Treating melanoma as an infectious disease

With 5-year survival rates being around 30% for patients with distant metastatic disease, cutaneous melanoma is the leading cause of skin cancer related deaths. Standard of care for the treatment of cutaneous melanoma envisages either a combination of BRAF and MEK inhibitors or immunotherapy. Both strategies lead to impressive antitumor responses but unfortunately not all the patients respond to the therapy and resistance can arise early and late during the treatment course. It is therefore crucial to search for novel therapeutic strategies that either increase the response rate or delay acquisition of resistance to these treatments.
Convincing evidence indicates that melanomas that are exposed to BRAF/MEK inhibitors exhibit elevated oxidative phosphorylation and thereby, increased dependency on mitochondria metabolism. In keeping with this, we recently demonstrated that interfering with mitochondrial translation by reducing the expression of a specific long non-coding RNA, severely impairs melanoma cell growth in vitro. Moreover, when combined to BRAF inhibition this treatment induces tumour regression in vivo in preclinical models. 
Originating from a bacterial ancestor, mitochondrial ribosomes (or mitoribosomes) are closely related to bacterial ones. Therefore, antibiotics that target bacterial ribosomes, such as tetracyclines, also inhibit mitoribosomes and promote mitochondrial dysfunctions. We therefore hypothesize/propose that mitochondria targeting antibiotics, when used in combination with MAP kinase inhibitors, may offer important clinical benefit. With this application, we propose to test this possibility and in particular assess whether this treatment regimen is capable of preventing and/or delaying the occurrence of drug resistance in a preclinical setting, using Patient-Derived Xenograft (PDX) as models.