Lung cancer is the most common cancer worldwide, with an estimated 1.8 million cases diagnosed each year and an estimated 1.6 million lung cancer related deaths annually.
Many of the first- and second-line drug therapies are based on cytotoxic agents such as platinum-based drugs and DNA topoisomerase I and II inhibitors. In recent times, there have been several advances in non-small cell lung cancer (NSCLC) management, thanks to the introduction of tyrosine kinase inhibitors and immunotherapy, with encouraging results. Anyway, overall survival rates for lung cancer remain low, particularly in metastatic disease. That is why the development of new therapeutic agents is still essential.
Recently, tyrosyl-DNA phosphodiesterase 1 and tyrosyl-DNA phosphodiesterase 2 (TDP1 and TDP2) have been recognized as pharmaceutical targets for lung cancer therapy, in combination with DNA Topoisomerase 1 (Top1) and DNA Topoisomerase 2 (Top2) inhibitors.
Within this project, I will discuss the rationale for the development of TDP 1 and TDP 2 inhibitors, as parts of a potential combination therapy with Top1 and Top2 inhibitors. Indeed, TDP1 and TDP2 inhibitors, in association with Top1 and Top2 poisons, could successfully boost the efficacy of topoisomerase-based anticancer treatments.
The whole project was born from the decennial team-work cooperation between the laboratory of Prof. Roberto Di Santo (Dep. Chemistry and Drug Technology ¿Sapienza¿, University of Rome) and the Laboratory of Prof. Pommier (Lab. of Molecular Pharmacology, National Cancer Institute, NHI, Bethesda USA) that will guarantee the good ending of the project. Indeed, this collaboration has led to the individuation of a promising hit compound from the in-house library of Prof. Di Santo, RDS 3037, characterized by an interesting inhibitory activity against TDP1 and TDP2. Thus, the main aim of the project is to optimize the identified hit for the individuation of possible drug candidates.
Currently, many types of cancer are treated with combinations of two or more different drugs. Indeed, it is well known that these multidrug therapies are less affected by the development of drug resistance.
With this in mind, we aim to refine the treatment of lung cancer with topoisomerase inhibitors, mining the DNA repair mechanisms responsible for the resistance to these first-line therapies. The rationale for targeting TDP1 and TDP2, in combination with Top1 and Top2 inhibitors, is linked to the hypersensitivity of TDP1-and TDP2-deficient cells to topoisomerase poisons.
In addition to TDP1 and TDP2, other pathways are involved in the DNA damage induced by Top inhibitors. Nevertheless, it is well known that tumor cells are commonly deficient in parallel DNA repair pathways. So, on this principle, TDP- and topoisomerase-targeted combination therapies should improve potency and selectivity towards cancer cells, taking advantage of their repair checkpoint deficiencies, providing new efficient strategies for lung cancer patients.
Moreover, since TDP1 and TDP2 are involved in many DNA repair processes, TDP-inhibitors could be associated not only with Top1 and Top2 inhibitors, but also with other cytotoxic agents such as taxanes and alkylating agents, currently used in the first- or second-line therapy of lung cancer.
In this scenario, TDP could represent an interesting and innovative target in order to enhance the anti-cancer armamentarium. However, the discovery of anti-TDP agents has been challenging since the very beginning, because many known inhibitors either lack selectivity or cellular efficiency that are deemed essential for drug development. Indeed, a relatively large number of TDP1 inhibitors have been reported from biochemical screen, but none of them has shown cellular activity. Furthermore, many TDP-2 selective inhibitors displayed unsatisfactory pharmacokinetic profiles. Consequently, the need for drug-like molecules instead of tool molecules represent a golden opportunity to do research in this field.