Developing new diagnostic and therapeutic approaches in adrenocortical carcinoma

Chortis, Vasileios (2017). Developing new diagnostic and therapeutic approaches in adrenocortical carcinoma. University of Birmingham. Ph.D.

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Abstract

Adrenocortical carcinoma (ACC) is an aggressive malignancy with high recurrence rates and poor response to chemotherapy. With this work, we have evaluated a potential new treatment target focusing on the mitochondrial NADPH generator Nicotinamide Nucleotide Transhydrogenase (NNT). NNT has a central role within the mitochondrial antioxidant pathways, which protect cells from oxidative stress. Our hypothesis was that NNT silencing will expose cells to cytotoxic levels of oxidative stress. We knocked down NNT transiently in NCJ-H295R ACC cells in vitro; this led to an increase in cellular oxidative stress and a strong cytotoxic and cytostatic effect. With stable NNT knockdown, we observed the emergence of a partially compensated phenotype over the course of time, with restored redox balance. Surprisingly, steroidogenesis was stimulated by transient NNT loss, challenging current perceptions about the impact of oxidative stress on steroidogenesis.

In our clinical study, we evaluated a new diagnostic tool for biochemical detection of ACC recurrence. Serial post-operative urine samples were collected from a large cohort of patients who had undergone complete ACC resection. Standardised review of longitudinal steroid measurements resulted in detection of disease recurrence prior to or concurrently with imaging with high sensitivity in cases where a pre-operative steroid profile had been provided.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):