Survivors of childhood cancer are often associated with adverse, late-onset side effects of earlier cancer treatments, which can be severe or even life-threatening. However, the underlying mechanisms of therapy- induced late effects in this growing population are not known. We developed a novel mouse model for the late effects of chemotherapy, in which juvenile exposure to doxorubicin (DOX) results in tissue accumulation of senescent cells in adult mice and persistent up-regulation of cyclooxygenase-2 (COX2), a key enzyme in prostanoid synthesis. Using this model, we found that treatment with aspirin, a COX inhibitor, following juvenile exposure to DOX improved the long-term adverse effects and reduced the levels of senescent markers in adult mice. Additionally, we have recently reported that inducible expression of COX2 in adult transgenic mice led to increased senescence and a panel of early-aging phenotypes. Given the suggested role of cellular senescence in side effects of chemotherapy, we hypothesize that COX2 plays an important role in chemotherapy-induced senescence and that targeting the prostanoid signaling can effectively suppress senescence.
Specific Aim 1 will establish COX2 as a mediator of chemotherapy-induced senescence using a novel mouse model and define its mechanism.
In Specific Aim 2, we aim to identify the prostanoid signaling as a better and more selective therapeutic target for cellular senescence. Completion of the proposed research will identify potential treatment strategies to prevent the long-term adverse effects of childhood cancer therapies, which will lead to a higher quality of survivorship. At the same time, it could provide a novel insight into the role of COX2 in normal and pathological aging processes.
This project focuses on elucidating the molecular mechanisms by which chemotherapy causes adverse long- term side effects. The results of the proposed studies may lead to the development of more effective strategies to prevent the late effects of chemotherapy. Such strategies could significantly increase the quality of life in childhood cancer survivors.