Title: Understanding the role Cdc42 signalling in non-functioning pituitary tumours
Funder: The Academy of Medical Sciences

Abstract: Non-functioning pituitary tumours (NFPTs) usually present as macroadenomas and show invasion of adjacent structures, leading to visual disturbance, blindness, pituitary apoplexy and hypopituitarism, with consequent lifelong treatment and a significantly reduced quality of life. While other pituitary tumour types have medical treatments available, NFPT treatment relies on surgery, followed by radiotherapy if tumour re-growth is noted, with the possibility of severe cerebrovascular and secondary tumour complications. The overall aim of this project is to identify novel biomarkers leading to future medical treatments for NFPTs. The foundation of this proposal is based on preliminary data which identified upregulated Cdc42 in aggressive NFPTs and Aip-silenced GH3 cells. The Cdc42 pathway plays a pivotal role in regulating cell proliferation, polarity, survival and invasion, and its dysregulation due to either over-expression or constitutive activation, occurs in different types of human cancers. The relevance of the Cdc42 pathway in pituitary tumours has not been previously investigated, and no data are available targeting it as a therapeutic option. Therefore, our specific aims are building on our preliminary data: (i) to validate the deregulation of Cdc42 pathway members in NFPTs and investigate if their alteration can predict tumour behaviour to improve and personalise clinical management, (ii) to identify inhibitors of the Cdc42 pathway to confirm their effectiveness in both cell lines and primary human pituitary cultures. Profs Korbonits and Dutta have a well-established collaboration over the last 6-years. The India laboratory has more than 200 NFPT samples with related clinical data, allowing the project to start immediately, while the UK laboratory is equipped with cutting-edge technologies for gene and protein expression studies. In the first 2-years in the UK, the candidate will learn novel techniques, validate Cdc42 pathway deregulation, optimise inhibitor treatments, engage with other projects and improve transferable skills such as presentation, manuscript writing, undergraduate supervision/teaching. He will be enrolled on various scientific and personal development courses. The UK host department will benefit from the applicant experience in sample preparation and proteomics. In the final year, the candidate will establish novel techniques in Chandigarh, and validate findings on an independent sample cohort, while preparing his data for international presentation and publication, and establishing the local translational endocrine tumour group. In summary, this is a mutually beneficial fellowship with a project concentrating on an exciting novel pathway in pituitary tumourigenesis, and with the potential to develop translational aspects addressing the unmet need for novel NFPT medical treatments.

Lay abstract: The pituitary gland is a small organ at the base of the brain secreting key hormones (chemical messengers in the blood). It develops tumours relatively commonly, in 1 out of 1000 people in the population. While these tumours usually are not highly aggressive, they can cause blindness and can lead to reduced fertility and severely interfere with everyday life. Patients often need neurosurgery and radiotherapy, with significant risk of complications, as well as lifelong hormone treatment. There are several types of pituitary tumours, mainly based on the hormones that they secrete. One particular subtype, which does not secrete excess of hormones, is called non-functioning pituitary tumour (NFPT) and causes symptoms due to tumour mass, compressing optic nerves or normal pituitary tissue. NFPTs have no established medical treatment, and patients’ rely only on surgery. This project aims to establish novel biomarkers and investigate new possible medical treatments for NFPTs. We will employ modern molecular techniques to explore the pathway of Cdc42, a key signalling molecule in the cell. Based on our preliminary data, we have identified deregulation of this pathway showing increased expression in more aggressive NFPTs compared to less aggressive and normal tissues. We aim to confirm and build on these findings and assess the efficacy of already available drugs in inhibiting this pathway in human pituitary tissue removed at surgery. These finding will provide the opportunity to develop drug treatment for these tumours.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS