STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma.
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.
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Christine M
CM
Heske
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Arnulfo
A
Mendoza
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Leah D
LD
Edessa
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Joshua T
JT
Baumgart
Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Sunmin
S
Lee
Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jane
J
Trepel
Synta Pharmaceuticals, Lexington, MA, USA.
David A
DA
Proia
Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Len
L
Neckers
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Lee J
LJ
Helman
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002648:Child; D004249:DNA Damage; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D012118:Resorcinols / Q000737:chemistry / Q000627:therapeutic use*; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D012118:Resorcinols; C000610389:STA-12-8666; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin
SN-38; drug conjugate; pediatric; sarcoma; topoisomerase 1 inhibitor