Cancer Therapy: Clinical Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1a in Advanced Solid Tumors

Purpose: Hypoxia-inducible factor 1 (HIF-1) a is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1a expression in preclinical models. We designed a pilot trial to measure HIF-1a inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1a, after treatment with oral topotecan. Experimental Design: Topotecan was administered orally at 1.6mg/m once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1a 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/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1a 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-1a 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-1a in tumor and reduction in tumor blood flow on DCE-MRI. Conclusions: This multihistology, target assessment trial of a small molecule inhibitor of HIF-1a showed that topotecan could decrease HIF-1a expression in advanced solid tumors. Clin Cancer Res; 17(15); 5123–31. 2011 AACR.