Ovarian Cancer Therapy via Conditional STING Pathway Activation
Abstract
The field of immunotherapy has rapidly advanced in several solid tumor types. However, in ovarian cancer (OvCa), the success has been rather modest to date. Here, we propose a new and improved therapeutic approach aimed at increasing the capacity of the patient’s immune system to fight off and eliminate her tumor. Our focus is on the Stimulator of Interferon Genes (STING), a molecule that is part of the DNA sensing pathway. Normally, this pathway is essential for sensing DNA from infectious agents (like bacteria, viruses, etc.). Once activated, the DNA sensing pathway leads to a series of immune activating events that eliminate the infection. Interestingly, more recent studies demonstrate that the STING-mediated DNA sensing pathway is also important for tumor biology. In cancer, STING activation leads to increased immunity against the tumor cells. This evidence comes from non-OvCa studies, and little is known about the value of this pathway in OvCa patients. Furthermore, the current (non-Food and Drug Administration-approved) drugs that can act as STING activators have several important shortcomings. They do not adequately penetrate the tumor cells and require direct injection into the tumor, an approach that would be challenging in OvCa patients, most of whom present with numerous tumor nodules. When administered systemically, current drugs also trigger significant side effects. We are proposing an innovative drug design that allows for precisely targeted STING activation. Using a chemical approach, we will synthesize three types of new compounds that will: (1) provide target specificity while preventing systemic effects; (2) promote cellular uptake; and (3) avoid the need for intratumor injection. Achieving these goals will have a significant impact on the treatment of OvCa and cancer immunotherapy approaches in general. One of our new compounds will be activated in the tumor environment by light. Irradiation of the tumor will be performed after drug injection, at the time of surgery, via external light sources. When blue light (which is nontoxic) is shown on the tumor, the pro-drug will be activated and will switch inside the cells from an inactive to and an active state. This concept is also used in cardiac pacemakers, as recently reported by researchers in the emerging field of optogenetics. The other two compounds we will generate will be converted into an active state only following processing by tumor-expressed enzymes. One of these enzymes is more abundant in more fibrotic tumors, and the other is present in more platinum-resistant tumors. Both features (fibrosis and drug resistance) are associated with aggressive OvCa, and thus our work will benefit patients in this category. To test the efficacy of all of these new pro-drugs, we will use a series of new animal models that are unique to our group. These mouse models mirror high-grade serous OvCa, the most common type of OvCA. Additionally, our tumor models also express mucin 1 (MUC1), a human tumor antigen that is abundantly expressed in human OvCa. Thus, these experiments will closely reflect the tumor biology seen in patients. Innovation: We will generate fundamentally new STING agonists that provide a highly innovative therapeutic approach. These new compounds will enable localized conditional, rather than uncontrolled, STING activation. We will use new preclinical OvCa models to implement a multi-dimensional experimental approach that takes into consideration three of the most important components of a tumor: cancer cells, immune cells, and stromal fibroblasts. Impact: Our project will spearhead efforts to generate new, selectively activated STING agonists and will test in vitro and in vivo (in versatile animal models) the ability of these drugs to control the disease without unwanted systemic effects. This work will instruct us regarding whether combination immune therapies (with vaccines, immune checkpoint blockers, e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910150
Entities
People
- Anda Vlad
Organizations
- United States Army
- University of Pittsburgh