Modulating TLR9 Activation for Lung Cancer Therapy
Initial Award Abstract
Lung cancer is the leading cause of cancer death in both women and men in the United States and worldwide accounting for even more deaths from solid tumors than breast, prostate, pancreatic and colorectal cancers combined. Tobacco smoking is the major causal agent for the lung cancer incidence. The large numbers of current and former smokers are at high risk for developing lung cancer, and there are currently no chemopreventive agents for effectively preventing lung cancer in humans. Thus novel therapeutic strategies are urgently needed to improve the clinical treatment of this serious disease.
Synthetic CpG containing oligo-deoxynucleotides (CpG-ODN) are being exploited as a novel therapeutic approach for treatment of several different human cancers. Their efficacy is currently under evaluation in clinical trails. CpG-ODN could be developed for using alone, or in combination with different type of cancer therapies such as radiation therapy, surgery and chemotherapy for cancer treatment. For example, in combination with standard paclitaxel or cisplatin chemotherapy, CpG-ODN have been used in phase III clinical trail as a first-line treatment for patients with advanced (stage IIIb or IV) non-small cell lung cancer (NSCLC).
Toll-like receptor 9 (TLR9) is the cellular receptor which mediates the antitumor activity of CpG-ODN. This receptor is expressed in B lymphocytes, plasmacytoid dendritic cells, monocytes and at lower levels in respiratory cells and lung cancer cells. Stimulation of TLR9 triggers Th1 immune responses including increased synthesis of cytokines such as IL-12 and interferon- (IFN-), leading to maturation, differentiation, and proliferation of natural killer (NK) cells, T cells and monocytes. These immunoadjuvant effects facilitate eradication of malignant cells.
We recently identified a novel protein termed Triad3A, and have generated knockout mice for this gene. Triad3A is an E3 ubiquitin-protein ligase that regulates ubiquitination and proteolytic degradation of TLR9. The Triad3A deficient mice are hyperresponsive to CpG-ODN. We hypothesize that the extent of TLR9 activation upon stimulation could be important in determining the efficacy of CpG-ODN in lung cancer therapy. To test this hypothesis, in this project we will: (1) establish lung cancer animal models in the Triad3A gene knockout mice to investigate whether reduction of Triad3A activity enhances the efficacy of CpG-ODN in inhibition of lung cancer growth, and (2) investigate the extent and the molecular basis of CpG-ODN induced immunological responses in the Triad3A knockout mice. Completion of this project will help us to elucidate whether Triad3A is a molecular target to enhance the therapeutic effect of CpG-ODN for lung cancer treatment, and provide us information for additional therapeutic strategies with CpG-ODN. |