The Extracellular Matrix as a Companion Therapeutic Target in Metastatic Lung Cancer
Abstract
Metastatic lung cancer accounts for more deaths than breast, colon, and prostate cancers combined. A significant challenge in treating lung cancers is the existence of different types of thoracic malignancies and their variable response to therapies. Lung adenocarcinoma (LUAD) is the most frequently diagnosed type of lung cancer. Importantly, LUAD causes significant morbidity due to its rapid spread into the brain, and there are no effective treatment options once this occurs. We use innovative approaches that incorporate genetic, biological, and computational methods to understand the differences between various types of human lung cancers. We also compared clinical samples of lung tumors that tend to metastasize versus those that do not. In this manner, we have identified a critical difference in how metastatic LUAD cells take advantage of their surrounding environment to grow and metastasize. A major constituent of the environment surrounding all cells is the extracellular matrix. The extracellular matrix consists of molecules that provide external structural support to cells and confers stability to blood vessels in a given tissue. Secretion of extracellular matrix molecules also allows cells to communicate to one another during normal physiological processes such as wound healing. Cancer cells can take advantage of such molecules to grow, spread, avoid the effects of anti-cancer drugs, and evade the anti-tumor response of the immune system. Our findings indicate a potential weakness of metastatic cancers, in that they may be over-reliant on a particular type of extracellular matrix molecule, which can be degraded with a novel compound called PEGPH20. Our objectives are to study how PEGPH20 affects the growth and spread of metastatic LUAD in various animal models. We predict that PEGPH20 will prevent LUAD cells from metastasizing. Moreover, PEGPH20 may also remodel the extracellular matrix of tumors in a manner that improves the delivery of current drugs and restores host immune response to malignant cells. The potential findings from our proposal could be imminently applicable in the clinic. PEGPH20 is already entering Phase 2 clinical trials in other cancers and is generating promising results. Elevated levels of specific extracellular matrix molecules from lung tumor biopsies may be used to accurately diagnose LUAD at risk for metastasis. Our studies may then provide a strong rationale for combining PEGPH20 with other drugs that inhibit tumor cell growth or re-activate immune response in these patients that are at risk for or already suffering from metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610227
Entities
People
- Don X. Nguyen
Organizations
- United States Army
- Yale University