Abstract 1608: Angiopoietin 2 is elevated in patients with RCC, and Ang2 inhibition improves antiantiogenic activity of sunitinib in a mouse model of RCC
| Autor: | Andrea J. Bullock, Xiaoen Wang, Michael B. Atkins, James W. Mier, Manoj Bhasin, Dongyin Yu, Rupal S. Bhatt, David C. Alsop, Angela Coxon, Jiaxi Song, Sabina Signoretti, Liang Zhang, Lin Wei, Jon Oliner |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
medicine.medical_specialty biology Sunitinib Angiogenesis business.industry Angiopoietin 2 Cancer urologic and male genital diseases medicine.disease female genital diseases and pregnancy complications Receptor tyrosine kinase Neovascularization Endocrinology Oncology Downregulation and upregulation Internal medicine Cancer research medicine biology.protein In patient medicine.symptom business medicine.drug |
| Zdroj: | Cancer Research. 73:1608-1608 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Background: Several small molecules targeting angiogenic receptor tyrosine kinases (TKIs) are approved for treatment of advanced RCC. While many patients (pts) respond to TKIs, resistance develops in all. Ang2 is a secreted glycoprotein that is upregulated at sites of angiogenesis and has been implicated in cancer neovascularization. Ang2 is elevated in many cancer states, and higher levels are associated with poor prognosis. Recent studies have also suggested efficacy of combined Ang and VEGFR inhibition as therapy in RCC. Mehtods: A panel of angiogenic genes was analyzed by RT-PCR in several tumor vs normal tissues. Plasma Ang2 levels in pts with RCC were measured in duplicate at baseline, on treatment with sunitinib (median 34.5 days after starting sunitinib), and at resistance to sunitinib. Finally, dual Ang1/2 (AMG 386) or Ang2 (L1-7) inhibition was also tested in a murine RCC xenograft model of resistance to VEGFR inhibition. Tumors were assessed for blood flow by arterial spin labeled (ASL) MRI. Results: Among the genes studied, Ang2 levels were 6.7 fold higher in human tumors vs normal (nl) tissues, and 12.6 fold higher in RCC vs nl. RCC ranked highest for Ang2 expression across all the tumor types tested, with Ang2 levels in RCC being 2.8 fold higher than in all other tumor types. VEGF and KDR showed similar results, with both exhibiting higher levels in tumors vs nl tissues (7.5 fold for VEGF and 2 fold for KDR). VEGF was 25.5 fold higher in RCC vs nl, and KDR was 6 fold higher in RCC vs nl. VEGF and KDR were also higher in RCC than all other tumor types (7.0 fold for VEGF and 6.5 fold for KDR). Plasma Ang2 was significantly higher in pts with metastatic RCC (n=50) compared to controls (n=26) and pts with stage I disease (n=39) (P Conclusion: Ang2 inhibition is elevated in pts with RCC, and Ang2 inhibition improves the activity of sunitinib in our mouse model of resistance. Plasma Ang2 levels increase in pts treated with sunitinib and may contribute to resistance to therapy. It is possible that the subset of pts with the highest Ang2 at resistance may be the optimal candidates for combination of these antiangiogenic agents. Citation Format: Xiaoen Wang, Andrea Bullock, Liang Zhang, Dongyin Yu, Lin Wei, Jiaxi Song, Manoj Bhasin, Sabina Signoretti, David C. Alsop, James W. Mier, Michael B. Atkins, Angela Coxon, Jon Oliner, Rupal S. Bhatt. Angiopoietin 2 is elevated in patients with RCC, and Ang2 inhibition improves antiantiogenic activity of sunitinib in a mouse model of RCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1608. doi:10.1158/1538-7445.AM2013-1608 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|