The aim of this project is to test the therapeutic synergy between the intratumoral immunotherapy MBTA developed by the research group of Prof. Karel Pacák, MD (based on the combination of mannan-BAM, TLR ligands, and anti-CD40 antibody) and the effect of polymethinium salts (PMS) studied by the research group of prof. Masařík. Our previous study demonstrated the migrastatic activity of PMS (the term 'migrastatic' is used for interventions interfering with cancer cell migration or invasion). Recent studies have shown that the migration machinery can promote metastatic spread. Therefore, successful migrastatic therapy given alongside standard therapy may reduce the risk of metastasis. Due to their structure and ability to bind to cardiolipin, PMS can act on the mitochondrial inner membrane (MIM). It has been shown that cancer cells differ in the content and distribution of cardiolipin in the MIM. Therefore, cancer cells may be more susceptible to PMS binding than physiologically normal cells. Many mitochondrial enzyme activities, particularly those related to oxidative phosphorylation (OXPHOS), can be affected by PMS binding to MIM. PMS were originally developed as mitochondrial probes and have interesting properties such as fluorescence, high selectivity for mitochondria, rapid import into cells, and high photostability. This could make PMS useful in phototherapy, as light enhances their cytotoxic effect on tumor cells. PMS are also potent inhibitors of dihydroorotate dehydrogenase (DHODH). DHODH-driven pyrimidine biosynthesis is a critical pathway linking OXPHOS to tumor cell proliferation and their ability to successfully invade and form metastatic foci. Thus, the combination of MBTA and PMS could simultaneously target several essential hallmarks of cancer cells (proliferation, metabolism, invasion and metastasis, evasion of immune surveillance). Within the tumor microenvironment (TME), a metabolic symbiosis between oxidative and glycolytic cells is very common. The metabolic symbiosis is based on the heterogeneity of the cells in the TME, and by inhibiting OXPHOS with PMS, this metabolic heterogeneity can be reduced. At the same time, MBTA may facilitate the recognition of cancer cells by the immune system. The project will make use of the mouse models developed to test MBTA and the full infrastructure of both participating laboratories.

Cíle udržitelného rozvoje

Masarykova univerzita se hlásí k cílům udržitelného rozvoje OSN, jejichž záměrem je do roku 2030 zlepšit podmínky a kvalitu života na naší planetě.