Discovery (Lead Identification)
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma and consists of three subtypes: activated B-cell (ABC), germinal center B-cell (GBC), and primary mediastinal B-cell (PMB). Despite advances in the front-line therapy for DLBCL, approximately one-third of patients will relapse. Substantially worse outcomes have been reported for patients diagnosed with ABC DLBCL and treated with standard chemoimmunotherapy, suggesting the need for novel strategies that improve treatment outcomes.
ABC DLBCL cell survival depends largely upon NF-κB signaling being constitutively active. The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB signaling, consists of three proteins (HOIP, HOIL-1L, and SHARPIN), and protects against apoptosis. Inhibiting LUBAC using HOIP and/or SHARPIN peptide inhibitors attenuates LUBAC activity and promotes ABC DLBCL cell death.
LUBAC peptide inhibitors present a new therapeutic strategy for the treatment of ABC DLBCL and could be combined with radiation, chemotherapy, or CAR-T therapy for ABC DLBCL or other cancers. Researchers at the National Cancer Institute (NCI) have developed HOIP and SHARPIN peptides that inhibit HOIP/HOIL-IL (E-035-2013) and SHARPIN/HOIL-IL (E-019-2017) interactions, respectively. Additionally, these peptides could be applied to treat rheumatoid arthritis, chronic autoinflammation, systemic lupus erythematosus, Crohn's inflammatory bowel disease, polyglucosan body myopathy, or psoriasis. The NCI is seeking statements of capability or interest from parties interested in licensing or in collaborative research to co-develop technologies that disrupt NF-B signaling and present new therapeutic strategies for ABC DLBCL and inflammatory disease treatment.