Novel molecular targets to counter angiogenesis, metastasis and chemo-resistance in tumors
Evasive resistance has proven to be a major limitation of anti-angiogenic cancer therapy, and is thought to underlie the transient favorable outcomes seen in responsive patients. Thus there remains a significant need to develop longer lasting anti-angiogenic therapies. Mechanisms of evasive resistance include compensatory upregulation of cytokines that circumvent or overcome anti-VEGF treatment, and increased metastasis that allows cells to escape the hypoxic environment in tumors. In recent work we have shown that the tyrosine phosphatase activity of the EYA proteins promotes the motility and invasiveness of both breast cancer and malignant peripheral nerve sheath tumor cells. Furthermore, the EYA proteins promote angiogenesis. We have evidence that EYAs are activated upon oxygen stress and thus may play a role in the critical angiogenic switch that permits tumor growth. In xenograft models inhibition of EYA leads to significant reduction in tumor growth rates. Based on these observations this project tests the hypothesis that the EYA proteins respond to intra-tumoral hypoxia and promote tumor angiogenesis, as well as metastasis. In addition, because of their role in promoting DNA damage repair EYA inhibitors can lower resistance to conventional DNA damaging agents used in cancer treatment.
This project combines the tools of cell biology, mouse models of cancer, and drug design to validate a novel mode of targeted therapy for solid tumors.