Novel agents for B-cell non-Hodgkin lymphoma: science and the promise

Abstract

There has been tremendous insight gained in the last two decades from basic science research. New molecular targets in neoplastic cells are emerging and provide the rationale for clinical development of novel agents in non-Hodgkin lymphoma. These novel agents can be broadly categorized into two groups. The first is by immunotherapy which includes novel monoclonal antibodies and immunomodulating drugs, which takes advantage of or optimizes immune system function. The other group of drugs target small molecules that may play an important role in tumorigenesis. The mechanisms of anti-tumor activity include targeting apoptotic pathways, inhibition of proteasomes, mammalian target of rapamycin (mTOR), cyclin-dependent kinases and histone deacetylases. The purpose of this review is to focus on these novel agents and the various treatment approaches that are currently being evaluated in non-Hodgkin lymphoma.

Fig. 1.

B-cell antigen targets.

Fig. 2.

Blockade of the NF-κB pathway in ABC DLBCL by bortezomib. NF-κB is regulated by members of the IκB family of inhibitors, principally IκBα, which binds to NF-κB dimers and retains them in the cytoplasm. In response to a wide variety of external signals, IκB is phosphorylated by the IKK complex, IκBα is then targeted for ubiquitination and proteasomal degradation. NF-κB is released and translocates to the nucleus, where it activates antiapoptotic and cell-proliferation genes. The stabilization of IκB through proteosome inhibition therefore prevents NF-κB activation.

Fig. 3.

Study schema. Patients initially received bortezomib alone at 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days (Part A) unless they had disease that the investigators judged to require immediate chemotherapy, as in cases of impending or ongoing organ compromise; these patients received only Part B. Patients with progressive disease in Part A later received bortezomib with DA-EPOCH (Part B). Molecular classification. Of 31 DLBCL cases analyzed by gene expression profiling, 16 were excluded due to ineligible subtype by classification or did not receive Part A, leaving 5 ABC and 10 GCB cases eligible for analysis of outcome. Of 24 paraffin embedded tumor biopsies analyzed by immunohistochemistry, 12 of each were categorized as GCB and ABC type.By combining both methods, cases were identified as GCB in 15 and ABC in 12 and included in the analysis of outcome with Part B.

Fig. 4.

Overall survival in patients with DLBCL. (A) Overall survival of 31 patients with de novo DLBCL who received DA-EPOCH-B. With a median potential follow-up of 49 months, the median survival was 8 months. (B) Overall survival of 27 patients with ABC or GCB DLBCL who received DA-EPOCH-B showed a median survival of 10.8 and 3.4 months, respectively (P = 0.0026).

Fig. 5.

On receipt of a death signal, the multidomain pro-apoptotic proteins Bax and Bak are oligomerized and activated, leading to mitochondrial outer membrane permeabilization. Once the mitochondrial membranes are permeabilized, cytochrome c is released into the cytoplasm and activates the caspase cascade, resulting in apoptosis. Anti-apoptotic Bcl-2 family proteins inhibits the release of cytochrome c by blocking activation of Bax and Bak. BH3-only proteins, which acts upstream of Bax and Bak, selectively binds with anti-apoptotic Bcl-2 family proteins to relieve their inhibition of Bax and Bad^– (Used with permission from Abbott Laboratories).

Fig. 6.

Histone deacetylase inhibitors can induce transformed cell growth arrest and death by different pathways. HDACs – histone deacetylases; HIF-1α – hypoxia induced factor-1α; HSP90 – heat shock protein 90; PP1 – protein phosphatase; ROS – reactive oxygen species; TBP2 – thioredoxin binding protein 2; Trx – thioredoxin; VEGF – vascular endothelial growth factor.