Hypoxia-inducible factor (HIF) 1α and 2α levels in cell lines and human tumor predicts response to sunitinib in renal cell carcinoma (RCC)

Abstract

5008 Background: Up to 40% of metastatic RCC patients (pts) achieve an objective [complete (CR) or partial (PR)] clinical response to sunitinib treatment (NEJM 2007:356:115–24). HIF1α and HIF2α actions underlie progression of RCC; and their relationship to clinical response warrants study. Methods: Metastatic clear cell RCC pts with archived frozen tumors, resected prior to sunitinib were eligible. HIF1α and HIF2α levels were determined from patient RCC lysates following immunoblot analysis, and scored as either: none, low, or high, based on staining intensity, relative to controls. Best clinical response to sunitinib was assessed by RECIST. In addition, pathways inhibited by sunitinib were studied on 10 unique RCC cell lines. Results: HIFα levels in tumors were strongly associated with sunitinib sensitivity. Pts with tumors containing high level of HIF1α (p=0.003) or high level of HIF2α (p=0.001) were more likely to achieve a favorable objective clinical response (CR or PR) to sunitinib, relative to tumors containing low or absent HIFα levels. For example, 76% (13 of 17) tumors with high HIF2α vs. 13% (2 of 15) tumors with no detectable HIF2α showed objective responses. Immunohistochemistry staining from paraffin-embedded RCC showed HIF1α is present in the nucleus of cancer cells, and not within the adjacent stromal cells. In RCC cells lines, sunitinib results in cell death exclusively in 5 of 10 lines showing high baseline HIF1α and 2α. In these 5 cell lines, sunitinib decreases levels of HIF1α and HIF2α by inhibiting translation of these proteins. Conclusions: HIF1α and 2α levels predict sensitivity to sunitinib therapy. In vitro, sunitinib functions to suppress levels of HIF1α and 2α, leading to cell death. These discoveries may provide the opportunity to optimize treatment, either by patient selection or directed therapy trials. Prospective studies are underway to validate these findings. Clinical response to sunitinib relative to level of HIF1α and HIF2α Pretreatment Tumor HIF levels # patients CR or PR (n=21) # patients Stable or Progression (n=28) p-value Hif 1α none 2 9 0.003 low 6 15 high 13 4 Hif 2α none 2 13 0.001 low 6 11 high 13 4 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer, Inc .