Overall survival rates for childhood malignancies have improved dramatically over the last few decades. Unfortunately, optimism created by these increasingly favorable outcomes has become muted by the realization over time that significant impairments in health and well being often result from aggressive anti- cancer treatments. Children may be particularly vulnerable to long term toxicity from cancer therapy due to their ongoing growth and development. In addition, their potential for five or more decades of subsequent life increase the time frame over which permanently weakened organs may fail or secondary cancers would arise. This proposal is in response to PQ6, seeking applications that propose development and validation of models that address treatment related long term adverse effects and their use to evaluate potential strategies for their amelioration. The goal of this proposed project is to generate and validate a mouse model of therapy-induced accelerated senescence, and to identify strategies that could reverse the multi-organ dysfunction and increased susceptibility to secondary cancers that result from such treatments. The central hypothesis of the proposal is that premature cellular senescence is an underlying mechanism that contributes to many of the late effects of therapy that plague survivors of childhood cancer. If true, then specifically monitoring cellular senescence would provide a direct window into those therapies that are most harmful in the long run. Additionally, it would raise the prospect of directly targeting senescent cells as a means to reverse damage to normal tissues from chemotherapy and radiation. It is believied that this approach would reduce the severity or incidence of certain long term treatment-related disabilities. To test these hypotheses the proposed work will 1) establish mouse models that reveal the extent of cellular senescence induction by chemotherapy or radiation; and 2) determine the impact of senescent cells on development of treatment related toxicities and secondary malignancies in mice. If successful, these studies would provide useful mouse models that allow accelerated identification of the potential for long term toxicities from current and future cancer therapeutic regimens. As a result, they may provide powerful methods to reduce such toxicities by altering drug combinations or timing intervals in ways that preserve anti-cancer effects while minimizing detrimental impacts. Additionally, these results would increase enthusiasm for use of novel drugs that deplete senescent cells (as they become available in the future) in combination treatments of cancer in children.
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