The Effects Of Paclitaxel (Ptx) And 2-Methoxyestradiol (2-Me2) On Tumor Oxygenation And Hif-1 Alpha In Breast Cancer

3517 Background: Radiation activates HIF-1a via a free radical mediated mechanism associated with reoxygenation. This response could be inhibited, resulting in reduced tumor vascularity and proliferation. Preclinical breast cancer models and a Phase Ib clinical trial (CT) were employed to look at the effects of chemo with or without an oral HIF-1a inhibitor, 2-ME2 (EntreMed) on tumor oxygenation and HIF-1a. Methods: Preclinical models of chemo effects on HIF-1a/oxygenation used 4T1 tumors and either doxorubicin (DOX) or cyclophosphamide (CTX). In addition, MDA-MB-231 tumors were treated with 2-ME2 (5days), and HIF-1a/MVD was assessed. In the CT, up to 15 pts with metastatic breast cancer, and biopsiable (>2 cm) non-bone sites were eligible. Tx was: D 1: PTX, 90 mg/m2; D 8: PTX, 90 mg/m2 with 2-ME2 (cohorts of 1,000/1,250/1,500 mg, qid). PTX was given 3 out of 4 wks. Bxs were done at enrollment, D8 (post-PTX), and D22 (post-PTX/2-ME2). Tumors were examined for changes in HIF-1a and CA9 levels, MVD, and genomic signatures of hypoxia. Plasma was obtained for osteoponin, PAI-1, and VEGF. Results: DOX and CTX both led to increases in HIF-1a, oxygenation, vascularity, and proliferation 4–10 days post treatment in the 4T1 model, while 2-ME2 reduced HIF-1a and MVD post treatment (5 d) in the MDA-MB-231 model. The CT opened in 6–2006, 9 pts have consented and 8 pts have undergone sequential biopsies and accrual continues. No DLT have been seen. Biopsy sites include chest wall, liver, and LN. Sufficient tissue/RNA/plasma has been obtained and the planned analyses will be presented. Conclusions: HIF-1a and tumor oxygenation appear to be modulated as a response to chemotherapy. The combination of PTX and 2-ME2 is clinically active, well-tolerated, and could serve as one of the first approaches to target HIF-1a in order to optimize therapy. Supported by Komen Grant BCTR0504044. [Table: see text]