The Mitochondrial Deoxynucleoside Salvage Pathway in the Metastatic Recurrence of NSCLC
Abstract
Lung cancer will contribute 26% in males and 25% in females of the estimated total cancer death around the United States in 2018, and 85% of the lung cancer will be non-small cell lung cancer (NSCLC). Even after cancer surgery removes the original cancer, many patients develop recurrence. Lung cancer is very difficult to cure. One main reason is that lung cancer cells are able to spread in the body through a process called metastasis. It is believed that a small group of cancer cells with stem-cell-like properties, called cancer stem cells, are responsible for cancer metastasis and recurrence. The accepted paradigm of cancer therapy aims at eradicating rapidly proliferating cancer cells. However, how to eliminate cancer stem cell and prevent metastatic recurrence remains a major challenge in the clinic. Here, we propose that mitochondria in cancer stem cells depend on an enzyme called deoxyguanosine kinase for their ability to mediate metastasis and recurrence. We also propose that an anti-HIV drug, didanosine, could be used to inhibit deoxyguanosine kinase in lung cancer stem cells. Therefore, we will examine the mechanism by which deoxyguanosine kinase contributes to lung cancer initiation and progression, as well as explore the feasibility of using didanosine to prevent lung cancer metastasis and recurrence by targeting cancer stem cells. Since didanosine is a Food and Drug Administration-approved anti-HIV drug with a low toxicity profile, the success of this proposal would potentially be translated to make an impact in lung cancer therapies and prolong the survival of lung cancer patients in the next 5 to 10 years. The role of deoxyguanosine kinase in lung cancer is virtually uncharted territory; the success of this project will also bring significant insight to advance the field of lung cancer research. Among Veterans and military personnel, not only is the incidence of lung cancer higher, but survival is lower than in civilian populations. This is likely due to the high percentage of smokers among active duty military and Veterans, as well as exposure to other risk factors such as Agent Orange, radon, asbestos, depleted uranium used in weapons, etc. The proposed study in this project aims at understanding how mitochondrial nucleoside metabolism contributes to the metastatic recurrence of NSCLC, with the long-term goal to devise novel strategies to prevent metastatic recurrence. The success of the study will be paradigm-shifting and will benefit active duty military, Veterans, and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810283
Entities
People
- Shengchen Lin
Organizations
- Penn State Milton S. Hershey Medical Center
- United States Army