Rebalancing STAT1 and STAT3 to Enhance Therapeutic Effectiveness in Patients with TNBC
Abstract
Overarching Challenges: Our studies seek to develop a novel therapeutic for patients with triple-negative breast cancer (TNBC) that will (i) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival and (ii) eliminate the mortality associated with metastatic breast cancer. Our novel therapy is named I-ON (for Interferon-beta fused with OSM-Receptor disrupting Nanobody). The foundation of our approach stems from our longstanding interest in breast cancer-associated cytokines, which are proteins produced by tumor or immune cells. Some of these cytokines are associated with poor patient outcomes; others are associated with good patient outcomes. Preventing OSM-Receptor Activation: One of the “bad” cytokines associated with poor patient outcomes is named OSM (Oncostatin M), which activates a cell surface OSM-Receptor (OSMR). When OSM binds OSMR on cancer cells, it activates a molecular program that gives the cells a greater chance of becoming resistant to chemotherapy and metastasizing. In addition, OSMR activation on cells of the immune system changes them in two important ways: (i) by preventing the immune cells from recognizing and destroying cancer cells and (ii) by inducing the immune cells to secrete addition factors that can further support therapy resistance and metastasis. The current proposal will take advantage of our understanding the molecular mechanisms that OSM uses to promote these bad activities; we will create a novel OSMR-targeting “nanobody.” This nanobody (which will have similarities to other therapeutic antibodies, such as Herceptin) will prevent OSM from binding to OSMR on cancer cells and immune cells. If OSM cannot bind to its receptor, molecular programs responsible for sustaining the cancer cells’ aggressive behaviors will be turned off. This approach will reprogram both the cancer cells and the immune cells so that they behave like the cells in tumors that respond well to current therapies. Activating Interferon-beta signaling in tumor and immune cells. In contrast to OSM, Interferon-beta (IFN-beta) is associated with good patient outcomes. When IFN-beta binds to its receptor on cancer cells, it activates a molecular program that reduces the cells chance of becoming resistant to chemotherapy or metastasizing. Moreover, IFN-beta induces the immune system to become more active, resulting in favorable responses to chemotherapy. While IFN treatment is currently approved to treat some cancers (hematological malignancies and melanoma), the high doses of IFNs needed for the therapy to work induces side effects that limit its effectiveness. Here, we propose to link IFN-beta with the OSMR targeting nanobody described above. Since OSMR expression is generally restricted to pathological diseases such as cancer, the fusion of IFN-beta with the OSMR targeting nanobody would concentrate its effect to the cells within the tumor. By delivering IFN-beta directly to the cancer cells and immune cells within the tumor, we can limit the side effects. Impact: The development of our I-ON therapy is an innovative, high-risk/high-reward effort with the potential to make a major impact toward ending breast cancer. The impact would be near term and well beyond a minor advancement. Upon production, optimization, and testing the I-ON therapeutic in the proposed studies, all reagents would be in hand to expand production for clinical trials. For patients with TNBC, we envision multiple potential uses for I-ON, which include: (i) as a pre-treatment before chemotherapy, to reverse the molecular programs responsible for resistance to chemotherapy and boost tumor immunity; (ii) as a co-therapy with current chemotherapy to prevent cancer cells from reprogramming themselves in response to chemotherapy, which allows them to survive; and (iii) as a post-chemotherapy treatment to boost tumor immunity and prevent residual tumor cells from acquiring m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010464
Entities
People
- Mark Jackson
Organizations
- Case Western Reserve University
- United States Army