Pilot-study: Nip therapy resistance in growth hormone-secreting pituitary tumours in the bud

Eva Coopmans, Erasmus University Medical Center Rotterdam

 

Aims

Acromegaly is a disease caused by a GH-secreting pituitary tumour and associated with significant morbidity and mortality if left untreated. The treatment of choice is 1st-generation somatostatin analogues (SSAs) but most patients (~55%) develop resistance.

Patient-specific therapy based on genetics may help selecting effective treatments. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations develop young-onset acromegaly with poor response to 1st-generation SSAs, while tumours with guanine nucleotide-binding protein α-stimulating polypeptide (GNAS) mutations respond well. The mechanisms underlying SSA resistance are unknown but may involve Gαi-2 or ZAC1 protein(Gadelha et al. 2013) .

I hypothesise that expression of the produced proteins of AIP, Gαi-2 and ZAC1 is different in Aip- and Gnas-mutated mice and might explain why AIP-mutated tumours respond worse than GNAS-mutated tumours to SSAs. With this grant, I would like to visit the laboratory of Professor Korbonits in London, UK. She is an expert in genetics of pituitary tumours. If I can confirm the differentially expressed genes in this pilot-study, we will set up a full-scale mice experimental design including treatment with pasireotide.

My aims are:
1. Analyse indices of disease progression;
2. Identify differentially expressed genes through RNA sequencing on pituitary tissue of octreotide-treated Aip- and Gnas-mutated mice.

 

Evaluation

I would like to send you a report regarding my activities in the department at the Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London.

I arrived to the laboratory and started training in laboratory techniques such as DNA and RNA extraction, PCR, RT-PCR and Western blotting under the direct supervision of senior postdoctoral fellow Sayka Barry and advanced clinical PhD students Chung Lim and Donato Iacovazzo. One month later, I successfully completed Home Office Training Course to obtain personal license to work with their pituitary related animal models. During the following months I had obtained ‘hands-on’ training with mice from PhD student Anisha Mistry and postdoctoral researcher Federica Begalli and generated preliminary data on bodyweight and IGF-1 levels during somatostatin analogue treatment in Aip- and Gnas-mutated mice under the close supervision of transgenic pituitary mouse model expert Dr Carles Gaston-Massuet.

To gain more experience with bioinformatics, I also started to investigate both the clinical and functional data from AIP variants described in pituitary tumour patients worldwide in order to combine the ACMG-AMP variant classification criteria with clinical and experimental data under the direct supervision of Prof Korbonits. I had taken over an ongoing project of setting up a locus-specific database for AIP variants. A manuscript from this work now in advanced stages. In the meanwhile, I am writing applications to gain further funding for my stay in the laboratory such as the Marie Curie Fellowship and a Niels Stensen Fellowship together with Prof Korbonits, and Dr Li Chan.

The difficulties in delivery I experienced was the start of the covid-19 pandemic that interrupted my stay in London. This made it harder for me to stay in London and find additional funding to extend my stay. In the near future I hope to become in the position again to go back to London and perform further experiments with their animal models.

In conclusion, the Bioscientifica Trust Grant was extremely fruitful both for myself as well as the projects I was involved in.

 

Grant awarded: €2.688.00