The overarching goals of the Genome Stability Program are to gain new insights into the molecular pathways that maintain genome integrity, how these processes are altered in cancer cells, and finally how these alterations may be exploited to kill tumor cells.
Each cell in the human body suffers an estimated 70,000 DNA lesions per day that arise spontaneously (depurination, deamination, oxidation, replication fork collapse) or from genotoxic insult (UV photoproducts). DNA damage can result from endogenous agents such as reactive oxygen species arising from mitochondria dysfunction or pro-inflammatory pathways, or exogenous environmental factors such as sunlight, radon, and air pollution. These DNA adducts, if not repaired, can cause mutations which also arise from DNA polymerase errors during replication. Mutations in key genes, tumor suppressor genes or activation of oncogenes are associated with the multi-step process of carcinogenesis. DNA damage along with many other factors influence the faithful passage of genetic material from mother to daughter cells, and genome instability including alterations in epigenetic marks, has emerged as one of the key hallmarks of cancer.
Genome Stability research focuses on several essential molecular processes that are disrupted in cancer cells. The specific aims of this Program are to:
- Define the molecular mechanisms of genome instability leading to cancer
- Identify novel therapeutic opportunities created by mutations in DNA repair genes
- Examine functional interactions in telomere maintenance, cellular senescence, and cell death in the processes of cancer and aging
- Develop strategies to sensitize and mitigate responses to ionizing radiation, genotoxic therapeutics and oxidative stress
- Define the functional interactions between DNA damage responses with innate and adaptive immunity
- Recruit, mentor and guide the next generation of cancer researchers working in genome stability.
Because these subjects are overlapping and intimately linked, program members generally work in more than one of these sub-areas. By collaboration and communication, research areas within the Genome Stability Program work synergistically with other Hillman Cancer Center programs for translation of fundamental discoveries in basic science into development of novel targets, drug discovery, and recognition of biomarkers—and, ultimately, hand-off for clinical application to specific cancer types.
Mechanisms of Genome Stability
Loss of genome integrity, characterized by the accumulation of mutations and chromosomal alterations, is a well-recognized hallmark of carcinogenesis. The goals are to define the molecular mechanisms of genome instability leading to cancer and identify how DNA repair deficiencies caused by gene mutations or targeted inhibition can be exploited to sensitize cancer cells to killing. Understand how DNA damage is converted to genomic alterations, and the factors that dictate pathway choice for processing DNA lesions. Fundamental knowledge gained from this research can lead to novel therapeutic opportunities given the importance of genome instability in cancer etiology, progression and survival.
Radiation and Oxidative Damage
This theme focuses on DNA repair pathways dedicated to removing oxidative DNA damage stemming from ionizing radiation, genotoxic therapeutics and oxidative stress. The goals are to develop strategies to sensitize and mitigate responses to ionizing radiation, genotoxic therapeutics and oxidative stress. Fundamental knowledge learned from these studies could lead to novel therapeutic opportunities to ameliorate off-target effects of radiation therapy on healthy tissue, and preferentially enhance the sensitization of tumor cells to killing by radiation and oxidant injury.
Genotoxic Stress Responses
Genotoxic stress and resulting genomic damage elicit diverse cellular responses ranging from activation of DNA repair, cell senescence, cell death pathways, and immune factors, which dictate biological outcomes. The goals are to define the functional interactions between DNA damage responses and genotoxic stress during replication, cell cycle checkpoints, inflammation, and immune responses. Define the functional interactions between DNA damage responses with innate and adaptive immunity. Mechanisms that determine cellular responses to genotoxic stress can be leveraged and manipulated to preserve genome integrity in healthy cells or promote elimination of malignant cells.
Aging and Cancer
Aging remains the greatest risk factor for the development of cancer. Although the reasons remain to be fully understood, both aging and cancer share the common hallmark of genomic instability. The goals are to examine functional interactions in telomere, mitochondria, cellular senescence, and cell death in the processes of cancer and aging. Understanding how collateral damage from chemotherapy or radiation therapy promotes aging can lead to intervention therapies in cancer survivors. Fundamental knowledge gained can lead to intervention strategies that reduce cancer risk with age.