Identification and preclinical evaluation of novel therapeutic targets in phaeochromocytoma

Principal Investigators

Scientific Staff

Sebastian Gulde – PhD
Daniela De Martino – Postdoc
Hermine Mohr – Postdoc
Tobias Wiedemann – Postdoc

Project Description

Project B11 aims at identifying novel potential therapeutic targets for phaeochromocytomas and paragangliomas (PPGLs). The group exploits an endogenous rat model of PPGLs (i.e. MENX rats) that recapitulates the human tumors. The observation that p27-defective mice and rats develop PPGLs, and that loss of p27 occurs in human PPGLs supports a role for this protein in PPGL tumorigenesis. The project hypothesizes that oncogenic effects associated with lack of functional p27 in adrenal cells are due to dysregulated gene expression. Thus, the group wants to identify p27 target genes and validate their function in PPGLs. In addition, novel downstream targets of PI3K signaling are validated and the therapeutic potential of drugs inhibiting the PI3K pathway is assessed in MENX rats.

Aims

(I) Determine the role of p27 in phaeochromocytomas and paragangliomas (PPGL) tumourigenesis. We want to identify p27-regulated genes in adrenomedullary cells, perform functional studies and generate transgenic mice.

(II) Evaluate a novel PI3K inhibitor (BKM120) and cyclin-dependent kinase (CDK) inhibitors for their efficacy against PPGLs in vitro and in vivo; identify CDK inhibition-associated molecular mechanisms.

(III) Validate the biological relevance of downstream effectors of the PI3K pathway in PPGLs.

PhD/MD-Thesis

PhD student: Sebastian Gulde
Starting date: 01.07.2017
Title of the thesis: The molecular landscape of neuroendocrine tumors

Publications

Multiple Endocrine neoplasia-type  4 MEN (MEN4) and other MEN1-like syndromes, Book Chapter, Pellegata NS, Journal: Endocrinology. Polyendocrine Disorders and Endocrine Neoplastic Syndromes. Springer Nature, 2018