One idea of personalized cancer therapy is to identify specific subgroups of cancer patients that will benefit from specific therapeutic strategies. Recently, the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research identified as the NCI's "Provocative Questions". This research proposal, while not specifically submitted as a NCI PQ grant, does address one such question "How does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In this regard, it is proposed that the cytoplasmic sirtuin, SIRT2 is a tumor suppressor protein and the deletion of these proteins in mice has resulted in the creation of several new murine models for the investigation of illness that have a strong genetic connection to aging. Human cancers, including lung adenocarcinomas increase as a function of increasing age, as well as the result of smoking. As such, it is proposed that cells lacking Sirt2, or exhibiting decreased SIRT2 deacetylation activity exhibit increased KRAS activity and this plays a role, at least in part, in the establishment of a lung adenocarcinoma-permissive phenotype. Since activated KRAS mutations are a hallmark in LACa this raises an intriguing question: is it possible that acetylation of KRAS can function as a rheostat to direct activity that is an early event in the initiation of lung adenocarcinomas? We propose that the answer is yes. In addition, identifying a post translational modification which regulates KRAS activity could have important therapeutic implications. First, there are no effective targeted therapies for Ras-driven cancers and, second, impaired activity of KRAS, as it happens when the protein is mutated, is involved in the chemotherapy (CT) and ionizing radiation (IR) tumor cell resistance. Given that KRAS-related cancers are generally refractory to standard therapies due to activated downstream signaling, the finding that acetylation may regulate its activity could reveal a promising therapeutic approach for these malignancies.
This research proposal addresses the question of how does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In this regard, the Sirt2 knockout mouse is an in vivo murine model that genetically connects the cytoplasmic sirtuin aging gene, Sirt2, the mutant KRAS protein, the cellular acetylome, and lung adenocarcinoma tumorigenesis.