Telomere biology is also intricately linked with human cancer. To avoid telomere loss associated to cell division, most cancers (95%) reactivate telomerase. In spite of the important role of telomere maintenance for cancer growth, inducing telomerase dysfunction in cancer cells remains an unmet clinical challenge. Indeed, telomerase inhibitors have largely failed in clinical trials of cancer, most likely owing to the fact that the effectivity of telomerase inhibition depends on the telomere length of the cancer cells. Telomerase is not the only telomere component altered in cancer, indicating that alternative or additional approaches are needed to induce telomere maintenance in cancer cells. We explored the idea of targeting shelterin as an anticancer strategy to inducer telomere damage independently of telomere length. We validated the inhibition of the shelterin component TRF1 as an effective therapy in both lung cancer and glioblastoma. We developed chemical inhibitors of TRF1 and found that TRF1 is regulated by key cancer pathways such as PI3K/AKT and RAS. In addition, we and others had identified mutations of the telomere binding protein POT1, a component of shelterin, in several types of human sporadic or familial cancer. These include chronic lymphocytic leukemia (CLL), familial melanoma, Li-Fraumeni like (LFL) syndrome families with cases of cardiac angiosarcoma (CAS), glioma, mantle cell lymphoma, and parathyroid adenoma.
We aimed to unravel the underlying mechanisms by which mutations in shelterin components contribute to, or even drive, tumour development. Our goal is therefore to unveil the role of shelterin mutations in cancer by establishing a comprehensive set of tools, and conduct a fundamental and far-reaching experimental program on the role of such mutations in human cancer. Our specific aims are (i) to generate novel knock-in mouse models to understand the role of POT1 mutations found in human cancer to develop personalized therapeutic strategies based on these alterations, (ii) to generate new knock-in mouse models to understand TRF1 post-translational modifications by multiple cancer pathways to identify new cancer targets based on TRF1/shelterin blockage, and (iii) to dissect the potential role of TRF1 in cancer stem cells.
We are convinced that targeting shelterin will develop into a novel and promising strategy to reverse one of the yet unmet hallmarks of cancer, the maintenance of telomeric integrity. Our proposal is an explicit high-gain research program, since it is one of our aims to develop novel anticancer strategies based on shelterin-mediated telomere protection.
