STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma

Abstract

Long-term survival in patients with metastatic, relapsed, or recurrent Ewing sarcoma and rhabdomyosarcoma is dismal. Irinotecan, a topoisomerase 1 inhibitor, has activity in these sarcomas, but due to poor bioavailability of its active metabolite (SN-38) has had limited clinical efficacy. In this study we have evaluated the efficacy and toxicity of STA-8666, a novel drug conjugate which uses an HSP90 inhibitor to facilitate intracellular, tumor-targeted delivery of the topoisomerase 1 inhibitor SN-38, thus preferentially delivering and concentrating SN-38 within tumor tissue. We present in vivo evidence from mouse xenograft models that STA-8666 results in more persistent inhibition of topoisomerase 1 and prolonged DNA damage compared to irinotecan. This translates into superior antitumor efficacy and survival in multiple aggressive models of both diseases in mouse xenografts, as well as in an irinotecan-resistant model of pediatric osteosarcoma, demonstrated by dramatic tumor shrinkage, durable remission and prolonged complete regressions following short-term treatment, compared to conventional irinotecan. Gene expression analysis performed on xenograft tumors treated with either irinotecan or STA-8666 showed that STA-8666 affected expression of DNA damage and repair genes more robustly than irinotecan. These results suggest that STA-8666 may be a promising new agent for patients with pediatric-type sarcoma.

Structure, Function, and Regulation of the Hsp90 Machinery

“…Additionally, the homing of amino-terminal inhibitors to cancer cells is exploited by inhibitors conjugated to cytotoxins. This promising concept has shown favorable effects in preclinical studies and is currently being tested in clinical trials (Heske et al 2016).…”

“…Combination approaches with Hsp90 and kinase inhibitors have been proven beneficial (Chiosis and Neckers 2006;Proia and Kaufmann 2015). Additionally, the aforementioned conjugation drugs that exploit the tumor selectivity of Hsp90 inhibitors to target a cytotoxin, represent a promising strategy to use Hsp90 inhibitors in therapy Heske et al 2016). Concluding, inhibitors that specifically target Hsp90:cochaperone complexes propose an exciting new field wherein we can interfere with the Hsp90 system while reducing unspecific side effects.…”

Targeting Burkitt lymphoma with a tumor cell–specific heptamethine carbocyanine‐cisplatin conjugate

“…Drug resistance is a major obstacle in cancer therapy . Monoclonal antibodies and small molecule tyrosine‐kinase or serine/threonine kinase inhibitors have not achieved improvements in survival in refractory tumors, although antibody–drug conjugates and small molecule ligand and drug conjugates using delivery strategies such as σ2‐opioid receptor, folate receptor, carbonic anhydrase IX inhibitor, PSMA, or HSP90 ligands and cytotoxic drugs have shown promise.…”

Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery

“…Hsp90, the famous heat shock protein, is the key factor for this chaperone machinery and allows cancer cells to adapt to severe stress [ 55 , 81 ]. In the past decade, tremendous efforts have been made to develop Hsp90 inhibitors as anticancer agents [ 2 , 82 , 83 ]. However, none of the directed Hsp90 inhibitors have achieved the goal and have been applied in clinical treatment [ 2 , 18 , 19 ].…”