Novel Multi-targeted Strategies Targeting T-cell Lymphomas and their Microenvironment

About This Grant

PROJECT SUMMARY Chemotherapy-resistant disease is frequently observed among the most common T-cell lymphomas (TCL), and few durable responses are achieved with novel agents. Consequently, outcomes are dismal, improved therapeutic strategies are needed, and clinical trial participation remains the “standard of care” for many of these patients. Our own work suggests that the mechanisms promoting treatment failure in the TCL are multifactorial and interdependent, including a “high-risk” genetic landscape, activation of oncogenic transcriptional programs, and the creation of lymphomagenic niches within the tumor microenvironment. These insights have led to the identification of novel therapeutic strategies and targets that are now being investigated in multiple clinical trials. However, the published (and unpublished) experiences with these, and alternative, targeted therapies demonstrate suboptimal rates and durations of response. Collectively, the historical and contemporary experience with targeted therapies suggests that a multitargeted approach will be required to improve survival in high-risk and chemorefractory TCL. The overarching premise for this application is grounded in our prior work demonstrating significant crosstalk between cell-autonomous mechanisms of oncogenesis and the tumor microenvironment (TME), and further, their mutual cooperation in promoting treatment failure. For example, we (and others) have shown that antigen- and costimulation-dependent signaling promotes the growth and survival of malignant T cells and confers their resistance to conventional chemotherapy. Antigen- and costimulation-dependent signaling cascades are propagated by exogenous ligands provided by constituents of the TME, particularly lymphoma-associated macrophages (LAM). We have demonstrated that LAM are transcriptionally polarized by malignant T cells, promote their growth and survival, and are a bona fide dependency in these lymphomas. Therefore, LAM are attractive, yet largely unexplored, therapeutic targets in the TCL. Our preliminary data suggests that malignant T cells and LAM survival are BCL- xL dependent. Therefore, we and our collaborators have developed novel BCL-xL antagonists that will be utilized in complementary and orthogonal PDX and GEM models to address our overarching hypothesis that BCL-xL is a dependency in both malignant T cells and within their TME, and to examine BCL-xL antagonists in rationally designed combinatorial strategies.