Oncotarget

Research Papers:

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

Christine M. Heske _, Arnulfo Mendoza, Leah D. Edessa, Joshua T. Baumgart, Sunmin Lee, Jane Trepel, David A. Proia, Len Neckers and Lee J. Helman

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Oncotarget. 2016; 7:65540-65552. https://doi.org/10.18632/oncotarget.11869

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Abstract

Christine M. Heske1, Arnulfo Mendoza1, Leah D. Edessa1, Joshua T. Baumgart1, Sunmin Lee2, Jane Trepel2, David A. Proia3, Len Neckers4, Lee J. Helman1

1Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

3Synta Pharmaceuticals, Lexington, MA, USA

4Urologic 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.


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