New treatment identified for peripheral nerve sheath tumors

A multicenter collaboration led by the Bellvitge Biomedical Research Institute (IDIBELL) - Institut Català d'Oncologia (ICO) and the Germans Trias i Pujol Research Institute (IGTP) identified a potential new treatment for an aggressive sarcoma arising in the nerves. The findings have been published in the journal Clinical Cancer Research.

A rare aggressive tumor arising in the nerves

It may sound strange, but tumors may also arise in the nerves. This is the case of the malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with a high tendency to metastasise. Sarcomas are a group of tumors originating from cells of the connective tissue, like bone, cartilage, muscle, fat or the nerve sheath, where MPNSTs arise. About 50% of MPNSTs appear in the general population, while the other 50% develop in the context of the genetic disease Neurofibromatosis type 1 (NF1), where individuals have a lifetime risk of 10-15% to develop this tumor, affecting both children and adults.

A valuable resource: A pre-clinical platform for precision medicine

Currently, there is a lack of an effective therapy for MPNSTs beyond a timely surgery, since conventional radio or chemotherapy do not show very good responses. This lack of therapeutic options prompted, almost 15 years ago, the teams of Dr Conxi Lázaro (Hereditary Cancer at IDIBELL) and Dr Eduard Serra (Hereditary Cancer at IGTP), together with the expertise of Dr Alberto Villanueva and the collaboration of different clinicians like Dr Ignacio Blanco, to develop a robust preclinical platform consisting of patient-derived xenografts (PDX) of human MPNSTs implanted in the nerves of immunodeficient mice and the establishment of multiple MPNST cell lines.

"It has been a patient and long collaborative work of many years that is now at its maturity. We are very happy that the platform has been a successful investment that is providing now all its potential. I would like to thank many people involved, particularly Dr Juana Fernandez, who directs the Mouse Lab platform at IDIBELL, that has been key for this success. I would also like to thank the constant support of the Fundación Proyecto Neurofibromatosis, whose invaluable and constant support, even in difficult times, allowed the development of this platform" mentioned Dr Lázaro, one of the senior authors of the work.

All models and primary tumors have been genomically characterised and compared, enabling their use in precision medicine strategies, where drugs are tailored to treat tumors based on specific mutations identified in each case. Over time, this resource has grown significantly, now comprising many different MPNST models, and serving as a foundation for drug screening to predict treatment responses.

"The most common type of MPNSTs initiate by losing the function of three important genes, called tumor suppressor genes: NF1, CDKN2A and PRC2 (either SUZ12 or EED). We have been fortunate that inhibitors targeting the pathways affected by these mutations already exist. Building on top of the work of other research teams -science and research is like being a 'casteller'- we initiated the project funded by La Marató de TV3, to combine these drugs and evaluate their potential for clinical application" stated Dr Serra, the other senior author of the work.

From drug screening to the clinics: research with impact

In a first step, researchers took advantage of a fruitful collaboration with Dr Marc Ferrer, at the National Center for Advancing Translational Sciences (NCATS) at NIH (USA), and used robotics to screen hundreds of combinations of different inhibitors of each class: MEKi, to target the loss of NF1, CDKi to target the loss of CDKN2A and BETi to target the loss of PRC2 function. The best combinations were selected, validated in vitro using an extensive panel of MPNST cell lines, and finally tested in vivo using the PDX preclinical platform, which represents both NF1-associated and sporadic MPNSTs. Researchers found good responses when using selected combinations of two different inhibitor classes, MEKi-BETi, but the best responses were obtained when using the combined action of the three inhibitors, MEKi-BETi-CDKi.

"Initially, we were excited with the combined MEKi-BETi treatment, observing for the first time in our PDX models, how human MPNSTs were shrinking. However, the most remarkable moment was when we observed some tumors disappearing completely with the triple MEKi-BETi-CDKi combination. After all the hard work, seeing the potential clinical applicability was an incredibly rewarding moment", explained Sara Ortega, the first author of the work, and a key driver of the project, which is part of her PhD thesis that will be defended this year.

At this point, it was the close collaboration with clinicians, especially Dr Héctor Salvador from the Pediatric Cancer Center at Hospital Sant Joan de Déu, that made possible the use of this preclinical results as the foundation for their application in clinical settings. Initially, the findings supported the compassionate use of the MEKi-BETi combination in paediatric patients with a MPNST. Dr Salvador together with Dr Claudia Valverde, from Vall d'Hebron Hospital, facilitated the access to new inhibitors, which are currently undergoing testing in clinical environments. Additionally, Dr Salvador and Alicia Castañeda have started to administer the MEKi-BETi combination as compassionate use for children affected by MPNSTs. For the MEKi-BETi-CDKi combination, further preclinical studies are needed to optimise administration regimens and minimise toxic effects. However, these promising results, combined with a clinical trial currently underway in the USA led by other clinical groups, aim to provide the necessary evidence to enable their broader clinical application in the near future.

"There is still a lot to do -further preclinical data, optimized treatment regimens, reduced toxicity- but the first steps for precision medicine in treating MPNSTs in the future are already in place" concluded the team.