Neuroendocrine (NE) tumours (carcinoids, pheochromocytoma, medullary thyroid carcinoma (MTC)) usually present with hormonal symptoms due to distant metastases. There is need for a better understanding of pathogenetic mechanisms and prognostic factors in NE tumours as well as novel treatment options. Somatostatin receptors (SSTR) are highly expressed, which allows scintigraphic imaging via radiolabelled somatostatin analogs. SSTR-mediated radiotherapy is one novel treatment option for NE tumours.
1. Profiling NE tumours by CGH, mRNA and siRNA arrays as well as by exome sequencing, to identify genetic changes and activated signaling pathways that can serve as targets for therapy.
2. Charactising CSC in carcinoid tumours by fluorescent-activated cell sorting (FACS) with respect to cell populations capable of self-renewal and tumour initiation.
3. Pyridylcyanoguanidines as inhibitors of NFkB/Rel transcription factors and NADsynthesis via the PARP enzymes. This effect is additive to radiation-induced DNA damage and suggests pyridylcyanoguanidines as radiosensitizers to SSTR-mediated radiotherapy.
4. Valproic acid - activator of Notch-1 and inhibitor of HDAC. An anti-epileptic drug with established safety profile induces apoptosis and retards the growth of tumour xenografts - may soon go into international phase II trials.
5. Enhancing the NET transporter to increase the efficacy of 131-I-MIBG-therapy by pretreatment with cisplatin or topoisomerase inhibitors.
6. Clinical projects on carcinoid heart disease, new prognosticators for midgut carcinoids (including transplantation as treatment), phenotypic expression associated with RET mutations in hereditary MTC and treatment with TKI, response of hereditary and sporadic pheochromocytomas to sunitinib and VEGF antagonists (in collaboration with Frida Abel, Genomics)
Our group has established the first human midgut carcinoid cell line (GOT 1) with maintained serotonin secretion and expression of SSTR 2&5. We have also established a human MTC cell line (GOT 2) carrying RET mutation. Both cell lines are studied as xenografts in nude mice.
Ola Nilsson, MD, PhD, professor Bo Wängberg, MD, PhD, docent
Svante Jansson, MD, PhD, docent Bengt Nilsson, MD, PhD, docent
Viktor Johanson, MD, PhD Per Bümming, MD, PhD
Christina Swärd, MD, PhD Andreas Muth, MD, PhD
Yvonne Arvidsson, PhD Anna-Karin Elf, MD, PhD student
Jacob Dahlberg, MD, PhD student Anders Bergström, MD, PhD student
Ellinor Andersson, PhD student Linda Inge, technician
Gülay Altiparmak, technician Paulin Brattberg, technician
Malin Berntsson, technician
I. Kölby L, Ahlman H, Wängberg B et al. A transplantable human carcinoid as model for somatostatin receptor- and amine transporter-mediated radionuclide uptake (2001) Am J Pathol 158:745-755
II. Johanson V, Arvidsson Y, Kölby L et al. Antitumoural effects of the pyridyl cyanoguanidine CHS 828 on three different types of neuroendocrine tumours xenografted to nude mice (2005) Neuroendocrinology 82:171-177
III. Johanson V, Ahlman H, Bernhardt P et al. A transplantable human medullary thyroid carcinoma as a model for tyrosine-driven tumorigenesis (2007) Endocr Relat Cancer 14:433-444
IV. Andersson E, Swärd C, Stenman G et al. High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids. Endocr Relat Cancer 16:953-966, 2009
V. Nilsson O, Arvidsson Y, Johanson V et al. New medical strategies for midgut carcinoids (2010) Anti-Cancer Agents in Med Chem (ACA-MC) 10:250-269
We are part of Sahlgrenska Translational Neuroendocrine Cancer Group (SATNEC). For more information of SATNEC, please visit: www.radfys.gu.se/satnec.