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
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering