Anti-cancer therapeutic approaches for targeting the ALT telomere maintenance mechanism

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Project Summary/Abstract During tumorigenesis, cancer cells need to acquire a telomere maintenance mechanism to proliferate indefinitely. Cancers of mesenchymal origin (such as sarcomas, endocrine tumors, glioblastoma, and some early childhood cancers), frequently acquire a telomerase-independent telomere maintenance mechanism, which has been termed Alternative Lengthening of Telomeres (ALT). Moreover, it has been shown that telomerase inhibition in telomerase positive human cancer cells can engage the ALT pathway. Although ALT cancers can be diagnosed by telomere fluorescence in situ hybridization (FISH) of tumor sections, and by using the C-circle assay (phi29 polymerase reaction) of tumor DNA, currently there are no therapeutic targets or clinical trials for ALT tumor treatment. Therefore, identification of potential therapeutic targets for ALT tumors may significantly improve the options for patients with ALT cancers by identifying and exploitering unique ALT cancer vulnerabilities. Ultimately, this should lead to personalized cancer treatment based on ALT status. From my recent studies, I found that the molecular mechanism of ALT is initiated by excessive and persistent clustering of telomeres in PML bodies. I have been further investigating that these processes are mediated by a series of post-translational modifications and segregation: ubiquitination by SUMO-targeted ubiquitination E3 ligase (RNF4), and segregation by ubiquitin- selective chaperone/AAA ATPase (p97; also known as VCP). In aim 1, I will further dissect the mechanism of RNF4 and p97 in ALT pathway and validate the therapeutic window of opportunity to inhibit the RNF4-p97 axis as an effective anti-ALT cancer strategy. One of the hallmarks of ALT cancers is the clustering of large amounts of telomeres in promyelocytic leukemia (PML) bodies. I have developed a biophysical system that reconstitutes PML bodies from minimal components and generates telomere clustering, thus mimicking ALT-associated PML bodies (APBs) in vivo. In aim 2, I will further engineer the biophysical system mimicking ALT cancer phenotype and apply this ALT model to proteomics and candidate gene screenings to identify novel therapeutic targets for ALT cancer. My primary career goal is to obtain an assistant professor position at a R1 university or research institute in the United States. My long-term career goal is to become an independent investigator and leader in the field of cancer cell biology. Training under a K22 award will serve as the basis for the future direction of my research, and the resulting publications will support my transition toward independence and prepare me to submit additional grant applications including R01s. The results that I obtain from Aim 1 and Aim 2 will allow me to further investigate the molecular mechanisms of the ALT pathway to identify new molecular targets and novel therapies for ALT cancers that are not currently available.