Sumoylation As a Novel Target for T-Cell Neoplasms

Despite breakthroughs in our understanding of peripheral T-cell lymphoma (PTCL) through studies such as genetic profiling, this disease has proven to be difficult to manage compared to it B-cell counterparts. There have been few advances in treatment regimens since the initial trials with CHOP-based chemotherapy (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) for many decades. In recent years, there have been more targeted therapies such as Brentuximab-Vedotin, however this is not applicable to most PTCL. Given the persistent poor outcomes in this patient population, novel therapeutic options are needed.

Similar to B-cell lymphomas, a subset of PTCL lymphomas exhibit alterations in cMYC expression. Recent studies have demonstrated a unique susceptibility of cMYC-driven B-cell lymphomas to the inhibition of SUMOylation. SUMOylation is a process of post translational modification (PTM), similar as ubiquitination. However, SUMOylation results in alteration of protein function, rather than explicit changes such as targeting for destruction. Using a recently descript PTCL model, LM-23, which overexpresses cMYC, we found that inhibition of SAE-1/2 with SB-4826, which are necessary for SUMOylation, led to decreased tumor growth in a subcutaneous tumor model, as well as cell death in in vitro models.

Here, we demonstrate a susceptibility of T-cell neoplasms (PTCL and T-lymphoblastic leukemia) to the inhibition of SUMOylation by targeting SAE-1/2 with SB-4826. Using multiple neoplastic T-cell lines, we demonstrate a low micromolar ICI50 for SB-4826 for neoplastic T-cell lines including LM-23 and Jurkat, similar to B-cell lymphoma cells lines. This ICI50 value is significantly lower than non-neoplastic T-cells, suggesting decreased effects on non-neoplastic counterparts of the functional immune system. Additionally, LM-23 tumor bearing mice treated with SB-4826 showed significant reductions in tumor volume compared to CHOP treated mice.

Additional studies on murine and human PTCL and T-ALL cell lines will be presented. While further preclinical studies are necessary, these studies identify SUMOylation as a novel therapeutic target in PTCL and T-ALL, especially cMYC- driven T-cell neoplasms.

Merchant:Innate Pharma: Research Funding; Oncovalent: Consultancy, Research Funding; Genmab: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; BMS: Speakers Bureau; IMMpact Bio: Research Funding; Amgen: Consultancy.