Attacking the Tumor Cell-Immune Milieu Interface to Overcome Richter's Transformation - Abstract The ability of cancer cells to progress and transform to more aggressive disease is the leading cause for failure of cancer-directed treatment. This is the case in Richter’s transformation (RT), a devastating complication of chronic lymphocytic leukemia (CLL). RT is associated with an overall survival less than 12 months. While standard chemotherapy results in potent but transient cytolytic effects, novel targeted agents such as ibrutinib are ineffective. The early promise of immunotherapy in RT (checkpoint inhibitors, T cell engagers) brings hope to combinatorial targeted and immune therapy. This requires comprehensive understanding of the intrinsic cellular pathways and extrinsic immune environment which coordinately drive CLL-to-RT transition. However, lack of in vitro or in vivo models and limited understanding of the disease mechanism are the bottlenecks for studying RT biology and designing better treatments. To address this challenge, we focused on first building the resources to study this deadly malignancy. Wang laboratory recently established a novel murine model that mimics CLL-to-RT transition based on silencing of Mga to activate MYC pathway in an existing murine CLL model. Characterization of murine model revealed significant metabolic changes during CLL-to-RT transition that are dependent on MYC and its target gene, NME1. MYC is known to promote lymphomagenesis via driving oncogenic transcriptional programs and modulating immune cells to promote lymphomagenesis. We demonstrated that targeting MYC via cyclin- dependent kinase-9(CDK9) inhibitor is effective in a murine model of RT. Furthermore, Danilov laboratory developed clinical trials (NCT03884998, NCT05168904, NCT03547115, NCT05665530) to examine combination inhibitors to treat RT. Preliminary results revealed favorable response with downregulation of MYC pathway in tumor cells and induction of the inflammatory immune environment. We hypothesize that definitive therapies for RT can be achieved by concurrent targeting of intrinsic oncogenic pathways and modulation of the immune milieu. Combined our expertise from disease mechanism (Wang) and clinical/translation research (Danilov), we propose to determine MGA/MYC/NME1 regulatory axis in driving CLL-to-RT transition via impacting cell-intrinsic properties (Aim 1) and extrinsic immune cell function (Aim 2), with a goal of exploiting novel immunotherapy modalities using our newly established murine RT model and clinical samples from ongoing clinical trials of immunotherapy and CDK9 inhibitors in RT and lymphoma. Altogether, the proposed studies serve to decode key oncogenic pathways and characterize the immune cells co-driving RT, reveal vulnerabilities and identify novel strategies to engage anti-tumor immunity, which is anticipated to help the design of the next generation therapeutic approaches to conquer RT.
