Developing new drugs for the treatment of lymphoma

Abstract

Despite the great progress that has been made over the last several decades in the treatment of lymphoma, the prognosis for patients with relapsed disease, and particular sub‐types of lymphoma like mantle cell and T cell lymphoma, remains quite poor. While major advances in the use of combination chemotherapy, monoclonal antibodies, peripheral blood stem cell transplants, and radioimmunotherapy, have provided new opportunities to alter the natural history of these diseases, and even improve cure rates among elected sub‐populations of patients, these ‘traditional‘ approaches have not benefited all patients, or sub‐types of lymphoma. The incredibly rapid pace of understanding the molecular basis for the discrete sub‐types of both non‐Hodgkin's lymphoma and Hodgkin's Disease is beginning to afford exciting new opportunities to both risk stratify patients, and to identify potentially novel ‘drugable’ targets. These advancements in understanding the major molecular defects in lymphoma, have provided a new context in which we can rethink the use of new and old drugs, and design new ones with unique mechanisms of action. The panoply of new targets and drugs now becoming available for the treatment of lymphoma is truly daunting. A plethora of new small molecules that target bcl‐2, mTOR, histone deactylases, and NF‐kB have shown promising preclinical activity, and are now promising early phase activity. In many cases, the empirical observations from early clinical trials have provided invaluable clues to potentially valuable drugs like bortezomib, depsipeptide, and SAHA, These empirical observations, based on the inclusion of patients with lymphoma on these studies, have thus far proven to be as or more valuable than any other ‘rational’ target based approach. In addition, beyond the novel small molecules affecting unique and heretofore unrecognized biological pathways, there continues to be a robust and important effort to identify new derivatives of older generation drugs with hopefully better activity, and less toxicity. For example, new generation anthracenediones and anti‐folates, and new formations of older drugs like doxorubicin, irinotecan, and vincristine afford new opportunities to favourably change the pharmacokinetic profile of these agents, and improve their overall safety profile. While it would not be possible to address each and every new such drug, we hope to touch on some of the major new themes and agents emerging for the treatment of Hodgkin's Disease and non‐Hodgkin's lymphoma.

Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)

“…10 Vorinostat (Zolinza [Merck, Whitehouse Station, NJ], suberoylanilide hydroxamic acid, SAHA) is an orally bioavailable inhibitor 11 of class I and II HDACs. 12 In preclinical studies, vorinostat has been shown to cause accumulation of acetylated histones and to induce cell-cycle arrest and apoptosis in a broad range of cancer cell lines, including CTCL lines. 12,13 Vorinostat also showed antitumor activity at in leukemia, lymphoma, and solid-tumor models in vivo.…”

“…12 In preclinical studies, vorinostat has been shown to cause accumulation of acetylated histones and to induce cell-cycle arrest and apoptosis in a broad range of cancer cell lines, including CTCL lines. 12,13 Vorinostat also showed antitumor activity at in leukemia, lymphoma, and solid-tumor models in vivo. [14][15][16][17][18] Phase 1 trials to evaluate the safety and activity of vorinostat were conducted in patients with advanced solid and hematologic malignancies, including CTCLs.…”

Pathogenesis and therapy of cutaneous lymphomas – Progress or impasse?

“…In leukemias, HDACs have been linked to the activity of translocated oncoproteins and the suppression of gene expression necessary for normal differentiation (54). Suberoylanilide hydroxamic acid (SAHA) and the cyclic peptide, depsipeptide (FR‐901228), belong to the group of histone deacetylase inhibitors (55). They present challenging therapeutic compounds for patients with both solid tumors and (extra)nodal lymphomas.…”

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

“…Since NF-κB plays a central role in the regulation of various gene expression involved in cell survival, apoptosis, carcinogenesis, and infl ammation, this molecule has been regarded as a very potential therapeutic target for many cancers (Baud and Karin, 2009). Bortezomib, a tripeptide with pyrazinoic acid, phenylalanine, and leucine with boronic acid, is a proteasome inhibitor that hinders activation of NF-κB by inhibiting cytoplasmic IκBα degradation (O'Connor, 2005). In preclinical studies, it inhibited proliferation of HL cell lines, and induced cell cycle arrest as well as apoptosis (Adams, 2003;Zheng et al, 2004).…”