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

Shivaani Kummar, Mark Raffeld, Lamin Juwara, Yvonne Horneffer, Agnes Strassberger, Deborah Allen, Seth M. Steinberg, Annamaria Rapisarda, Shawn D. Spencer, William D. Figg, Xiaohong Chen, Ismail Baris Turkbey, Peter Choyke, Anthony J. Murgo, James H. Doroshow, Giovanni Melillo

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5123-5131
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number15
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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