Détails sur le projet
Description
Approximately 50% of patients with cancer will be treated with radiotherapy. However, radiation can pose some unwanted risks, such as generation of secondary tumors and metastasis, especially if it is administered at sub-lethal doses. Furthermore, radiotherapy is often unsuccessful because of tumor radioresistance. Although these unfavorable consequences of radiotherapy could be overcome by delivering higher doses of ionizing radiation, a dose escalation treatment is limited by the toxicities to noncancerous tissues. Therefore, the molecular mechanisms underlying radioresistance and methods to counteract such resistance must be understood in order to maximize the curative potential of radiation therapy for patients with localized prostate cancer.
Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumor growth and metastasis. Experimental evidence shows that progression of a growing tumor is characterized by induction in the tumor tissue of angiogenic factors. Furthermore, radiosensitivity of solid tumors is defined not only by intrinsic factors, but also by the tumor microvascular network, and tumors expressing high levels of proangiogenic factors are more resistant to radiotherapy. Mitogen-activated protein kinase kinase 5 (MEK5) is a kinase often associated with aggressive prostate cancer. Furthermore, MEK5/ERK5 is known to be crucial for survival of endothelial cells. Akt is one of the most upregulated oncogenic kinases in prostate cancer, and it is responsible for tumor cell proliferation, invasion, angiogenesis, and metastasis, as well as survival against anti-cancer treatments, including radiotherapy. Importantly, our data show that MEK5 downregulation renders prostate cancer cells more sensitive to radiation and MEK5 downregulation impairs activation of Akt in response to gamma-radiation. Thus, in this study, we propose that MEK5 induces radioresistance in prostate tumor cells, at least, in part due to activation of Akt in response to ionizing radiation. Furthermore, we hypothesize that MEK5 ablation in tumor cells will cause reduced expression of pro-angiogenic factors in response to radiation, and concurrently, MEK5 knockdown will induce endothelial cell death and inhibit tumor-associated angiogenesis.
Using human prostate cancer cell lines and animal models, our short-term goal is to establish the efficacy of MEK5 inhibition as a means to sensitize tumors to radiotherapy and impair tumor-associated angiogenesis. Moreover, we seek to elucidate the mechanistic details of MEK5 action in response to ionizing radiation by focusing on the contribution of Akt to MEK5-induced radioresistance and by performing large-scale gene expression analysis that will reveal additional genes and pathways that cross-talk with MEK5 signaling. Ultimately, we aim to develop a small molecule inhibitor of MEK5 that in combination with radiation will radiosensitize tumor cells, and, at the same time, impair tumor-associated angiogenesis.
Statut | Actif |
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Date de début/de fin réelle | 1/1/14 → … |
Financement
- Congressionally Directed Medical Research Programs: 360 000,00 $ US
Keywords
- Investigación sobre el cáncer
- Oncología
- Ciencias sociales (todo)