Developing small molecule inhibitors to target treatment refractory melanoma.

Background

Cutaneous melanoma is a neoplasm of melanocytes, the pigment producing cells in the skin, and is the most aggressive and lethal form of skin cancer. The incidence of melanoma has increased dramatically over the past three decades, including in Australia where it is now the fourth most commonly diagnosed cancer. It is estimated that over 16,800 Australians will be diagnosed with melanoma in 2024 and over 1,300 people will die. Metastatic dissemination of melanoma is a serious complication for the successful treatment of the disease, and represents the most common cause of death for melanoma patients.

We have identified a transcriptional program in melanoma tumour cells that triggers dissemination of melanoma cells and allows survival. The program simulates chronic interferon-γ exposure, and also results in extracellular matrix alterations. These changes have been observed in melanoma patients that are resistant to standard of care therapy. We have now linked the driver of this signature, the transcription factor BRN2, with worse patient outcome following this therapy. It is possible to directly target BRN2 binding to DNA using small molecule inhibitors. Targeting BRN2 directly increases specificity, as it is not widely expressed in normal adult tissue.

Aims

This project aims to develop novel small molecule inhibitors of BRN2 for single agent or combination therapy of patients with therapy refractory melanoma. Generation of novel BRN2 targeting agents could benefit additional cancer types where the transcription factor is highly expressed including glioblastoma and neuroendocrine prostate cancer.

Scholarship Details Page: https://www.qimrberghofer.edu.au/education/for-university-students/international-phd-scholarship/