Harnessing the metabolic adaptations of cancer cells for improved radiotherapy response

In unicellular organisms, there is an evolutionary pressure to reproduce as quickly as nutrients become available. In multicellular organisms, terminally differentiated cells use mostly respiration i.e. Krebs cycle, in order to maximize ATP production per glucose molecule. In cancer cells, metabolism is profoundly altered, whereby cells use glucose not for the production of energy, but to maximize the synthesis of biomass (e.g. production of nucleotides for DNA replication, lipids for membrane synthesis, etc.). Cancer cells have a constantly available pool of nutrients and their survival depends on the availability of precursors. Therefore, cancer cells devote much of their energy ensuring that precursors are available. Amongst the precursors, deoxyribonucleotides (dNTPs) are particularly important as they are essential for the synthesis of DNA and cancer cells must have high levels of dNTPs in order to sustain high rates of cell division.

Because imbalanced or high levels of dNTPs are highly mutagenic, stochastic genetic transitions within the cancer cell population are increased, favoring overall cancer cell survival. Furthermore, high levels of dNTPs benefit cancer cells by reducing the accuracy of DNA polymerases, generating a self-perpetuating circle of mutation acquisition. 
Additionally they may mediate resistance to antimetabolites such as 5FU, gemcitabine and methotrexate.

A central enzyme that controls the production of dNTPs in mammalian cells is the Ribonucleotide Reductase (RNR), which converts NTPs to their corresponding dNTPs. Different compounds targeting RNR are currently used in cancer therapy and further investigation in RNR and nucleotide metabolism might uncover novel routes to cancer therapy and improve the use of Ionizing Radiation therapy.

My studies have revealed a new pathway that balances dNTP production during cell cycle progression and after genotoxic stress (1, 2).

RNR is not the only enzyme that regulates dNTP homeostasis and we have identified novel regulators of dNTP pool homeostasis and an intricate allosteric control operated by the dNTPs themselves. We will investigate in detail the metabolic mechanisms that lead to unbalanced production of dNTPs in cancer and their relation with Ionizing radiation sensitivity. Recent evidence suggest NUDT1 and NUDT15 (enzymes involved in dNTP sanitation i.e degradation of damaged precursors) as novel and potent targets for cancer therapy. We will unravel the function and regulation of Nudt1 and Nudt15 nudix type hydrolases and their role in central nucleotide metabolism and cancer progression. Future development of this project could lead to specific targeted therapies to modulate metabolism of cancer cells and improve the efficacy of Radiotherapy in tumors with selected genetic aberrations.