This project is a major part of the Developmental Therapeutics Program drug discovery and development program within the Division of Cancer Treatment and Diagnosis. The emphasis is on preclinical drug discovery and preclinical drug development. The DTP-Tumor Hypoxia Laboratory (THL) provides support to the Screening Technologies Branch, DTP, DCTD, NCI, in the development of pharmacological and genetic strategies targeting tumor hypoxia and the hypoxia inducible factor 1 (HIF-1) pathway. The main focus of the THL is the discovery and development of novel therapeutic strategies targeting hypoxic cell signaling. Over the last several years, the THL has contributed to the implementation of a targeted screen for the discovery of small molecule inhibitors of HIF-1, a transcription factor involved in angiogenesis and tumor progression. One of the active leads dentified in the high-throughput screen (HTS), topotecan, is currently in clinical testing at the Clinical Research Center, NIH, to evaluate its ability to inhibit HIF-1 alpha expression in patients with metastatic cancer (Protocol NCI 05-C- 0186). Ten patients have been treated and accrual continues. Tissue biopsies taken from patients before treatment and after two cycles of therapy have shown that inhibition of HIF-1 in cancer tissue can be achieved with oral administration of topotecan. This result has led to further studies in preclinical models to explore the combination of topotecan with antiangiogenic agents. In particular, the laboratory has demonstrated that the combination of topotecan with bevacizumab, a monoclonal antibody against VEGF, exerts synergistic antitumor and antiangiogenic activity in tumor xenograft models.
