Precision Therapy of Lymphoma Inspired by Functional and Structural Genomics

Precision Therapy of Lymphoma Inspired by Functional and Structural Genomics

Louis M. Staudt, M.D., Ph.D.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous diagnostic category that is comprised of two prominent molecular subtypes, termed activated B cell-like (ABC) and germinal center B cell-like (GCB).  We defined a “chronic active” form of B cell receptor (BCR) signaling that activates NF-kB and sustains ABC DLBCL viability.  Over one fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR that augment BCR signaling.  To attack chronic active BCR signaling therapeutically, we initiated clinical trials in relapsed/refractory DLBCL of ibrutinib, an irreversible and highly selective inhibitor of BTK.  Ibrutinib monotherapy induced a high rate of complete and partial responses in ABC DLBCL, while GCB DLBCL tumors rarely responded.  Genetic analysis of responding tumors demonstrated enrichment for those with CD79B mutations, but most responses were observed in tumors with wild type BCR subunits.  This observation allowed us to define a non-genetic mechanism of BCR activation that depends on reactivity of the lymphoma BCR to self-antigens.   We have also defined other oncogenic signaling pathways in ABC DLBCL that cooperate with BCR signaling to sustain cell survival, including the MyD88 pathway, which is activated by oncogenic MYD88 mutations in ~40% of cases.  Tumors with both MYD88 and CD79B mutations respond frequently to ibrutinib, highlighting the functional cooperation between the MYD88 and BCR pathways.  To extend the efficacy of ibrutinib in ABC DLBCL, we have identified additional therapeutic targets that regulate oncogenic signaling in this lymphoma subtype including: 1) ubiquitin ligases, such as LUBAC, 2) the MYD88-associated kinase IRAK4, 3) the PI(3) kinase pathway, 4) the BET proteins BRD4 and BRD2, which control IkB kinase activation of NF-kB, and 5) BCL2.  Several synergistic, mechanism-based drug combinations that exploit these redundant survival pathways will be discussed.