Cutaneous melanoma is the most lethal skin cancer and the fifth most common cancer in Switzerland. In the last decade, immunotherapy and targeted therapy combinations have improved the survival of metastasized melanoma. However, the disease remains highly lethal. With immunotherapy more than 60% of patients still experience a progression of the disease within five years. For patients with NRAS-mutated melanoma (~28% of the cases), the most aggressive subtype, there is currently no effective treatment alternative available.
Andreas and his team aim to develop the first effective targeted therapy against NRAS-mutated melanoma. Studying patient-derived melanoma cells at the University Hospital Zurich, they found that when the NRAS-mutated melanoma cells develop resistance, they change their metabolism in response to targeted therapy. This metabolic cell state of the drug-resistant cells is distinct from healthy cells and could therefore be harnessed for the development of novel drugs. The team has identified a group of molecules which effectively target this distinct phenotype and kill the NRAS-mutated, drug-resistant cancer cells. The combination of targeted therapy with the new molecule proved to be a strongly effective solution in vitro and in vivo. It appears that melanoma cells cannot easily adapt to both drugs given simultaneously.
In his Entrepreneur Fellowship, Andreas intends to improve and optimize the discovered molecules into a drug for metastatic melanoma, and perhaps even other cancers. He will use the 18 months for an in vitro hit to lead phase development. By screening through chemical analogues and synthesizing and optimizing chemical leads, Andreas and his team aim to drive their solution towards the pre-clinical stage of a drug development project.
Affiliation: Prof. Mitchell Levesque
Start date: 10/2021