HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors

Abstract

The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic.

A Novel HSP90 Inhibitor–Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer

“…For this, we explored a dose range below the previously identified maximum tolerated dose (MTD) of 200 mg/kg (16) to establish efficacy in the context of a clear therapeutic window. For mice dosed with STA-8666 at 150 mg/kg, tumors regressed below detectability after 3 initial doses (Fig 1A).…”

“…No statistically significant change in HSP70 expression was observed, reflecting the biologically insignificant HSP90-inhibitory activity of STA8666 (8). Interestingly, analysis of the small number of tumors treated with lower doses of STA-8666 that developed resistance to this compound (data in Figs S1B,C) showed a similar profile of HSP70 and HSP90 expression to transiently treated tumors, except that 2 of 3 resistant tumors had barely detectable levels of pH2AX (Fig S4), potentially suggesting greater capacity to efflux the compound.…”

“…STA-8666 (8) is a recently described tripartite molecule designed to address the issue of targeted delivery of cytotoxic agents to the tumor by using heat shock protein 90 (HSP90) as a tumor targeting agent. As a result of stresses existing within tumors and the tumor microenvironment, HSP90 is both highly overexpressed and in an activated configuration in tumors relative to normal tissue (9, 10).…”

“…STA-8666 is comprised of an HSP90-targeting moiety fused via a cleavable carbamate linker to the cytotoxic compound SN-38 (the active metabolite of irinotecan (11)), which inhibits topoisomerase I to induce double and single strand DNA breaks. As with irinotecan, carboxylesterase (CES) activity in normal tissues (primarily liver) and tumors cleaves the linker region, releasing SN-38 over an extended period (8). Hence, STA-8666 has the potential for greater antitumor activity than other SN-38 delivery vehicles because of its ability to be concentrated in tumor tissue, where intratumoral cleavage provides high, selective SN-38 exposure.…”

“…The first study of STA-8666 reported exceptional biological activity of this compound against xenograft models of pancreatic and breast cancer, and demonstrated activity was dependent on the ability of this compound to interact with HSP90 (8). In this study, we therefore evaluated STA-8666 in SCLC xenografts, benchmarking against standard first and second line therapies, determining whether tumors resistant to such therapies were responsive to STA-8666, and performing parallel mechanistic analysis.…”