STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma
| Autor: | Arnulfo Mendoza, Christine M. Heske, Joshua T. Baumgart, Len Neckers, David A. Proia, Leah D. Edessa, Jane B. Trepel, Sunmin Lee, Lee J. Helman |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Pathology sarcoma Drug Evaluation Preclinical Mice SCID Hsp90 inhibitor chemistry.chemical_compound Mice 0302 clinical medicine Rhabdomyosarcoma Recurrent Ewing Sarcoma drug conjugate Child Mice Knockout biology Tumor Burden 030220 oncology & carcinogenesis Female Sarcoma medicine.drug Research Paper medicine.medical_specialty SN-38 Antineoplastic Agents Sarcoma Ewing Irinotecan 03 medical and health sciences topoisomerase 1 inhibitor Internal medicine Cell Line Tumor medicine Animals Humans HSP90 Heat-Shock Proteins neoplasms business.industry Topoisomerase Cancer Resorcinols medicine.disease Xenograft Model Antitumor Assays Disease Models Animal 030104 developmental biology pediatric chemistry biology.protein Camptothecin Topoisomerase I Inhibitors business DNA Damage |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Christine M. Heske 1 , Arnulfo Mendoza 1 , Leah D. Edessa 1 , Joshua T. Baumgart 1 , Sunmin Lee 2 , Jane Trepel 2 , David A. Proia 3 , Len Neckers 4 , Lee J. Helman 1 1 Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 3 Synta Pharmaceuticals, Lexington, MA, USA 4 Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Correspondence to: Christine M. Heske, email: christine.heske@nih.gov Keywords: sarcoma, SN-38, drug conjugate, topoisomerase 1 inhibitor, pediatric Received: July 22, 2016 Accepted: August 30, 2016 Published: September 06, 2016 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. |
| Databáze: | OpenAIRE |
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