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

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.

©2011 AACR.

Figures

Fig. 1

Percentage of HIF-1α–positive cells in samples from baseline and post-treametment tumor bisopises from seven evaluable patients, reported per patient (A) and as mean ± SD (B). Immunohistochemistry staining for HIF-1α shown for patient 4 (breast cancer) at baseline and after two cycles of topotecan (C).

Fig. 2

Ktrans (upper row) and kep (lower row) color maps obtained from DCE-MRI of a 63-year-old man (patient 10) with liver metastases before (A, C) and after treatment during cycle 2 (B, D) show significant reduction in values consistent with response to therapy (arrows); patient had partial response lasting six cycles.

Fig. 3

VEGF (A) and GLUT-1 (B) mRNA epxression in pre- and post-treatment biopsies of six evalubale patients. Results are expressed as percentage mRNA expression realtive to baseline levels, arbitrarily considered equal to 100%. In patients 10 and 15, levels of GLUT-1 mRNA were undetectable in the post-treatment biopsies.

Fig. 4

DCE-MRI results. Ktrans (A) and kep (B) values by patient at baseline and follow-up DCE-MRIs. *No follow-up DCE-MRI at that time point.