Discovery of mevalonate and UBIAD1 inhibitors as novel drugs targeting melanoma skin cancer

Melanoma is the most aggressive skin tumor, extremely difficult to treat and with high mortality rate.

Overcoming reduced sensitivity and acquired resistance to targeted therapy is a major goal of current melanoma research.

Therefore, there is an urgent need for development of novel drugs that can cure and prolong the survival of melanoma patients.

Molecular targeted therapy by using a drug that reduces the growth and spread of cancer cells via inhibition of specific protein or pathway is a milestone of precise medicine and treatment.

Recent observations demonstrate that BRAF and MEK inhibitors induce increased reactive oxygen species (ROS) in melanoma and as a consequence tumor cells activate adaptive antioxidant mechanisms to keep their cellular redox state below a deadly threshold. Thus, it has been proposed that removal of antioxidant could be exploited for therapeutic benefits.

In our ERC Consolidator grant RENDOX we have characterized the mevalonate metabolic pathway and discovered that this metabolic pathway as well as its enzyme, UBIAD1, have antioxidant properties and are critical caretakers of oxidative stress and ferroptosis in pathological conditions, such as melanoma progression.

The MELASTOP project is grounded on the validation and repositioning of pre-existing inhibitors, such as statins and parabens derivatives (UBIAD1i) as novel therapeutic drugs to treat melanoma resistance, which represents an extraordinary opportunity to improve the current limitation.

The current ERC PoC proposal aims at lead optimization, preclinical validation, IPR positioning, marker assessment and other commercial activities including go to market strategy and dialogue with potential collaborators of these mevalonate and UBIAD1 inhibitors.

We envision that this PoC represents a unique medical and commercial opportunity to treat and cure BRAF-resistant melanoma patients in urgent need of new treatment options.