Tumors 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.
A study funded by Genmab, KWF (Dutch Cancer Society) and the European Research Council and conducted by researchers from the Netherlands Cancer Institute (NKI) in Amsterdam in collaboration with Genmab, have now developed a new strategy to tackle this problem.
The researchers report that, for the first time, an approach to target different cell groups within single tumors based on their respective characteristics shows positives results. The results of the study were published online in the January 15, 2018 edition of Nature Medicine. 
New target in resistant tumors
Although much progress has been made in the treatment of cancer, cures remain uncommon, because tumors 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 tumor cells to proliferate. This can be effectively treated by a tailored treatment using a BRAF-inhibitor. Unfortunately, many tumors develop resistance to this drug, even when it is combined with a so-called MEK-inhibitor, which hits the same signaling pathway.
A research group led by Daniel S. Peeper Ph.D at the Peeper Laboratory, a brand-new Division of Molecular Oncology and Immunology of the Netherlands Cancer Institute, had previously discovered that such resistant melanomas start producing another protein called AXL, a signaling molecule expressed on many solid cancers and implicated in tumor biology.
AXL, a member of the TAM (TYRO3, AXL and MER) family of receptor tyrosine kinases and overexpressed by many tumor cell types, plays a key role in tumor cell proliferation, survival, invasion and metastasis.
The protein sits on the outside of the tumor cell and therefore constitutes a good target in principle for treatment. Its expression is associated with drug resistance and poor prognosis
“Therefore, we set up a collaboration with Genmab, which had developed an advanced medicine against AXL,” Peeper said.
A novel antibody-drug conjugate or ADC, comprising an antibody coupled to a cytotoxic molecule may offer great promise. This investigational agent, called HuMax®-AXL-ADC, is an ADC which specifically binds to tumor cells expressing the AXL-protein. The researchers demonstrated that multiple types of AXL-high tumors can be effectively eliminated using this targted approach.
Consisting of a human monoclonal antibody directed against AXL and conjugated, via a protease-cleavable linker, to the cytotoxic agent monomethyl auristatin E (MMAE), HuMax-AXL-ADC, following administration, binds to AXL, which is expressed on the surfaces of a variety of cancer cell types. Then, upon endocytosis and enzymatic cleavage, MMAE is released into the tumor cell cytosol, where it binds to tubulin and inhibits tubulin polymerization. This, in turn, may result in G2/M phase arrest and apoptosis.
Combination treatment 2.0
Julia Boshuizen, MSc, a Ph.D graduate student at the Peeper laboratory discovered that melanomas that were resistant to BRAF- and MEK-inhibitors indeed harbored a large number of AXL-high cells. However, she also observed that most tumors 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 tumor with a bucket of marbles in two colors: 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.”
“If you wipe out the yellow marbles only, the red ones remain, and vice versa. So, to get rid of both colors, we thought it may be a good strategy to combine BRAF/MEK-inhibitors with HuMax-AXL-ADC,” Boshuizen concluded.
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 tumor cells, rendering HuMax-AXL-ADC even more effective in a combination treatment. This rationally developed combo-treatment effectively eliminated both groups of tumor cells, resulting in longer responses.
From Bench to bedside
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.
HuMax-AXL-ADC is currently in Phase I/II development for five different types of solid tumors including patients with melanoma, to assess the safety, side effects and the first signs of efficacy. The trial drug is fully owned by Genmab and the ADC technology used with HuMax-AXL-ADC is licensed from Seattle Genetics.
Last Editorial Review: January 15, 2018
This article was first published in Onco’Zine.