Combination strategy may offer longer term benefits in cancer, notes research

A new strategy to tackle the issue of long-term treatment efficacy in cancer patients has been developed by researchers from the Netherlands Cancer Institute in collaboration with international biotechnology company, Genmab.

The collaborative work has been published in the journal Nature Medicine and demonstrates the novel approach to treating cancer — targeting different cell groups within single tumours based on their respective characteristics.

Previous work, led by Prof. Daniel Peeper at the Netherlands Cancer Institute, had revealed that treatment resistant melanomas (which often carry a mutation in the BRAF-gene) start producing another protein called AXL. This protein actually sits outside the tumour cell, making it a potentially ideal target for treatment. “Therefore, we set up a collaboration with the international biotechnology company Genmab, which had developed an advanced medicine against AXL,” Peeper explained.

The potential treatment — an antibody-drug conjugate (ADC) — comprises an antibody coupled to a cytotoxic molecule and is called HuMax-AXL-ADC. This product specifically binds to tumour cells expressing the AXL-protein and then kills them. The researchers who developed this strategy found that multiple types of AXL-high tumours can be effectively eliminated in this way.

However, one of the PhD students from the Peeper laboratory, Julia Boshuizen, discovered that in the melanomas that were resistant to BRAF- and MEK-inhibitors although there were numerous AXL-high cells there were also considerable numbers of cells with little or no AXL. As these cells with little or no AXL were still sensitive to BRAF- and MEK-inhibitors, Boshuizen can up with a strategy to combine the treatments.

“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 said. “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.”

Using this combined approach, the team was able to demonstrate that melanomas resistant to the standard treatment were still highly responsive to the new AXL-medicine in mice. Additionally, 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. Moreover, as both groups of tumour cells were eliminated when using this combination treatment it was found to be beneficial in the longer term.

As a result of this work, 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.