Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

Abstract

<b><i>Background:</i></b> Topoisomerase I is an enzyme that plays a crucial part in DNA replication and transcription by the relaxation of supercoiled double-stranded DNA. Topoisomerase I inhibitors bind to the topoisomerase I cleavage complex, thereby stabilizing it and preventing the religation of the DNA strands, leading to DNA damage, cell cycle arrest, and apoptosis. Various topoisomerase I inhibitors have been evaluated in solid tumors, and irinotecan and topotecan have been approved for the treatment of epithelial malignancies. None of them have been approved for sarcoma, a diverse group of rare solid tumors with an unmet need for effective treatments. <b><i>Summary:</i></b> Topoisomerase I inhibitors have been evaluated in preclinical studies as single agents or in combination in solid tumors, some of which have included sarcomas where activity was observed. Clinical trials evaluating topoisomerase I inhibitors for the treatment of sarcoma have shown limited efficacy as monotherapy. In combination with other cytotoxic agents, topoisomerase I inhibitors have become part of clinical routine in selected sarcoma subtypes. Regimens such as irinotecan/vincristine/temozolomide are used in relapsed rhabdomyosarcoma, irinotecan/temozolomide and vincristine/topotecan/cyclophosphamide are commonly given in refractory Ewing sarcoma, and topotecan/carboplatin showed some activity in advanced soft tissue sarcoma. This review provides an overview of key studies with topoisomerase I inhibitors for the treatment of sarcoma. Topoisomerase I inhibitors are currently also being assessed as “payloads” for antibody-drug conjugates (ADCs), allowing for the targeting of specific antigen-expressing tumor cells and the delivery of the inhibitor directly to the tumor cells with the potential of enhancing therapeutic efficacy while minimizing systemic toxicity. Here, we also provide a brief overview on topoisomerase I-ADCs. <b><i>Key Message:</i></b> Topoisomerase I inhibitors are an important component of some systemic therapies for selected sarcomas and have potent cytotoxic properties and pharmacological characteristics that make them relevant candidates as payloads for the development of sarcoma-specific ADCs. ADCs are antibody-based targeted agents allowing for efficient and specific delivery of a given drug to the tumor cell. Topoisomerase I-ADCs are a novel targeted delivery approach which may have the potential to improve the therapeutic index of topoisomerase I inhibitors in the treatment of sarcoma and warrants investigation in a broad variety of mesenchymal malignancies.

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“…Additionally, constrained rotation during transcription and replication causes overwinding upstream and underwinding downstream of forks, generating positive and negative supercoils. Nucleosome formation further induces positive supercoiling . Thus, topoisomerases are required to relieve such tightening, especially in cancer cells where frequent replication and transcription heighten DNA supercoiling.…”

“…To maintain DNA integrity despite increased supercoiling, cancer cells may upregulate topoisomerases and become more dependent on efficient unwinding, making them more susceptible to topoisomerase inhibitors. Consequently, topoisomerases naturally emerge as suitable anti-cancer targets …”

“…Type IA generate 5′-DNA tyrosyl adducts and relax supercoils via strand-passing. Type IB, including TOP1 and TOP1mt, produce 3′-phosphotyrosyl linkages in eukaryotes and relax DNA by controlled rotation. , TOP1 and TOP1mt were once considered the sole CPT targets, however, some evidence suggests certain CPT analogues may have additional targets, − necessitating further research to elucidate the definitive profile.…”

“…Normally TOP1ccs reverse rapidly after re-ligation, remaining undetected. However, crystal structures reveal TOP1 tightly encircles DNA, explaining its control of supercoiled DNA relaxation. , After loosening DNA, TOP1 reseals breaks by reversing its tyrosine-DNA phosphodiester bond. Perfect 5′-hydroxyl alignment at the DNA end is required for ligation.…”

“…Nucleosome formation further induces positive supercoiling. 16 Thus, topoisomerases are required to relieve such tightening, especially in cancer cells where frequent replication and transcription heighten DNA supercoiling. To maintain DNA integrity despite increased supercoiling, cancer cells may upregulate topoisomerases and become more dependent on efficient unwinding, making them more susceptible to topoisomerase inhibitors.…”