Novel therapeutics for aggressive non-Hodgkin's lymphoma

Abstract

Application of advances in genomic and proteomic technologies has provided molecular insights into distinct types of aggressive B- and T-cell non-Hodgkin's lymphomas (NHLs). This has led to the validation of novel biomarkers of classification, risk-stratification, and druggable targets. The promise of novel treatments from genomic research has been slow to materialize because of the lack of a therapeutic signature for the distinct NHL subtypes. Patients with lymphoma with aggressive disease urgently require the development of novel therapies on the basis of investigation of dysregulated intracellular oncogenic processes that arise during lymphomagenesis. Although monoclonal antibodies have made significant contributions to the armamentarium of B-cell NHL therapy (eg, anti-CD20), parallel development of small-molecule inhibitors (SMIs) to intracellular targets has lagged behind. Despite these deficiencies, several promising anti-NHL therapies are in development that target immune kinases of the B-cell receptor signaling pathway, mammalian target of rapamycin complex, proteasome, DNA/histone epigenetic complex, antiapoptosis, neoangiogenesis, and immune modulation. This review focuses on novel SMI therapeutic strategies that target overlapping core oncogenic pathways in the context of the 10 hallmarks of cancer. Furthermore, we have developed the concept of a therapeutic signature using the 10 hallmarks of cancer, which may be incorporated into novel phase I/II drug development programs.

Fig 1.

Targets and therapies for B-cell non-Hodgkin's lymphoma (B-NHL) within the context of the 10 hallmarks of cancer and overlapping oncogenic signaling pathways. (A) B-cell antigen receptor (BCR) composed of membrane immunoglobulin and associated Igα/Igβ (CD79a/CD79b) when bound to antigen (Ag) leads to BCR aggregation, while the α-β heterodimer transduces signals that rapidly activate Src family kinases Lyn (Blk and Fyn) and immediate downstream tyrosine kinases spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), initiating a complex signaling cascade involving multiple adaptors, protein kinases, phosphatases, GTPases, and transcription factors that result in distinct consequences, including differentiation, survival, apoptosis, proliferation, and tolerance. Negative feedback loops that regulate BCR signaling (Lyn/CD22/Shp-1 pathway, SHIP, Cbl, Dok-1, Dok-3, FcγRIIB1, PIR-B, and BCR internalization) are not included in figure. In aggressive B-NHL, uncontrolled activation and proliferation of B-cells resulting from chronic active BCR signaling have been targeted and include (1) Syk (fostamatinib), (2) Btk (PCI-32765), (3) protein kinase C beta (PCKβ; enzastaurin), and (4) mammalian target of rapamycin (mTOR; temsirolimus, everolimus, deferolimus), highlighted in green with red inhibitor sign. Therapeutic targets in orange with red inhibitor sign with question mark are targets in B-NHL for which drugs are or may be available for evaluation in clinical trials. The aberrantly activated nuclear factor kappa B (NF-κB) pathway has been targeted by overwhelming stress response by inhibiting (5) proteasome (bortezomib). Insensitivity to growth inhibitory signaling by epigenetic modulation has been evaluated by blocking (6) histone deacytelace (vorinostat, mocetinostat). Targeting other epigenetic enzymes such as DNA methyltrasferase (DNMT) is of interest, particularly as combinations. Agents promoting apoptosis (7) BCL2/BCLX_L (ABT263) have entered clinical trials with promising activity. (B) Limitless replicative potential can be halted by inhibiting cell-cycle kinases (8) G1-S-G2 phase (cyclin-dependent kinases, checkpoint kinases) and (9) M phase (Aurora A/B). (C) Key hallmarks in the extracellular-stromal compartment critical for targeted therapies include (10) immune evasion (lenalidomide; inhibits T regulatory cells [Tregs]), invasion, and metastasis; neo-angiogenesis (bevacizumab, vascular endothelial growth factor receptor/platelet-derived growth factor receptor tyrosine kinase inhibitors); cytokines (AMD3100); and tumor-stroma interactions. BCAP, B-cell adaptor for phosphatidylinositol 3-kinase; PI3K, phosphoinositide 3-kinase; PLCγ2, phospholipase C gamma 2; BLNK, B-cell linker; GRB2, growth factor receptor-bound protein 2; LAB, linker of activated B cells; SOS, son of sevenless; CARMA1, Caspase recruitment domain–containing membrane-associated guanylate kinase protein 1; MALT, mucosa-associated lymphoid tissue; IKK, IκB kinase; TSC2, tuberous sclerosis protein 2; Me, methyl; His, histone; HDAC, histone deacetylase acetylation.