Angiogenesis is one of the hallmarks of cancer and a much-pursued therapeutic target. Most anti-angiogenic agents in clinical use target VEGF, VEGF receptors, or related tyrosine kinases, and have shown significant promise in the neoadjuvant context. However incomplete inhibition, evasive mechanisms, increased metastasis, and the development of resistance have limited long-term success, underscoring the need for a better understanding of the nuances of angiogenic regulation and the identification of new targets for therapy. Recent evidence points to a role for the DNA Damage Repair (DDR) pathway in pathological angiogenesis under conditions of hypoxic stress, as is observed in growing tumors. The DDR pathway is also a recognized promoter of resistance to DNA damaging cancer treatment such as chemotherapy and radiation. Here we propose a novel molecular target, the Eyes Absent protein tyrosine phosphatase (EYA-PTP) to simultaneously target tumor angiogenesis and chemo-resistance. In preliminary studies we have shown that the EYA-PTP activity promotes DDR and angiogenesis, and that inhibition of the EYA-PTP or deletion in host endothelial cells signficantly attenuates tumor growth and angiogenesis. In this project we plan to (1) study the interplay between host endothelial EYA, tumor angiogenesis, and chemo-resistance, and (2) use existing and newly developed EYA-PTP inhibitors as anti-angiogenic and chemosensitzation agents in cell?line based and patient-derived orthoptoic xenografts. The overall impact of this proposal is that it will define a new pathway involved in both tumor angiogenesis, and resistance to DNA damaging first-line therapies. Using both genetic and chemical biology approaches we will have demonstrated that the EYA-PTPs are tractable cancer therapeutic targets.
Targeting angiogenesis in cancer treatment has many advantages: the treatment is directed to the host endothelial cells and is thus not tumor-specific and host endothelial cells are more genetically stable than cancer cells hence less likely to develop resistance. This project investigates a new pathway that is involved in both tumor angiogenesis and in resistance to chemotherapy and radiation. Using tool inhibitors that we have identified, we will validate an unusual protein tyrosine phosphatase called Eyes Absent as a novel and tractable target for the development of cancer treatments. This new approach could slow down tumor growth and reduce the doses of chemotherapy and radiation necessary for effective treatment of cancer.
| Wang, Yuhua; Pandey, Ram Naresh; Riffle, Stephen et al. (2018) The Protein Tyrosine Phosphatase Activity of Eyes Absent Contributes to Tumor Angiogenesis and Tumor Growth. Mol Cancer Ther 17:1659-1669 |
| Riffle, Stephen; Hegde, Rashmi S (2017) Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids. J Exp Clin Cancer Res 36:102 |
| Riffle, Stephen; Pandey, Ram Naresh; Albert, Morgan et al. (2017) Linking hypoxia, DNA damage and proliferation in multicellular tumor spheroids. BMC Cancer 17:338 |
