XPO-1 as a novel therapeutic target in GATA-3 expressing mature T-cell lymphomas
Ryan Wilcox
PhD, MDRegents of the University of Michigan
Project Term: October 1, 2021 - September 30, 2024
GATA-3 identifies high-risk subtypes of mature T-cell lymphomas (MTCL), as its target genes, which we have systematically identified, have significant cell-autonomous and non-cell-autonomous (by regulating constituents of the tumor microenvironment) roles in these MTCL. As our preliminary data suggests that XPO-1 inhibition is a novel, and largely unexplored, therapeutic strategy in these MTCL, we will examine its cell-autonomous (Aim #1) and non-cell-autonomous (Aim #2) role in GATA-3+ MTCL.
Most patients afflicted with the more common aggressive non-Hodgkin’s lymphomas (NHL) are cured with modern chemotherapy regimens. Unfortunately, a less common group of aggressive NHL (i.e. the “T-cell lymphomas”) is resistant to similar chemotherapy regimens, explaining why most patients with these lymphomas will experience disease recurrence following treatment. We have demonstrated that an important regulatory protein (i.e. GATA-3) is highly expressed in the most common T-cell lymphoma subtype in North America. This protein, by binding DNA, regulates the expression of genes that promote the growth and survival of malignant T cells. Therefore, GATA-3 has emerged as a novel, and largely unexplored, therapeutic target in these aggressive NHL. A specialized “gatekeeper protein” transports select gene messengers across the nuclear membrane, and we have shown that this gatekeeper selectively transports a substantial subset of GATA-3 dependent messengers. Therefore, pharmacologic inhibition of this gatekeeper represents a novel strategy to indirectly target GATA-3, and will be investigated. Whereas conventional cancer treatments directly target the cancer cell (the “seed”), many novel and emerging cancer therapies are targeting constituents of the local environment (the “soil”), and cells of the immune system are chief among those constituents of the environment being targeted. We are particularly interested in targeting a cell type (called macrophages) that often function as the immune system’s clean-up crew, but directly (and indirectly) promote the growth and survival of malignant T cells. Current dogma suggests that macrophages are entirely dependent on a specific factor (a cytokine, called CSF-1) for their survival. Macrophages express on their surface a specific receptor for this factor (called CSF-1 Receptor), and this receptor is currently the target for various therapeutic strategies seeking to deplete cancer-associated macrophages. Studies in a variety of cancer models demonstrate that macrophage depletion bolsters anti-tumor immunity and suppresses tumor growth, and these strategies to deplete macrophages by targeting CSF-1 Receptor are either FDA-approved in some cancers or the subject of ongoing clinical trials in others. However, our work challenges the current paradigm, as our preliminary data demonstrates that malignant T cells produce alternative factors that promote the growth and survival of macrophages, and confer resistance to CSF-1 Receptor-directed therapies. In an effort to identify novel therapeutic strategies, we performed a high-throughput screen of ≈200 novel agents and identified a selective inhibitor of the “gatekeeper protein”. Therefore, we will investigate the extent to which this gatekeeper protein, in addition to directly targeting malignant T cells by impairing the expression of GATA-3 dependent genes, indirectly targets lymphoma cells by depleting macrophages within their environment.