Leveraging Spliceosome-Targeted Therapies to Harness the Immune System Against Metastatic Breast Cancer
Abstract
This application aims to address the overarching challenges to (1) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival, and (2) eliminate the mortality associated with metastatic breast cancer. We approach these critical challenges by exploiting a newly discovered therapeutic vulnerability in breast cancer: mistakes in RNA splicing, which lead to activation of anti-tumor immune responses. We propose to take advantage of these mistakes to stop breast cancer growth and eliminate metastasis. All human genes encode their function through reading of DNA sequences into RNA. RNA serves as the messenger to deliver the instructions (and make proteins) so that cells can carry out their normal functions. The odd thing about human genes is that the sequences that hold the instructions are split into sections, with many genes being split into more than 10 different sections. When these genes are transcribed into RNA, the separate sections have to be stitched together by a tightly controlled process called RNA splicing. This process of splicing produces very complex combinations of RNAs (instructions) that help to specify the different functions of each type of cell in the human body (e.g., muscle cells have very different RNA splicing than neurons or breast cells). During normal human health, this process is highly regulated. But in cancer, RNA splicing is often times broken or dysregulated. As a consequence, while normal cells and tissues can tolerate minor mistakes in this process, cancer cells, which are already burdened by many mistakes in RNA splicing, cannot tolerate any further disruptions of this key process. As a consequence, cancer cells, especially triple-negative breast cancer (TNBC) cells, can be selectively killed by inhibitors of splicing. Importantly, we have discovered that drugs that partially inhibit splicing can have dramatic impact on TNBC tumor progression in preclinical studies, sometimes causing complete tumor regression, and are well tolerated by healthy tissues and patients. Mistakes in splicing result in aberrant RNAs, or defective instructions, in tumor cells. Our preliminary studies indicate these aberrant RNAs trigger two different types of immune responses against breast cancer. First, these RNAs tend to fold and form shapes that mimic some RNA viruses. As a result, they can stimulate the cell’s (and patient’s) antiviral defense, which has evolved to cause death of virus-infected cells, and stimulate the entire organism’s immune system including T cells and NK cells. When this happens in tumor cells, this can result in selective tumor killing. Second, some of the aberrant RNAs may be translated into similarly errant proteins. These aberrant proteins may be recognized as foreign by the immune system and stimulate immune cells to attack the tumor. Interestingly, both outcomes may be utilized to fight tumors, especially when combined with immunotherapies that require a strong and activated immune system. Immunotherapies are revolutionizing the treatment of many cancers. Immune checkpoint blockade therapies (ICBT) have been remarkably effective in several cancer types including metastatic melanoma and non-small cell lung cancer, with durable responses in 20%-40% of patients. These treatments target pathways that put the brakes on the immune system, thereby unleashing anti-tumor immunity. These successes exemplify the power of the immune system against malignancies. However, ongoing clinical trials suggest that although some breast cancer patients may also benefit from ICBT, the percentage of responders is low compared to melanoma and lung cancer patients. In fact, most breast cancers are considered immunologically cold, i.e., lacking recognition by immune cells and not expressing enough proteins that are foreign to the immune system. Importantly, targeting RNA splicing may hold the potential to engage the immun
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210866
Entities
People
- Thomas Westbrook
Organizations
- Baylor College of Medicine
- United States Army