Targeting the Regulation and Actions of Telomerase Reverse Transcriptase (TERT) in Bladder Cancer
Abstract
Each year, over 81,000 Americans are diagnosed with bladder cancer. Bladder cancer is linked to environmental risk factors that are especially common in Veteran and active Service member populations, including exposure to tobacco, industrial solvents, radiation, and chemical weapons such as Agent Orange. Thus, unsurprisingly, bladder cancer is the fourth most frequently diagnosed cancer among Veterans. Unfortunately, one third of bladder cancer patients suffer from advanced-stage tumors and have a high risk of dying from their cancer. Standard treatment often includes removal of the bladder in order to limit cancer spread. Even after surgery, cancer will return for half of these patients, and they will need to undergo aggressive chemotherapy and immunotherapy treatments. However, these treatments are only somewhat effective, and approximately 70% of patients with invasive bladder cancer die from the disease, leading to 17,240 deaths each year in the United States. Thus, there is an urgent need for new therapies to treat bladder cancer. We aim to develop new therapies to treat bladder cancer by targeting genes and proteins that control tumor cell growth and survival. In human cells, the ends of DNA are capped by protective ends called telomeres. Telomerase, which includes the protein TElomerase Reverse Transcriptase (TERT), is an enzyme complex that extends the length of telomeres. Telomerase and TERT are critical for maintaining telomere length in stem cells as they rapidly grow and divide. However, telomerase activity is not needed in normal body cells, and telomerase genes are turned off. In tumor cells, telomerase often becomes active due to mutations in the part of the TERT gene that controls expression, called the promoter. These mutant TERT promoters are like having a gas pedal stuck in the “ON” position in your car. High telomerase activity protects the DNA inside tumor cells as they rapidly divide, leading to the notorious fast growth and immortality of cancer cells. Because these mutant TERT promoters are unique to cancer cells, targeting mutant TERT promoters may offer a new tactic we will use in our proposal for specifically attacking tumor cells while sparing normal, healthy cells. As of yet, no TERT therapies have been developed to treat cancer. We propose to find compounds that reduce the activity of the mutant TERT promoter (fix the damaged gas pedal so it turns off in cancer cells) and assess the ability of these compounds to limit tumor growth in mice. Ultimately, this work will set the stage for the development of new drug therapies to treat patients with advanced-stage bladder cancer. New therapeutic options are critical for patients who do not respond to available immunotherapies and have no remaining treatment options. We expect that these patients will respond to mutant TERT promoter-directed therapy because about 70% of bladder cancers have TERT promoter mutations. Therapies that reduce mutant TERT promoter activity will lead to tumor cell death, which is known to stimulate the body’s immune response. By activating the immune system, TERT therapies may enhance the effect of existing immunotherapies, offering a powerful combination therapy. Mutant TERT promoters are also involved in the growth and survival of other incurable cancers, so our work has the potential to benefit an even greater number of patients. Based on our previous experience and current findings, we expect to bring a new TERT-based therapy to a Phase I clinical trial in the next 5 years. We are very excited to begin our work!
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910144
Entities
People
- Dan Theodorescu
Organizations
- Cedars-Sinai Medical Center
- United States Army