Inhibition of Noncanonical NF-kappaB for Treatment of Ovarian Cancer
Abstract
Rationale and Objective: There are numerous studies suggesting that NF-kappaB signaling is important for the survival and progression of cancer. However, there are actually two NF-kappaB signaling pathways: the canonical (well-studied and important for acute inflammation and immune responses) and the non-canonical NF-kappaB pathway (nc-NF-kappaB), which is understudied and whose roles are not understood. A few studies, including our own recent publication in the context of ovarian cancer, have reported that high levels of nc-NF-kappaB signaling are found in human and mouse tumors and tumor cell lines, suggesting that this pathway may contribute to disease. However, it remains unclear how nc-NF-kappaB contributes to cancer progression. This is an extremely important question because demonstrating that nc-NF-kappaB activity is supportive of ovarian tumors would identify it as a completely new therapeutic target. Our objective is to provide evidence that inhibiting the non-canonical pathway is a new treatment strategy and to test two potential translational approaches. Critical Problem: The current options for treatment of ovarian cancer are limited and resistance and recurrence are significant challenges; thus, new therapies are an urgent need. The potential for inhibition of canonical NF-kappaB has long been recognized due to its effects on tumor cells, but translation of these approaches into the clinic has proved disappointing. We believe that this is due to the immune-suppressive effects that occur in a patient as the canonical inhibitors suppress the antitumor effects of macrophages. The potential impact of modulating the tumor microenvironment is great, but a clear understanding of interactions is needed to achieve overall therapeutic outcomes. We propose that the different approach of specific inhibition of nc-NF-kappaB will achieve both limitation of tumor growth and decrease of the immune-suppressive effects of macrophages. Proposed Research: Our preliminary data suggest that increased nc-NF-kappaB may instruct macrophages to display pro-tumor functions that support progression of disease. We have made a new mouse model that enables regulatable increases in nc-NF-kappaB in macrophages and will combine these with established models of ovarian tumor progression to provide evidence that nc-NF-kappaB in macrophages results in pro-tumor cells and, thus, that nc-NF-kappaB is a therapeutic target for inhibition. While this will provide significant insights in basic biology, our main focus is to develop new treatment options; thus, we will perform studies investigating two interventions with potential clinical applicability. The first is treatment with a small peptide called SN52 that is designed to specifically inhibit non-canonical NF-kappaB signaling. The potential of similar strategies is being recognized and peptides are commercially available. The second is use of nanoparticles that will deliver a nucleic acid inhibitor of non-canonical signaling directly to tumor-associated macrophages. We have developed and tested this delivery system in other contexts; others are developing nanoparticle delivery systems, some of which have reached patient trials, and the ability to modify macrophage functions in the tumor microenvironment is accepted as having major therapeutic potential. Therefore, we selected these approaches for potentially rapid translation into clinical usage. Relevance to Vision and Mission: We will answer critical questions: (1) Is the nc-NF-kappaB pathway a major contributor to cancer progression and thus an unrecognized target for novel therapy? (2) Can interventions alter interactions between tumor cells and those of the immune system resulting in inhibition of tumor progression or, ideally, eradication of tumor cells? Preclinical evidence that the nc-NF-kappaB pathway is a target for treatment and that specific inhibition can be achieved via the proposed approach
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210308
Entities
People
- Fiona E. Yull
Organizations
- United States Army
- Vanderbilt University