Project description
Novel drugs to overcome resistance to targeted therapy in melanoma treatment
Targeted therapies use drugs that reduce the growth and spread of cancer cells via the inhibition of specific proteins or pathways. Recent studies have shown that melanoma targeted therapies based on BRAF and MEK inhibitors increase reactive oxygen species in melanoma, resulting in activation of antioxidant mechanisms that keep tumour cellular redox state below a deadly threshold. The removal of antioxidants could be exploited for therapeutic benefits. Previously, the research team of the EU-funded MELASTOP project discovered that the mevalonate metabolic pathways have antioxidant properties and are critical regulators of oxidative stress in pathological conditions, including melanoma progression. Now, the project aims to validate the repositioning of the existing mevalonate pathway inhibitors as novel therapeutic drugs to treat melanoma resistance.
Objective
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.
Fields of science
Not validated
Not validated
Keywords
Programme(s)
Funding Scheme
ERC-POC - Proof of Concept GrantHost institution
35122 Padova
Italy