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Melanoma brain metastases (MBMs) are a serious issue affecting up to half of all patients with stage IV melanoma, typically leading to a poor outlook. While immune therapy using anti-PD-1 can help, it only works for about 20% of MBM patients, which is much lower than the response seen in other melanoma patients who don’t have cancer affecting the brain. A combination of anti-PD-1 and anti-CTLA-4 therapies has shown some promise, with about half of patients responding well, though it does come with higher side effects. This combination treatment also loses its effectiveness for those with more severe MBMs. The unique environment in the brain for these tumors demands focused research. Recent studies have shown that the nervous system and immune system influence each other in complex ways. The peripheral nervous system impacts blood cell production, while the central nervous system manages inflammation and immune memory in other organs. Damage to nerves draws in macrophages, a type of immune cell, to help with healing. These cells play a role in cancer growth and in resistance to anti-PD-1 therapy. Studies have shown that these tumors can cause nerve damage which makes them resistant to common treatments. Patients whose tumors have spread into surrounding nerve tissues often do not respond well to therapy. Research has also shown that such nerve damage can trigger a series of immune responses that end up tiring out the cells meant to fight the tumor. Some experimental treatments in mice, like specifically turning off certain genes in nerves within the tumors, have shown that managing this nerve damage could potentially enhance the effectiveness of immune therapies. These discoveries are guiding new clinical trials that aim to improve treatment for brain tumor patients by specifically targeting the interactions between nerves and the immune system in tumors.

The project is particularly interested in the mechanisms involved in the regulation and control of energy metabolism, mainly at the mitochondrial level, as well as its relationship with neurodegenerative processes. The role of oxidative stress and mitochondrial dysfunction are currently being investigated in neurodegenerative conditions, such as inborn errors of intermediary metabolism, Parkinson's disease, diabetic neuropathy and intoxication with environmental contaminants. Through the development of this proposal, we intend to shed light on the role of the metabolism of the obligate cofactor tetrahydrobiopterin (BH4) for the enzymatic synthesis of tyrosine, biogenic amines, serotonin and dopamine, as well as nitric oxide. On the other hand, we intend to characterize the possible role of BH4 as a signaling molecule for synaptic dopamine release vs. its potential neuroprotective effect. The study of the modulation of this metabolism in various neurotoxic conditions will open doors to characterize those affected by inborn errors of metabolism associated with brain deficiencies of BH4, which is a subject not explored in South America, and unprecedented worldwide in the characteristics proposed here. CNPq: Support for Research Projects / MCT/CNPq Call for Proposals No. 06/2008 Young Researchers. Process: 572135/2008-4 (Funding R$ 226,800.00).