From Cold to Hot: Leveraging RNA Splicing Therapeutics to Unleash Antitumor Immunity for Breast Cancer Patients
Abstract
This application aims to address the overarching challenges to (1) revolutionize treatment regimens by replacing them with ones that are more effective and 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 splicing gene transcription products, which lead to activation of antitumor immune responses. We propose to leverage these mistakes to stop breast cancer growth and eliminate metastasis. The majority of human genes are not encoded by continuous stretches of DNAs. Instead, segments that encode gene products are separated by those that do not encode. A process called "splicing" is required to remove the non-encoding parts of the gene and connect the coding segments before a continuous RNA can form and be translated to the final protein. Normal cells can well tolerate splicing mistakes. Cancer cells, especially triple-negative breast cancer (TNBC) cells driven by certain oncogenes such as MYC, are much more sensitive, providing opportunities to selectively eliminate TNBC cells. Importantly, we have recently discovered that drugs that partially inhibit splicing can have a dramatic impact on TNBC tumor progression and sometimes cause complete tumor regression. Mistakes in splicing can result in aberrant RNA sequences. Our preliminary studies indicate that these aberrant RNA sequences may trigger two different responses. First, these RNAs tend to form double strands, a structure that mimics some viruses. As a result, they can stimulate cells antiviral defense, which has evolved to cause death of affected cells, and enhance the entire organism s immune system including T cells and NK cells. This can result in selective tumor cell killing. Second, some of the aberrant RNAs may be translated into aberrant proteins. Because these proteins are different from existing human proteins, they may be recognized as foreign and stimulate further immune reactions. Interestingly, both outcomes may be effectively utilized to fight tumors, especially when combined with immunotherapies that require a strong and activated immune system. It should be noted that drugs targeting splicing show significant impact on TNBC in preclinical models and thus far are well-tolerated in patients. 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 lune cancer. These treatments target negative regulators of the immune system, thereby unleashing antitumor immunity. Durable responses are reported in 20%-40% of patients with limited toxicity. 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 remarkably from ICBT, the percentage of responders is disappointingly low as compared to melanoma and lung cancer patients. In fact, most breast cancers are considered immunologically "cold," i.e., lacking infiltration of immune cells and not expressing enough proteins that are "foreign" to the immune system. Intriguingly, targeting splicing holds the potential to improve the efficacy of immunotherapy by enhancing the immune system in general and by triggering expression of more foreign proteins. Our preliminary study provides strong evidence supporting this hypothesis. In this application, we will further explore this possibility. Importantly, we will evaluate a clinical grade splicing inhibitor. This inhibitor (H3B-8800) has already been granted orphan drug status for acute myelogenous leukemia/chronic myelomonocytic leukemia (AML/CMML) patients. We will apply this inhibitor to a broad range of patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs)
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810573
Entities
People
- Thomas Westbrook
Organizations
- Baylor College of Medicine
- United States Army