DNA topoisomerases are validated targets for a broad range of widely used anticancer drugs. They include the topoisomerase II (TOP2) inhibitors, etoposide, teniposide, doxorubicin, daunorubicin and mitoxantrone, and the topoisomerase I (TOP1) inhibitors, topotecan and irinotecan. Both topotecan and irinotecan are derivatives of the plant alkaloid camptothecin. To overcome the limitations of these camptothecin derivatives (chemical instability, short half-life, resistance of cancer cells overexpressing multidrug-resistance efflux pumps and rapid reversibility of the TOP1 cleavage complexes), we have developed a different chemical series of TOP1 inhibitors, the indenoisoquinolines, which overcome the camptothecin limitations. Three indenoisoquinolines are in early clinical trials at the Center for Cancer Research of the US National Cancer Institute, LMP400 (indotecan), LMP776 (imidotecan) and LMP744. We will report on these new drugs, which are now transitioning to Phase 2 clinical trials. We also report on the determinants of response to the TOP1 inhibitors (“signature”), which include homologous recombination deficiency (HRD prominently represented by BRCA inactivation), overexpression of TOP1 and overexpression of a gene newly linked with response, SLFN11 (Schlafen 11), and could be used for patient selection and improving precision medicine. We will also report the burgeoning field of tumor-targeted delivery TOP1 inhibitors in clinical trials, which includes liposomal formulations (Onivyde), PEG conjugates (CRLX101; NKTR-102; PLX038, NK012), ADC (antibody drug conjugates: IMMU-132; IMMU-130; DS-8201a). These tumor-targeted TOP1 inhibitors aim to target tumors while sparing the bone marrow without having the dose-limiting toxicity of alternative payloads.
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In conclusion, TOP1 inhibitors are targeted therapies that are being improved by introducing novel chemical inhibitors, novel tumor-targeted delivery and predictive biomarkers (TOP1, SLFN11, HRD).