The efficacy of telomerase inhibition–based therapies, such as imetelstat, depends on the tumor telomere length at the beginning of treatment. The efficacy of telomerase inhibition–based therapies, such as imetelstat, depends on the tumor telomere length at the beginning of treatment. The tumors with longer telomeres require a longer treatment period (longer lag period) to have therapeutic effects compared to tumors with shorter telomeres (left). Tumor telomeres (with shorter or longer) start gradually shortening with telomerase inhibition targeted agents. This leads to delay of effect (e.g., tumor shrinkage) and potentially generates adverse effects (such as increased toxicities) due to the long treatment period. However, adding a telomerase-mediated telomere uncapping agent such as 6-thio-dG results in a much quicker effect that reduces the lag period irrespective of tumor initial telomere length (right). The gold line would represent an ideal chemotherapeutic agent demonstrating an immediate reduction in tumor volume. Ilgen Mender et al. Cancer Discovery 2015;5:82-95 ©2015 by American Association for Cancer Research