Newly developed therapeutic strategy offers potential in treating type 1 skin tumors linked to neurofibromatosis

Researchers at the German research institute Trias i Pujol (IGTP) have made progress in exploring potential treatments for skin tumors associated with neurofibromatosis type 1. Their findings in cellular models have been published in the journal JCI Overview.

Neurofibromatosis type 1 is a rare genetic disorder that leads to the development of skin tumors called cutaneous neurofibromas. Almost all adults with this disease have these neurofibromas, ranging from tens to several thousand tumors affecting the skin of all areas of the body. In addition to causing discomfort, cutaneous neurofibromas are disfiguring, negatively impacting patients’ mental health and quality of life.

Current treatment involves monitoring the tumors and removing them surgically if necessary. “Surgery is the only solution at the moment, but it is a partial and limited solution, because neurofibromas can grow back after an operation and continue to arise in other parts of the body. In addition, the scars they cause leaves are not minor,” says Meritxell. Carrió, Bernat Gel and Eduard Serra, the corresponding authors of the study.

In the study, researchers from the IGTP’s Hereditary Cancer group explored how certain cells – Schwann cells and fibroblasts – interact with each other in skin neurofibromas, revealing a genetic signature indicative of their communication. This signature confirms that their interaction could be a determining factor in the growth of cutaneous neurofibromas.

Scientists have identified a key player in the protein signature: the GPR68 receptor. When activated by a molecule called Ogerin and combined with Selumetinib, a MEK inhibitor already approved for use in plexiform neurofibromas, this receptor triggers a notable decrease in the survival of primary Schwann cells derived from cutaneous neurofibromas.

Essentially, this combination not only stops the proliferation of Schwann cells, but also promotes their terminal differentiation and ultimately leads to their death. This significant result was further validated using a sophisticated 3D model of neurofibromas grown from induced pluripotent stem cells.

The effect is not limited to the Ogerin-Selumetinib combination. The researchers observed similar results when they used other substances that activate GPR68 or mimic the action of a cellular messenger called cAMP.

Helena Mazuelas, the first author of the published work, emphasizes that the identified strategy opens the possibility of using different types of drugs: “In this work, we identified the GPR68 receptor and analyzed the effect of one of its activators . demonstrated that, in fact, any treatment that results in an increase in cAMP in cells responsible for tumor growth can be valid.

“There are many drugs that would serve this purpose, many of which are already being tested in humans for other diseases unrelated to neurofibromatosis type 1, and which could potentially work for neurofibromas as well. We are looking for them.”

The main takeaway from these experiences is the lasting impact of the treatment. While selumetinib alone only temporarily stops the proliferation of Schwann cells, the combination with Ogerin makes it possible to permanently stop their expansion, maintaining this effect even after the end of treatment.

These results obtained in vitro suggest a new approach in the treatment of cutaneous neurofibromas. By disrupting the balance of two critical cellular pathways – the Ras pathway (affected by MEK inhibitors like selumetinib) and the cAMP pathway (targeted by cAMP elevators like Ogerin) – this combination therapy appears to be a promising strategy. This could potentially shift the current treatment paradigm for neurofibromatosis type 1 skin tumors from surgery to a more targeted pharmaceutical approach.

Provided by the German Research Institute Trias i Pujol