Targeting Metastatic Cancer Cell Clusters with Ex Vivo Modified Fibrinolytic Platelets
Abstract
A woman died from breast cancer every 13 minutes in the United States, according to data from 2012 from the Susan G. Komen Foundation. Metastases are the leading cause of death in cancer patients, and there are no current treatments directed to target, neutralize, or destroy circulating tumor cells (CTCs). CTCs originate from the primary tumor and migrate to distant tissues via the bloodstream and the lymphatic system. Platelets play a preponderant role in promoting CTC survival while they navigate the bloodstream where shear stress and immune cells otherwise eliminate them. Platelets coat the surface of CTCs to protect them against these threats, release pro-oncogenic and angiogenic factors, and help CTCs to escape out of the vasculature and subsequently grow to create new areas of metastases. It is known that platelet depletion in animal models significantly reduces metastases; however, this kind of platelet depletion cannot be achieved for treating patients without a serious risk of calamitous bleeding. Supported by our FY14 Breast Cancer Research Program Breakthrough Award, we have developed modified platelets able to bind CTCs but unable to assist them in navigating the harsh environment of the bloodstream, thus these “platelet decoys” compete with platelets for CTC binding and neutralize them in the bloodstream. We have demonstrated that they deploy an antiplatelet effect, significantly reducing breast cancer cell arrest and transfer from the bloodstream to distant tissues and significantly delaying metastases in mouse models. The treatment was well tolerated in the animal model with no evidence of side effects. The anti-platelet effect will have additional benefits in reducing the incidence of cancer-associated blood clots, which are commonly seen in patients with advanced cancer. This expansion proposal seeks to build on our work and create a new generation of CTC-targeting platelet decoys that have the ability to break down clusters of migrating CTCs. Multiple lines of evidence have now demonstrated that CTC clusters have a dramatically increased level of metastatic potential compared to single CTCs. We propose to load platelet decoys with a Food and Drug Administration-approved medication already used in treating strokes, called tissue plasminogen activator (tPA), to achieve the breakdown of these aggressive clusters of cancer cells. This is a drug capable of breaking fibrin apart, which is a protein that acts like a cement to hold and consolidate CTC clusters and platelets. We predict that decoys will target the aggregates via their cancer cell binding ability and deliver tPA at this exact location, causing the breakdown of the aggregates into individual cells. These individual cells are more susceptible to the harsh environment of the bloodstream as well as the immune system. Thus, the overarching challenges we propose to address are (1) to eliminate the mortality associated with metastatic breast cancer and (2) to revolutionize treatment regimens by replacing them with ones that are more effective and impact survival. Multiple patient populations could benefit from such an anti-metastatic fibrinolytic platelet decoy therapy. First, patients with advanced breast cancer undergoing surgery in order to remove their primary tumor. The procedure causes significant risk of tumor cell leakage in the bloodstream during the surgery. Consequently, fibrinolytic decoys could be transfused to the patient right before surgery to neutralize escaping tumor cells and abate their metastatic potential. Second, according to SEER (Surveillance, Epidemiology, and End Results) cancer statistics, around 93% of woman diagnosed with breast cancer do not have metastases. Thus, this therapy could be use as preventive measure in patients at high risk of future metastasis and administered along with chemotherapy cycles. Third, fibrinolytic decoys could help patients with advanced cancer by slowing down their exi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910667
Entities
People
- Anne-Laure Papa
Organizations
- George Washington University
- United States Army