Rational combinations of enzastaurin with novel targeted agents for patients with B-cell non-Hodgkin's lymphoma

Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignant neoplasm in adults. Combination chemotherapy regimens have been the main-stay of treatment for NHL for several decades. In the 1990s, the introduction of rituximab marked the beginning of the era of immunotherapy with monoclonal antibodies and revolutionized the treatment of B-cell NHL (B-NHL). Chemotherapy combined with anti-CD20 monoclonal antibodies has improved survival in both indolent and aggressive B-NHL; this combination has become the standard of care for these patients. However, a substantial subset of patients does not achieve a cure or long-term disease remission. In recent years, advances in the knowledge of NHL biology have improved our understanding of cell growth, proliferation and cell death in malignant cells. This has promoted the identification of new targeted treatments and new agents that have shown promising efficacy for future B-NHL therapies. Protein kinase C beta (PKC-b), a serine/threonine kinase, is involved in several signal transduction pathways, from differentiation and cell growth to survival and cell migration. It has been shown that PKC-b isoverexpressed in 20-25% of diffuse large B-cell lymphomas (DLBCLs) at diagnosis and 90% of DLBCLs at relapse. Therefore, PKC represents a potential targeted therapy for lymphomas. Enzastaurin (LY317615.HCl), an acyclic bisindolylmaleimide,is one of several new molecules directed against PKC-b. Enzastaurin is an ATP-competitive selective inhibitor of PKC. Enzastaurin suppresses the phosphoinositide 3-kinase (PI3K)/acutely transforming retrovirus (AKT) pathway,which blocks the phosphorylation of glycogen synthase kinase 3 beta (GSK3-b), mammalian target of rapamycin (mTOR) and ribosomal protein S6. It also suppresses cyclin D1 synthesis, induces dephosphorylation of p90 and ribosomal S6 kinase (RSK), regulates the MAPK pathway and seems to be involved inthe interferon-regulated JAK/STAT pathways. Furthermore, it affects BAD, a pro-apoptotic member of the Bcl-2 family proteins, which is particularly important in lymphoma.Based on promising preclinical results and the good tolerability profile, enzastaurin has been introduced in clinical trials as a treatment for patients. Enzastaurin has been used alone or in combination with other agents in more than 40 clinical trials (source: www.clinicaltrials.gov), and 9 of these focused on indolent or aggressive NHL.....