Development of Small-Molecule BAX Inhibitors to Prevent Cancer Therapy-Induced Cardiomyopathy
Abstract
Topic: Cardiomyopathy Area of Encouragement: Development of novel therapeutic approaches for primary and secondary cardiomyopathies Essentially all treatments for cancer can cause heart damage. The most serious manifestation of this damage is a disease called heart failure, in which the strength with which the heart pumps blood is reduced. This is a potentially serious condition as it can be fatal or require heart transplantation. The fact that cancer treatments can cause serious heart disease creates a major problem. While it is critical to treat cancer, sometimes these efforts can be undercut by the development of heart problems. This situation has resulted in a significant number of cancer patients dying of heart failure. In addition, it is also responsible for increased cancer deaths because sometimes cancer treatments are not employed as vigorously as they might be for fear of causing heart failure. While a number of cancer drugs can cause heart failure, one of the most important is doxorubicin, sold as Adriamycin and some other brands. Doxorubicin is a critical component of regimens used to treat a wide variety of malignancies in adults and children including many solid tumors and leukemias. Doxorubicin damages heart cells in many ways. These multiple abnormalities have made it very challenging to identify a single defect that one could design a drug to fix. Many of these abnormalities ultimately lead to the cell dying through an active suicide process in which cells kill themselves when they are stressed or damaged. But even this is complicated as it appears that two different types of cell suicide, called apoptosis and necrosis, are involved. The leaders of this project had previously been studying these apoptosis and necrosis cell suicide processes. In the course of this work, they made an observation that fortuitously is applicable to how doxorubicin causes heart failure. They discovered a single protein called BAX that plays important roles in both cell suicide processes. This suggested that, if BAX could be inhibited, perhaps doxorubicin-induced heart failure could be prevented. Using mice in which the BAX gene had been “deleted,” they observed that doxorubicin was no longer able to cause heart failure. Accordingly, they used chemical approaches to make the first drug to inhibit BAX, which they named BAI1. When BAI1 is given to mice, it also blocks doxorubicin-induced heart failure. They next figured out how BAI1 prevents BAX from doing damage. They determined that BAI1 binds to BAX and prevents BAX from assuming the shape needed for BAX to cause either suicide program. They also figured out how binding of BAI1 to BAX prevents BAX from killing heart cells that had been exposed to doxorubicin. Now, BAI1 would be useful to prevent doxorubicin-induced heart failure only if it did not interfere with the ability of doxorubicin to treat cancer. Fortunately, the latter proved to be the case. Doses of BAI1 that protect the heart against doxorubicin still allowed doxorubicin to do its job to kill cancer cells and treat cancer in mice. Further, the researchers have begun to figure out how BAI1 protects the heart without interfering with doxorubicin treating cancer. While the development of BAI1 as a drug to prevent doxorubicin-induced heart failure is very significant, substantial additional work is needed to have a drug that might work in cancer patients being treated with doxorubicin. The development of a drug for use in humans is the objective of the current project, which has two goals: (a) to optimize the efficacy and safety of BAI1 and (b) to understand in detail how BAI1 is protecting the heart without interfering with the chemotherapeutic function of doxorubicin. This project brings together scientists with very different expertise. One of the leaders is an expert in chemistry, protein structure, and designing drugs. The other leader is a cardiologist who has long studie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010791
Entities
People
- Richard N Kitsis
Organizations
- Albert Einstein College of Medicine
- United States Army