Jagged as a Therapeutic Target in Breast Cancer
Abstract
Our goal in this proposal is to test a potential new treatment for triple-negative breast cancer that targets a protein found on breast cancer cells called Jag1. Triple-negative breast cancer, commonly abbreviated as TNBC, is diagnosed in approximately 40,000 women each year in the United States. Unlike other forms of breast cancer, which can often be treated with targeted hormone therapy, TNBC generally requires treatment with chemotherapy, radiation, or surgery. Targeted therapies for TNBC are badly needed to improve the quality of life for patients. Additionally, TNBC is more likely than other breast cancers to recur and form metastases, where cells from the breast tumor spread through the blood circulation to other parts of the body, such as the brain, lungs, liver, or bone. Once a tumor has become metastatic, it is often difficult or impossible to treat and can lead to death, so there is a significant need to develop therapies that block metastasis. TNBC tumors frequently produce the protein Jag1 and present it on the surface of the cancer cell. The presence of Jag1 in tumors correlates with poor outcomes for breast cancer patients. Jag1 activates a form of cellular communication called Notch signaling. This Notch signaling is thought to promote tumor growth by increasing the tumor’s ability to recruit blood vessels from neighboring tissue so that the tumor receives oxygen and nutrients. Researchers have previously attempted to stop tumor growth by blocking all of Notch signaling, but currently available inhibitors of Notch signaling have failed due to severe gastrointestinal toxicity. We have developed a new class of proteins, called Notch decoys, which only block specific elements of the Notch signaling pathway. Some of these decoys specifically inhibit the Notch signaling caused by Jag1. We have tested the Notch decoys on human tumors implanted into mice, and we have shown that Jag1-specific Notch decoys reduce tumor growth, tumor blood vessels, and the ability of those vessels to carry blood and oxygen to the tumor. Furthermore, the Notch decoys did not cause gastrointestinal toxicity like the previously studied global Notch inhibitors. We have preliminary evidence that Jag-specific decoys stop tumor cells from moving into or out of blood vessels, a key step in metastasis, and so our treatment may block metastatic spread of TNBC. We have now developed a new Jag1-inhibiting Notch decoy, called the N110-20 decoy, which is optimized for purification in order to use it in human treatments. In this proposal, we would test N110-20 decoy in mice to confirm that it also blocks TNBC tumor growth and blood vessel recruitment in the same way as the previous Notch decoys. For these tests, we will use two more sophisticated mouse models of TNBC that better model human TNBC behavior and better model immune responses to breast cancer. During these tests, we will also determine if N110-20 decoy works to block metastases from the breast tumors into other organs. We will monitor the gut, kidneys, and livers of these mice to see if there are toxic effects of N110-20 at any dose. In this proposal, we want to test the more general question of whether Jag1, which is produced and presented by the aggressive tumor cells of TNBC, promotes the growth of blood vessels and metastatic spread. We will test this by manipulating the level of Jag1 on TNBC tumors in the same mouse models as above. We can use this information to understand what processes are blocked by the decoy and thus optimize its use. If this project is successful, we will have a treatment that can inhibit tumor growth in patients with Jag1-positive TNBC tumors. We have already shown that N110-20 decoy can be produced in a form that can be given to human patients, but it will still have to go through substantial preclinical and clinical testing before it would be approved for patient use. However, we anticipate that by the end of this project, we w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810019
Entities
People
- Jan Kitajewski
Organizations
- United States Army
- University of Illinois at Chicago