Table 2.

Challenges for the discovery and use of topoisomerase inhibitors

Challenges	Possible answers (new approaches)
1. New topoisomerase targets	Type IA (TopA and Top3) inhibitors Top2β-specific inhibitors
2. New topoisomerase inhibitors (in addition to #1 above)	Chemically stable camptothecins Non-camptothecin Top1 inhibitors Top1 catalytic inhibitors New Top2 inhibitors with novel structures Orally bioavailable inhibitors Targeted delivery (nanoparticles for time-staggered and tumor-specific delivery)
3. Pharmacodynamic (PD) biomarkers to rapidly evaluate tumor drug response	Top1 and Top2 cleavage complexes induction Top1 and Top2 down-regulation DNA damage (γ-H2AX) Apoptotic response (caspase activation) Additional PD biomarkers based on further elucidation of the molecular DNA repair pathways and DNA damage responses (DDR) downstream from topoisomerase poisoning in model systems
4. Cancer patient selection	Identification and implementation of predictive biomarkers and “drug response signatures” (based on OMIC tools: tumor gene expression and somatic mutations, proteomic and metabolomic) for patient stratification New predictive biomarkers based on molecular biology and pharmacology studies in model systems High tumor Top1 and Top2 levels Pharmacogenomics tests (germline mutations affecting drug pharmacokinetics and metabolism)
5. Optimize drug combinations	Based on the further elucidation of the molecular DNA repair pathways and DNA damage responses (DDR) downstream from topoisomerase poisoning in model systems Based on synthetic lethality related to tumor-specific defects (ERCC1-deficiency for combining Top1 and PARP inhibitors) Based on system pharmacology in model systems to reveal the pathways (molecular networks) and novel genetic and molecular determinants that drive tumor response Based on experimental data obtained in model systems Based on non-overlapping drug toxicities and side effects (current approach) Based on clinical trials (current empirical approach)