Novel Epigenetic Reprogramming to Inhibit or Reverse EMT in Lung Cancer
Abstract
Lung cancer causes one-fifth of cancer deaths worldwide and is the leading cause of cancer deaths in the United States as well as among Veterans. The disease would be eminently more treatable if not for its high frequency of invasion into normal tissues and spread to distant sites. However, stressful conditions present in cancers cause malignant cells to escape from the tumor by altering cell shape, inhibiting cell-cell interactions, and inducing migration. The process underlying these changes is referred to as the epithelial-mesenchymal transition or EMT. In addition to promoting metastases, the EMT facilitates the development of tumor stem cells, which are inherently more resistant to radiation, chemotherapy, and many targeted biologic agents used in cancer treatment. The EMT process is not just an on-off switch, but a series of switches, each with positive and negative regulators. We discovered a new regulation step involving Neuropilin-2 (NRP2), which interacts with other cell surface receptors to activate intracellular signaling and promote malignant progression. In this proposal, we hypothesize that NRP2 is critically involved in the regulation of a key modifier of gene expression, EZH2, which controls many of the genes required for invasion and metastasis. We also hypothesize that another component, ZEB1, works together with EZH2 to change the gene expression repertoire. Our experiments will examine the relationship between the effects of ZEB1 and EZH2 on selected genes known to be involved in the EMT process and whether specific changes in cell signaling molecules mediated by NRP2 are required for EZH2 activity. As a complementary approach, we will examine the repertoire of genes affected by NRP2 inhibition in lung cancer cell lines, expecting to see linkage to known EZH2 pathway components. To bring these basic studies to the level of preclinical therapeutics, we will examine to what degree individual and combined inhibition of ZEB1 and EZH2 affect the development of EMT or lead to its reversal. Lastly, we plan to test the effectiveness of the best inhibitory combination in animal models of lung cancer invasion and metastasis. This work addresses two Lung Cancer Research Program Areas of Emphasis: (1) Understanding the molecular mechanisms of progression to clinically significant lung cancer and (2) understanding of susceptibility or resistance to treatment. This study is highly relevant for individuals with already identified lung cancer including Veterans and other members of the military. We believe the NRP2 pathway represents a new therapeutic target. The eventual goals are to inhibit invasion, metastasis, and drug resistance. While lung cancer may have already spread by the time it s diagnosed, more recent molecular analyses have shown that metastatic tumor deposits can be the source of additional new metastases. Therefore, inhibiting metastasis at nearly any time point should be advantageous. In addition, inhibiting the EMT process is likely to reduce a substantial amount of acquired drug resistance. This represents the biggest challenge to today s targeted therapies, which often work well initially, but invariably fail because of acquired drug resistance. The proposed studies should be accomplished in the projected 1-year period and should lay the foundation for a larger proposal, which ideally will include an initial clinical trial within a period of 2-3 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610226
Entities
People
- Harry Drabkin
Organizations
- Medical University of South Carolina
- United States Army