Identifying Novel Approaches for Melanoma Prevention Using Mouse Models with Humanized Telomeres
Abstract
Every year, there are about 100,000 new cases of metastatic melanoma that will be diagnosed in the United States. Despite recent advances, melanoma remains the deadliest form of skin cancer with an estimated median survival range of 7-9 months. Immunotherapies have revolutionized the treatment of many cancers in the immuno-oncology field, including melanoma treatment, providing a new hope for cancer patients. However, clinical benefit obtained with immunotherapies has been heterogenous. Thus, understanding how host immunity is regulated will help the management and treatment against melanoma. Telomeres are caps of chromosomal ends, known as an aging clock, which are critical for human cell proliferation and survival. Telomerase is an enzyme that lengthens telomeres; however, the enzyme is not expressed in adult human cells in healthy individuals. During melanomagenesis, telomere length shortens as melanocytes proliferate, leading to telomere dysfunction and chromosomal destabilization, which generate genetic diversities in developing tumors that required for their malignant progression. In advanced melanomas, mutations and activation of the telomerase gene restore chromosomal stability in tumor cells, which eventually evolve into malignant and metastatic melanomas. In addition, tumor infiltrating lymphocytes (TILs) proliferated extensively in vivo. Persistence of TILs and tumor repression in melanoma patients directly correlated with the length of their telomeres. The critical roles of telomeres in melanoma have not been exploited to benefit the clinical management of melanoma, partly because telomere length homeostasis is not evolutionarily conserved, and telomere dysfunction does not occur in most existing animal melanoma models. To overcome this barrier, we have developed two novel and complementary mouse models. In Aim 1, we will use model 1, in which oncogenic Braf mutation is induced in telomerase knockout mice. Developing tumor cells in these mice are trapped in states of perpetual telomere dysfunction and genomic instability. We will test the hypothesis that pharmacological modulation of tumor suppressor pathways in tumor cells with destabilized chromosomes by our unique nanoparticles will activate host tumor immunity, thereby prevent melanoma at this critical point of tumor progression. In Aim 2, we will use a novel mouse model with humanized telomeres. Melanoma will be initiated by oncogenic Braf mutation in these mice. We will test the new concept of melanoma prevention using the novel nanoparticle developed in Aim1, and a new strategy of melanoma treatment by inducing telomere stress in tumors that have activated their telomerase. Telomeres in tumor cells will be specifically damaged by incorporating a nucleoside analog to release the damaged DNA, which activate cytotoxic T cells. This treatment will work synergistically with immune checkpoint inhibitors to eradicate cancer cells. Our proposal addresses the FY22 MRP challenges of A new paradigm of prevention includes inhibiting the initiation of melanoma and the development of metastases. New pre-clinical mouse models that recapitulate telomere function in human melanomas will contribute to the development of new paradigms of melanoma prevention and management, especially strategies to target tumor cells that are genetically destabilized due to telomere dysfunction and thereby inhibit the initiation of melanoma and melanoma metastasis. The project is especially relevant to the MRP focus areas of Identify and understand risk factor determinants for melanoma, Identify how the tumor microenvironment impacts tumor initiation, response to therapy, progression, recurrence, and/or dormancy, and Delineate the molecular pathways that influence metastatic spread, recurrence, and/or dormancy. In short, telomere destabilization and telomerase activation affect the development of melanoma in humans. Thus, a paradigm shift in the cancer f
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310964
Entities
People
- Gavin P. Robertson
Organizations
- Penn State Milton S. Hershey Medical Center
- United States Army