Nanobot pumps destroy nerve agents
21.08.2018 | American Chemical Society
How do muscles know what time it is?
21.08.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.
The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...
New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference
Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
17.08.2018 | Event News
08.08.2018 | Event News
27.07.2018 | Event News
21.08.2018 | Medical Engineering
21.08.2018 | Physics and Astronomy
21.08.2018 | Power and Electrical Engineering