Preclinical Modelling of Adenoid Cystic Carcinoma

Abstract

Adenoid cystic carcinoma (ACC) lacks accurate preclinical models. Those models that do exist often fail to recapitulate the biology of the disease, lacking expression of the key genetic aberration found in ACC, a MYB::NFIB translocation, or differ in histology to the tumour. This significantly hampers the understanding of the development of ACC and of drug development. The aim of this project was to generate and utilise preclinical models of ACC so as to develop novel therapeutic strategies. As well as this, I sought to understand the influence of the genetic aberrations and the different cell types found in ACC on tumour development. To achieve these aims, patient derived xenografts previously established in the lab were used to develop 2D and 3D organoid models of ACC. Following optimisation, these models were found to accurately recapitulate ACC as seen in patients. They were then used to carry out in vitro and in vivo drug assays, investigating a BRD4 targeting PROTAC as a therapy for ACC. These models were also used to investigate the role of cell type in the observed efficacy to this drug.

Secondly, normal salivary gland organoids were used to generate a genetic model of ACC using CRISPR. This model contained the most common aberration found in ACC patients, a MYB::NFIB translocation. The model facilitated understanding into the gene and protein expression changes that occur in ACC tumours in comparison to the normal salivary gland. Other common mutations found in ACC patients, such as NOTCH1 activating mutations and p53 loss-of-function mutations were also introduced to model metastatic or recurrent ACC. The generated organoid model was also used to understand the role of cell type in the oncogenicity of the translocation in ACC.