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New personalised therapy target out manoeuvres BRAF-MEK resistance

Tumours often comprise groups of cancer cells that show differential drug sensitivities.

This is one of the reasons that initially effective treatments usually do not lead to long-term benefit in patients.

Researchers from the Netherlands Cancer Institute in Amsterdam, in collaboration with the international biotechnology company Genmab A/S, have now developed a new strategy to tackle this problem.

They report, for the first time, an approach to target different cell groups within single tumours based on their respective characteristics.

Nature Medicine publishes their findings on January 15.

Although much progress has been made in the treatment of cancer, cures remain uncommon, because tumours develop resistance over time to the drugs used.

It is becoming more and more clear why this happens, for instance in melanoma, the most aggressive form of skin cancer.

Melanomas often carry a mutation in the BRAF-gene, which causes the tumour cells to proliferate.

This can be effectively treated by a tailored treatment using a BRAF-inhibitor.

Unfortunately, many tumours develop resistance to this drug, even when it is combined with a so-called MEK-inhibitor, which hits the same signalling pathway.

A research group led by Prof. Daniel Peeper at the Netherlands Cancer Institute had already previously discovered that such resistant melanomas start producing another protein, AXL.

The AXL- protein sits on the outside of the tumour cell and therefore constitutes a good target in principle for treatment.

Prof Peeper says “Therefore, we set up a collaboration with the international biotechnology company Genmab, which had developed an advanced medicine against AXL.”

It concerns a so-called antibody-drug conjugate (ADC), comprising an antibody coupled to a cytotoxic molecule.

This product, called HuMax-AXL-ADC, specifically binds to tumour cells expressing the AXL-protein, and can thereby kill them.

The researchers demonstrated that multiple types of AXL-high tumours can be effectively eliminated in this way.

PhD student Julia Boshuizen from the Peeper laboratory discovered that melanomas that were resistant to BRAF- and MEK-inhibitors indeed harboured a large number of AXL-high cells.

However, she also observed that most tumours still contained considerable numbers of cells with little or no AXL.

Because the researchers had already found that those cells remained sensitive to BRAF- and MEK-inhibitors, she came up with a plan.

“We compared the resistant tumour with a bucket of marbles in two colours: yellow ones that have little AXL, which are sensitive to BRAF- and MEK-inhibitors; and red marbles that express lots of AXL and fail to respond to BRAF/MEK-treatment.” She continues “If you wipe out the yellow marbles only, the red ones remain, and vice versa. So, to get rid of both colours, we thought it may be a good strategy to combine BRAF/MEK-inhibitors with HuMax-AXL-ADC.”

The team managed to show that melanomas that were resistant to the standard treatment in mice, were still highly responsive to the new AXL-medicine.

Moreover, they found that BRAF/MEK-inhibitors stimulated the production of AXL in tumour cells, rendering HuMax-AXL-ADC even more effective in a combination treatment.

This rationally developed combo-treatment effectively eliminated both groups of tumour cells, resulting in longer responses.

With this research project, the investigators have provided important pre-clinical evidence for the efficacy of the new AXL-medicine, as well as for the combination with BRAF- and MEK-inhibitors for melanoma patients.

Genmab is currently testing HuMax-AXL-ADC in patients with a number of different types of tumours, including patients with melanoma, to assess the safety, side effects and the first signs of efficacy.  

Source: Netherlands Cancer Institute

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Founding partners

European Cancer Organisation European Institute of Oncology

Founding Charities

Foundazione Umberto Veronesi Fondazione IEO Swiss Bridge

Published by

ecancer Global Foundation