Mikkel Christian Schou Andersen

Meningiomas and their surrounding tissue - Proteomics, epigenetics and selective progesterone modulation

1) Meningiomas are mostly (80-90%) benign connective tissue tumors and derive from the sack enveloping the brain. Studies show 1% of the population has a meningioma-like tumor on scans. Complete removal of meningiomas residing in the skull is only possible in 63% of the cases (in particular when located on the skull base). Radiotherapy is used on inoperable and small symptomatic tumors. The current treatment is based mainly on retrospective, low-evidence studies, and the risk of radiotherapy-induced tumors and damage to nearby sensitive structures is present. Therefore, there is a need for development of new and better treatment strategies to supplement or replace radiotherapy and in some cases surgery.

The project revolves around classification of benign tumors inside the skull and examinations of the swelling they cause in the surrounding brain tissue. Furthermore, the project will include a medical trial on rodents, where the objective is to make the tumors shrink or stop evolving.

2) Meningiomas are most likely related to benign tumors in the uterus, which are sensitive to estrogen and progesterone. Progesterone receptors are expressed in 56-83% of all meningiomas. Anti-progesterone compounds have been shown to reduce the size of benign uterine tumors, however with little or no effect on meningiomas.

Further research into anti-progesterone treatment of progesterone receptor positive meningiomas can potentially reveal new and potent non-surgical and adjuvant meningioma treatment strategies. New selective progesterone receptor modulators (which have never been used on meningiomas) have shown promising results on benign uterine tumors and could possibly have similar effects on meningiomas.

Swelling of the surrounding brain tissue can lead to permanent disability or death for the patients. This swelling is difficult to treat and not very well understood, which is why we will explore this on protein and epigenetic-based levels using Proteomics and DNA-methylation.

Therefore, the project needs to be conducted now and not in 5 years. The project, if successful, could cause a paradigm shift in the treatment of recurrent benign intracranial connective tissue tumors and unresectable (tumors not suited for surgery) for the benefit of the patients and the healthcare system. Furthermore, we are conducting specialized analyzes, which could give rise to new targets for treatment of the tumors.

3) The above is achieved by using tumor tissue from patients who are operated for meningiomas. Cells from the tumor are transferred to a rat model, where a new tumor will grow. Hereby, we can both take out brains of the rodents and study the brain in detail - with before described methods - and safely and effectively test new drugs in a lifelike environment before the drugs at a later stage can be tested in humans. The last stage in a human model will not be explored in this PhD project.

Specific tasks to be solved: 1. make tumor cells maintain progesterone receptor expression, 2. establishing a viable rodent model, 3. performing DNA-methylation and proteomics on human tumor tissue and rodent tumor tissue and proteomics on adjacent brain tissue. 4. Test anti-progesterone drug on rodent model, randomized.

For the preparation of the project and to ensure feasibility, we have gathered a team to consisting of an upcoming PhD student (applicant), brain surgeons from both Odense University Hospital and Rigshospitalet. In addition to experts in the field of pathology, nuclear medicine, animal experiments as well as proteomics and DNA methylation, we have teamed up with international partners from Otto-Von-Guericke University and Cambridge University, who are specialized in meningiomas and animal models.