Improving Treatment Sensitivity through Syk using Novel Translational Models of Uveal Melanoma

About This Grant

PROJECT SUMMARY/ABSTRACT Uveal melanoma (UM), the most common primary adult intraocular malignancy, is a devastating cancer. Up to 50% of patients will develop metastatic disease with a median overall survival of <2 years. Despite extensive sequencing efforts, genomic studies of UM have failed to identify new treatment targets. Thus, novel approaches must be used to improve therapeutic efficacy for UM and prolong survival for patients with this dismal, understudied condition. A hallmark feature of aggressive UM is the loss of expression of BAP1 (BRCA1 associated protein 1), the single most consistent alteration associated with UM-related death. BAP1 is a deubiquitinating enzyme with known function in DNA damage repair, and while poly ADP ribose polymerase (PARP) inhibitors have been of interest for BAP1 deficient cancers to capitalize on their dysfunctional DNA damage repair system, clinical trials have failed to show good efficacy. Our data identified Syk as a target to sensitize UM to PARP inhibitors. Syk is a non-receptor tyrosine kinase with tumor suppressor function in some cancers and proto-oncogene function in others. Our preliminary data showed Syk upregulation in UM compared to benign melanocytes, which was greater in high-risk UM with BAP1 loss. Following these data, treatment of UM cells with Syk inhibitor improved therapeutic sensitivity to PARP inhibitors. It is our central hypothesis that Syk upregulation in UM contributes to treatment resistance and can be targeted to improve therapeutic response. We will address this hypothesis using novel models that fulfill an unmet need in UM research, including one-of-a-kind UM patient-derived organoids (PDOs) and disease-relevant orthotopic xenografts, which demonstrate progression to liver metastasis. In AIM 1 we will define the role of Syk in UM treatment response using PDOs. To explore PARP inhibitor response dependency on Syk, we will evaluate treatment response to Syk and PARP inhibition alone and in combination in a large cohort of PDOs and, separately, in Syk knockdown cell line models (Sub-AIM 1A). We will define the mechanisms associated with UM treatment response to PARP and Syk inhibition by studying DNA damage and replication stress (Sub-AIM 1B). In AIM 2 we will define the in vivo efficacy of Syk inhibition to improve PARP inhibitor response in UM. We will use PDO-generated xenograft models simulating human metastatic progression to determine the therapeutic efficacy of combination Syk and PARP inhibition for metastatic UM. Successful outcome of this proposal will fill a key knowledge gap for UM by investigating a novel therapeutic strategy, Syk inhibition, to improve treatment response. Experiments will include subanalysis by UM BAP1 status, which is of critical importance given that tumors with BAP1 loss are most likely to metastasize. The use of novel, more representative models of human disease, including PDOs and PDO-generated orthotopic xenografts, will improve the likelihood of successful translation of these findings. Together, these results will support future development of clinical trials using personalized medicine approaches to improve survival for patients with UM.