Project B17

Mechanisms and prediction strategies for refractory corticotroph tumours

The primary cause of endogenous hypercortisolism is excessive adrenocorticotropic hormone (ACTH) production from corticotroph tumours (Cushing’s disease). Most of these tumours are benign microadenomas. However, aggressive and metastatic corticotroph tumours constitute almost one third of all aggressive pituitary tumours and pituitary carcinomas. These are particularly challenging tumour entities with adverse prognosis and increased mortality. At present, there are no approved histopathological and genetic markers to predict aggressive tumour behaviour, and effective therapies are few. In the previous funding periods, we established the role of somatic genetic drivers in clinically active corticotroph tumours and provided conclusive evidence that somatic TP53 variants associate with aggressive tumour behaviour and shorter survival in patients with corticotroph tumours. While this is promising, the specific mechanisms that confer aggressive features to the usually benign corticotroph neoplasms are elusive. The development of means to predict and target aggressive tumour behaviour and define populations that might benefit from certain treatment modalities remain an unmet need of highest importance in Cushing’s disease.

In the final funding period, we aim to address these problems with the following objectives:

(I) firmly establish and validate surrogate markers of prognosis and therapy response in patients with Cushing’s disease

(II) elucidate the genetic basis of familial Cushing’s disease

(III) establish and standardise functional drug testing for the management of patients with refractory corticotroph tumours.

Our overarching aim during the last funding period is to translate our findings into tools that will allow clinicians to monitor disease progression and achieve the personalised management of this difficult to manage disease.

© SFB/TRR205