Mechanisms of Vascular Mimicry Impacting Tumor Progression and Response to Therapy in Breast Cancer
Abstract
Tumors require nutrients and oxygen supplied by the bloodstream to fuel their growth and spread to other organs (metastasize). It has been known for some time that tumors often ensure their blood supply by sending signals that tell the body’s professional vessels to grow, a process called angiogenesis. This idea formed the foundation for a class of drugs (anti-angiogenics) that block these signals reaching the professional blood vessel cells with the hope that such drugs would starve the tumor and lead to its death. Unfortunately, clinical trials of anti-angiogenics have been quite disappointing, especially in breast cancer, where these drugs are no longer approved by the Food and Drug Administration (FDA) for use in patients. Recently, it was discovered that tumor cells can form do-it-yourself blood vessels, made from tumor cells mimicking the body’s professional blood vessel cells, without the requirement for the signals that are blocked by anti-angiogenics. This process, called vascular mimicry (VM), is linked to spread of the tumor to other organs and worse survival for breast cancer patients. It has been proposed that VM may one reason why anti-angiogenics don’t work very well in patients, based on the idea that if tumors can form do-it-yourself blood vessels, why would they care if the professional vessels were present or not. However, despite being a compelling idea, actual evidence that VM is a reason for poor performance of anti-angiogenics is lacking, probably due a hazy understanding of precise mechanisms that control VM. Moreover, a better understanding of how VM is controlled may provide clues as to how to design or select drugs to target VM in patients. Using a multi-scale approach encompassing mouse breast cancer models, human patient data, and genetic tracing technologies, we have discovered several new factors that modulate VM in breast cancer. In the current proposal, we plan to dig deeply into the precise mechanisms by which these factors influence VM using state-of-the-art technologies and mouse avatars of human cancer. By measuring whether genes are turned on or off when we add or remove these novel VM regulators, we have already identified genes that are activated in VM tumors. If we then look in patients who benefitted or not from anti-angiogenic therapy, we find for the first time that VM genes are specifically turned on in patients who did not benefit from therapy. These observations suggest that measuring these genes may predict whether a patient will benefit from anti-angiogenic therapy and that inhibiting VM may increase the ability of anti-angiogenics to kill tumors. Therefore, we will try to identify drugs that block VM by using genetic screening technologies that our lab has developed and pioneered. Considered in its entirety, successful completion of the research in the current proposal will vastly increase our understanding of how VM occurs, its importance in breast cancer patients’ response to anti-angiogenic therapy and provide a foundation for developing or selecting drugs to inhibit VM alone or in combination with other therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810703
Entities
People
- Gregory Hannon
Organizations
- New York Genome Center
- United States Army