Leflunomide Treatment for MEN1 Patients - the LUMEN1 Trial
Status:
Not yet recruiting
Trial end date:
2025-01-01
Target enrollment:
Participant gender:
Summary
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder due to mutations
in the tumor suppressor gene MEN1 with the corresponding gen product menin. MEN1 is
characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary
tumors which can release excessive amounts of hormones (= functional active tumors). Other
tumors (e.g. carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas,
collagenomas, lipomas) have also been described. There is no geno-phenotype correlation but
the disease occurs after a second hit of the corresponding gene within the endocrine organ
leading to an uncontrolled growth.
MEN1-patients have a decreased life expectancy, mainly due to pancreatic neuroendocrine
tumors (pNETs) which are often multiple and more aggressive than in non-MEN1 patients. To
date, no prophylactic treatment exists to prevent tumor development in this hereditary
disease.
Leflunomide has been used as a treatment for rheumatoid arthritis for many years. It is a
potent inhibitor of the dihydroorotate dehydrogenase (DHODH). According to some preclinical
studies, leflunomide showed antineoplastic activities in several malignancies, including
prostate, breast, bladder, multiple myeloma, leukemia, and lymphoma. A recent study
identified an interaction between MEN1 mutation and DHODH inhibition. In this study,
leflunomide selectively killed MEN1 deficient cells in vitro, prevented the occurrence of
pancreatic tumor development in xenograft models and led to tumor regression / stabilisation
in three MEN1 patients with advanced aggressive pancreatic neuroendocrine tumors.
Accordingly, leflunomide could be used as a new treatment option for patients with known MEN1
germline mutation and associated endocrine disease. The aim of this study is, therefore, to
evaluate the antitumor effect of leflunomide treatment on MEN1-associated tumors in patients
with known MEN1-syndrome.