Emerging therapeutic options

DLBCL remains the most common NHL

• The focus of new research in DLBCL is to improve the cure rate, particularly in poor risk patients¹⁰
  • Key areas of research include optimizing combinations of older and newer agents and the sequencing of specific therapies⁵⁹

Potential new molecular targets in designing treatments for DLBCL

• Gene expression profiling, insights into molecular pathogenesis, and improvements on existing therapies have fostered the identification of a number of molecules and signaling pathways that are implicated in the pathogenesis of DLBCL (Table 10). These advances have led to the identification of potential therapeutic targets in the treatment of DLBCL⁴⁵

Table 10. Emerging therapeutic approaches in DLBCL (as of June 2010).^60-62

Targets under investigation

mAbs as a therapeutic approach

• mAbs target antigens that are preferentially or exclusively expressed on the surface of B cells⁶³
• Antigen targets under investigation for DLBCL include CD19, CD20, and CD22, among others^61,63
• In preclinical studies, mAbs have been shown to induce cytotoxicity through 1 or more of the following proposed mechanisms: antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis or direct cell death, and complement-dependent cytotoxicity (CDC)⁶⁴
  • ADCC occurs when mAbs attract immune-effector cells, such as natural killer cells, which recognize and kill antibody-labeled target cells⁶⁴
  • Some mAbs have been shown to trigger an intracellular signal when bound to their target antigens on the cell surface, resulting in apoptosis or direct cell death^65,66
  • CDC requires recruitment of the complement cascade. The result of this cascade is that complement proteins ultimately penetrate the cell membrane, and this leads to the lysis of the target cell⁶⁴

CD19

• CD19 is a cell surface molecule that positively regulates antigen receptor signal transduction in mature B cells⁶⁷
• CD19 and CD21 form a receptor on B cells and various B-cell lymphomas including NHL⁶⁸
• Anti-CD19 immunotoxin conjugated with ricin A chain has been described in clinical literature, as well as a nonfucosylated anti-CD19, bispecific antibodies, and an Fc-engineered anti-CD19 mAb^60,68-70

CD20

• CD20 is expressed specifically on B cells during most stages of B-cell development, but is absent in stem cells, plasma cells, and cells of other hematopoietic lineages^71,72
• Typically, CD20 is not downregulated or shed upon binding to a mAb^71,72
• Emerging mAbs that target CD20 with novel proposed mechanisms of action are now under investigation in B-cell malignancies^66,73
  • Preclinical studies show that type II antibodies appear to cause higher direct cell death induction and are less reliant on CDC as a mechanism of killing malignant B cells than type I antibodies^66,73 (Table 11)
  • Glycoengineering of the antibody results in stronger FcγRIIIa binding, which enhances ADCC in vitro⁶⁶

Table 11. Characteristics of type I and type II anti-CD20 mAbs as demonstrated in vitro.⁷³

CD22

• CD22 is widely expressed on B cells and may be important in B-cell activation modulation of antigen-receptor signaling and cell-surface–receptor circulation⁶³
• CD22 is a B-cell–specific adhesion molecule that is commonly expressed in NHL and may regulate B-cell receptor (BCR)–mediated signal transduction⁶⁰
• The CD22 target is under investigation both with antibodies and antibody-drug conjugates^69,74,75

CD40

• CD40 is constitutively expressed on immature and mature B cells and is upregulated during activation of B cells^63,76
• Activation of CD40 in cancer cells may induce growth inhibition and sensitization to apoptotic stimuli⁶⁰
• Preclinical studies investigating anti-CD40 mAbs have shown that these mAbs induce apoptosis and ADCC in NHL B cells⁶³

Bcl-2 family

• Bcl-2 is a proto-oncogene located at 18q21 that promotes B-cell survival via inhibition of apoptosis and confers chemotherapy resistance⁴⁵
• Bcl-2 deregulation is most commonly associated with the t(14;18), present in approximately 15% of DLBCLs; however, protein expression can be detected in approximately 50% of DLBCLs, independent of the translocation⁴⁵
• Small molecule inhibitors target the intrinsic apoptosis pathway by inhibiting family members, including Bcl-2, Bcl-X_L, and Mcl-1, and may cause cells to undergo programmed cell death⁷⁷
• For more information about the role Bcl-2 plays in apoptosis, visit www.ResearchApoptosis.com

Histone deacetylase (HDAC)/Bcl-6

• Chromosomal translocations in DLBCL may result in the inappropriate expression of Bcl-6, a transcriptional repressor involved in germinal center formation¹⁵
• Dysregulated constitutive expression of Bcl-6 may lead to maturation arrest and confer a proliferative advantage for B cells⁴⁵
• Furthermore, in DLBCL, acetylation plays a key role in downregulating Bcl-6, with HDAC required to lift this repression⁴⁵
• Pharmacologic inhibition of HDAC with small-molecule HDAC inhibitors in tumors expressing Bcl-6 may lead to inhibition of this anti-apoptotic pathway⁴⁵
• HDAC inhibitors prevent histone deacetylation, thereby maintaining the chromatin in an open structure and promoting transcription of tumor suppressor genes⁷⁸
• These newly expressed tumor suppressor genes may then inhibit tumor cell cycle progression and induce apoptosis of tumor cells⁷⁸

Microenvironmental factors

• Immunomodulatory agents are structural and functional analogs of thalidomide and are currently being investigated in B-cell lymphomas⁷⁹
• While the mechanism of action is unknown, immunomodulators may work by inhibiting tumor necrosis factor alpha (TNF-alpha), targeting angiogenesis, and activating the immune system, primarily T cells and natural killer cells^79,80

mTOR, AKT, and PI3 kinase inhibitors

• The PI3K/AKT/mTOR pathway may play an important role in the development of lymphoma⁸¹
• mTOR is a serine/threonine kinase that controls cell cycle progression and protein translation, and influences the organization of the cytoskeleton⁸²
• This system regulates the expression of cyclin D1 and c-Myc, important factors in cellular proliferation and growth^81,82
• Inhibition of this pathway may be an important strategy in the treatment of lymphoma⁸³

Proteasome

• Proteasomes are complexes within the cell that break up proteins. By inhibiting proteasomes, the degradation of tumor suppressors such as p53 can be prevented^84,85
• Proteasome inhibition has already become the standard of care in the treatment of multiple myeloma and is being investigated in NHLs⁸⁵
• Proteasome inhibitors have been shown to inhibit NFκB activation⁷⁹

Syk

• Recent studies have suggested a role for dysregulation of the tyrosine kinase Syk in B-cell malignancies^83,86,87
• Syk is predominantly expressed in B-cell lines and has been implicated in the signal transduction pathway of the BCR⁸⁷
  • BCR activation results in tyrosine phosphorylation of Syk, which activates the PI3K/AKT pathway and promotes the survival of B cells⁸³
• The suggested role of Syk activity for B-cell survival provides a strong rationale for targeting it therapeutically⁸³
• Preclinical studies have shown that inhibitors that target Syk may induce apoptosis in DLBCL and may inhibit BCR signaling as well^87,88

View References for this site section