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Clin Cancer Res. 2011 Aug 1;17(15):5123-31. doi: 10.1158/1078-0432.CCR-11-0682. Epub 2011 Jun 14.

Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors.

Author information

1
Center for Cancer Research and Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 21702, USA.

Abstract

PURPOSE:

Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1α, after treatment with oral topotecan.

EXPERIMENTAL DESIGN:

Topotecan was administered orally at 1.6 mg/m(2) once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1α and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment.

RESULTS:

Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m(2)/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1α nuclear staining became undetectable after treatment (7.5%-50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1α in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI.

CONCLUSIONS:

This multihistology, target assessment trial of a small molecule inhibitor of HIF-1α showed that topotecan could decrease HIF-1α expression in advanced solid tumors.

PMID:
21673063
PMCID:
PMC3149769
DOI:
10.1158/1078-0432.CCR-11-0682
[Indexed for MEDLINE]
Free PMC Article

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