Dataset Information

Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors.

ABSTRACT:

Purpose

STA-1474, prodrug of the heat shock protein 90 inhibitor (HSP90i) ganetespib, previously demonstrated activity in canine preclinical models of cancer; interestingly, prolonged infusions were associated with improved biologic activity. The purpose of this study was to identify the ideal treatment schedule for HSP90i in preclinical models of KIT-driven malignancies and in dogs with spontaneous mast cell tumors (MCT), where KIT is a known driver.

Experimental design

In vitro and murine xenograft experiments and clinical studies in dogs with MCTs were used to define the effects of HSP90i-dosing regimen on client protein downregulation and antitumor activity.

Results

Continuous HSP90 inhibition led to durable destabilization of client proteins in vitro; however, transient exposure required >10× drug for comparable effects. In vivo, KIT was rapidly degraded following a single dose of HSP90i but returned to baseline levels within a day. HSP90 levels increased and stabilized 16 hours after HSP90i and were not elevated following a subsequent near-term exposure, providing a functional pool of chaperone to stabilize proteins and a means for greater therapeutic activity upon HSP90i reexposure. HSP90i administered on days 1 and 2 (D1/D2) demonstrated increased biologic activity compared with D1 treatment in KIT or EGFR-driven murine tumor models. In a trial of dogs with MCT, D1/D2 dosing of HSP90i was associated with sustained KIT downregulation, 50% objective response rate and 100% clinical benefit rate compared with D1 and D1/D4 schedules.

Conclusions

These data provide further evidence that prolonged HSP90i exposure improves biologic activity through sustained downregulation of client proteins.

SUBMITTER: London CA

PROVIDER: S-EPMC6696991 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors.

London Cheryl A CA Acquaviva Jaime J Smith Donald L DL Sequeira Manuel M Ogawa Luisa Shin LS Gardner Heather L HL Bernabe Louis Feo LF Bear Misty D MD Bechtel Sandra A SA Proia David A DA

Clinical cancer research : an official journal of the American Association for Cancer Research 20180831 24

<h4>Purpose</h4>STA-1474, prodrug of the heat shock protein 90 inhibitor (HSP90i) ganetespib, previously demonstrated activity in canine preclinical models of cancer; interestingly, prolonged infusions were associated with improved biologic activity. The purpose of this study was to identify the ideal treatment schedule for HSP90i in preclinical models of KIT-driven malignancies and in dogs with spontaneous mast cell tumors (MCT), where KIT is a known driver.<h4>Experimental design</h4><i>In vit ...[more]

PMID: 30171047

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Project description:BackgroundYKL-40, a secretory glycoprotein, is involved in tumor cell proliferation, metastasis, and angiogenesis in human cancers. Its overexpression has been correlated with unfavorable prognosis in many human cancers. In veterinary medicine, elevated YKL-40 levels in the serum of canine cutaneous mast cell tumors (cMCTs) were observed in our previous study. However, the expression pattern of YKL-40 in canine cMCT tissues, along with its association with clinical and pathological features, is still unknown. This study aims to retrospectively investigate the expression level of YKL-40 in the tissues of canine cMCTs and its correlation with clinical features, pathological characteristics, and clinical outcomes. Forty formalin-fixed paraffin-embedded cMCT tissues collected from forty dogs were diagnosed as low-grade (n = 20) or high-grade s(n = 20) MCT according to the Kiupel grading system. The expression level of YKL-40 in cMCT tissues was investigated using immunohistochemical staining and immunoreactivity score (IRS).ResultsYKL-40 was expressed in all cMCTs at different levels, with significantly stronger expression in low-grade cMCTs compared to high-grade cMCTs. The expression level was also associated with tumor diameter, histological grade, mitotic counts, vessel density, and survival of cMCTs. The overall survival of cMCT dogs showed significant differences (p < 0.01) among mild (n = 15, MST 219 days), moderate (n = 19, MST not reached), and high (n = 6, MST not reached) YKL-40 expression groups. Among low-grade cMCTs, overall survival was significantly different between mild YKL-40 expression (MST 319 days) and moderate to high YKL-40 (MST not reached) expression (p < 0.01). In high-grade cMCTs, overall survival was not correlated with YKL-40 expression (p = 0.6589).ConclusionsThis study found that the YKL-40 expression level was significantly stronger in low-grade than in high-grade canine cutaneous mast cell tumors and was associated with various clinical and pathological features. Stronger YKL-40 expression level correlated with longer survival time, especially in low-grade cMCTs. Therefore, YKL-40 could serve as a prognostic marker for cMCTs.

Dataset Information

Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors.

Purpose

Experimental design

Results

Conclusions

Publications

Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors.

Similar Datasets

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