Endocrine tumour biology
We focus on clinical and biological aspects of rare endocrine diseases, such as adrenocortical cancer and neuroendocrine tumours with special emphasis on the multiple endocrine neoplasia type 1 syndrome (MEN1). We try to understand the basic mechanisms causing these diseases, and perform clinical trials in order to evaluate treatment regiments. As being part of the Uppsala Centre of Excellence for Neuroendocrine Tumors, a national referral centre, we are in a good position to translate our results and experiences into new and better clinical practise.
Carriers with mutations in the gene MEN1 develop multiple tumours of the parathyroids, endocrine pancreas and pituitary. MEN1 is thought to be a tumour suppressor gene, but it is unclear why MEN1 inactivation leads to tumour formation only in some endocrine organs. We try to address this question through analyses of the consequences of MEN1 inactivation, and through studies of other factors that may interact with MEN1. In our experimental studies we use contemporary cell- and molecular techniques, as well as animal models and tissue samples from patients. Through our collection of clinical data and materials from some 60 MEN1 families, we can convert our basics studies to clinical practise, for example through prospective clinical trials.
Our second research area concerns adrenocortical carcinoma, an aggressive cancer with poor prognosis. In order to evaluate existing treatment options, we have initiated and, together with several collaborators, conducted a randomized clinical trial (FIRM-ACT). The study, involving more than 300 patients, has recently been completed, and the results will shortly be at hand.
Tumors of the endocrine pancreas and the adrenal
Neuroendocrine tumors of the pancreas are rare, and most have a more indolent behavior than exocrine pancreatic cancers. The tumors may produce bioactive amines or peptides that can give rise to characteristic endocrine symptoms/syndromes e.g. insulinoma syndrome with hypoglycemia, but the majority are silent and therefore described as non-functioning. Eighty-five percent occur sporadically but the rest develop in the context of an inherited trait; multiple endocrine neoplasia type 1 (MEN1) or von Hipple Lindau.
MEN1 is an autosomal dominantly inherited disease, and gene carriers develop multiple tumors in many endocrine organs but also some non-endocrine tissue. Our research group has long focused on MEN1 and explored pre-clinical and clinical aspects of the syndrome, especially with regard to the pancreatic and adrenal lesions and molecular effects of MEN1 gene inactivation.
Apart from our continuous work to evaluate and refine our management strategies for patients with MEN1 as well as applied treatment protocols for patients with advanced sporadic neuroendocrine tumors of the pancreas, we have during the last year focused on three lines of investigations;
MEN1 tumorogenesis and haploinsufficiency
Our hypothesis is that the MEN1 gene is a haploinsufficient suppressor resulting in growth advantage in endocrine cells of carriers of the MEN1 trait (heterozygous), but also alterations of the phenotype of the non-tumorous surrounding tissue. In a recent study supporting our hypothesis we used five-week-old conventional MEN1 knock-out mice to show that Ki67 proliferation index in heterozygous islets of Langerhans was indeed twice as high compared to that found in islets of wild type littermates. Furthermore, numerous genes were differentially expressed in these islets, e.g. up-regulated genes ontogenetically belonged to growth factor families, mitochondrial membrane transport, apoptosis inhibition and transcriptional regulation, and down-regulated genes involved cell structure and chromatin modification. In order to further understand the very onset of transformation, i.e. the effect of MEN1 heterozygosity per se, we have preceded by performing proteomics as well as microRNA array on heterozygous MEN1 mouse adrenals compared to that of wild type littermates. Interestingly, several proteins involved in lipid metabolism are obviously differentially regulated. We currently run cell line experiments to evaluate if inhibition of some of these proteins might compromise cell growth, and thus may be candidate targets for future drug development. Preliminary data in adrenocortical cancer cell lines are promising.
Angiogenesis and pre-clinical PET
In an earlier project, aiming to identify vascular and endothelial alterations in the MEN1 pancreatic endocrine tumors, we could show increased PDGF-BB and PDGF receptor beta in heterozygous islets and tumors as well as increased VEGFR2, FGFR, Ang2/Tie2 and HIF1-alpha. Interestingly, pericyte content was increased and distribution was altered already in young heterozygous islets, whereas in tumors glomerular-like structures of pericytes were noted. The increased blood flow observed even in small pancreatic mouse lesions, but also the macro-tumors of MEN1 patients, indicates that PET technique applying an angiogenesis-detecting tracer could be of value to visualize the tumors as well treatment response. We have therefore started to assess various potentially relevant PET tracers by performing autoradiography as well as micro-PET/CT of our MEN1 mouse model. Furthermore, micro-PET-MR is now available in house, and we are currently planning a project applying this new technique in our MEN1 mouse model.
The PI3K/Akt/mTOR pathway in MEN1 tissue
Inhibitors of the PI3K/Akt/mTOR pathway have entered the oncological arsenal of targeted therapies. Data on tumorigenesis and signal transduction in neuroendocrine tumor are however limited, so we aim at recognizing how menin interacts with the PI3K pathway and how mTOR and PI3K inhibitors function in the complete absence of menin as well as in MEN1 heterozygous cells. In these ongoing studies we use various drugs inhibiting this pathway as well as our MEN1 mouse model treated with these inhibitors. Preliminary data indicate that menin is essential for maximal effect of mTOR inhibition (rapamycin, everolimus) in neuroendocrine cell lines.
Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. The median survival for patients with metastatic disease is 25 weeks. We have performed an investigator-initiated initiated academic international phase III trial (the FIRM-ACT study) which has established a benchmark therapy; cisplatin, etoposide, doxorubicin in combination with mitotane (EDP+M) as first line therapy in advanced ACC. Currently several new studies are being launched within the efficient ACC-network already established during the years of fruitful FIRM-ACT cooperation:
- Participate in the second round of clinical studies of treatment of ACC, together with the FIRM-ACT investigator-network, in order to compare efficacy of new treatments to the results of the treatments studied in FIRM-ACT
- Participate in studies of adjuvant therapy, e.g. a randomized study of mitotane vs expectancy in patients radically operated for ACC with low or medium Ki67 index (Adiuvo I study). A second adjuvant study will soon start; Adiuvo II where adjuvant mitotane is randomized vs cisplatin in patients radically operated for tumors with high Ki67 index.
- Launch a phase II trial for treatment of advanced ACC.
Serous ovarian cancer
Malignant epithelial tumors make up for approx. 75% of ovarian cancers, and are the most lethal of the gynaecological malignancies. Overall 5 year survival is 40% Poorly-differentiated serous tumors have the worst prognosis, and are believed to arise from the surface of the ovary or in the tubar epithelium. Maximum tumor debulking surgery combined with platinum/taxanes is the mainstay of treatment today. Most poorly-differentiated serous cancers initially respond well to therapy, however, a majority will relapse within two years. When matched for stage, histopathological differentiation, and surgical outcome there is a high degree of uncertainty regarding what impacts survival, indicating that there are unknown factors involved.
Novel tumor markers, and novel pathways for drug-interaction may improve personalized treatment of these patients, and we aim therefore to
- Identify genetic aberrations in serous ovarian cancer using SNP-genotyping, as well as Exome-sequencing.
- Identify markers for long-term survival (>5 years)
- Identify potential therapeutic targets/pathways in serous ovarian cancer
We have collected samples from a group of patients treated for serous ovarian cancer as well as matched controls, and SNP-genotyping has been performed. After deep-sequencing we intend to verify the results in a larger cohort of patients. The results are In Pressin International J of Gynecological cancer