Drug Targets for Lymphoma

Drug Targets proteasome for Lymphoma Cancer with Approved Drugs

Drug targets Cancer drugs Company
26S proteasome Bortezomib Millennium Pharmaceuticals, et al.

Naturally occurring and synthetic drugs designed to target the ubiquitin-proteasome system are currently used for hematological cancers, including lymphoma. These drugs largely interfere with the E1 and E2 regions of the 26S proteasome, blocking proteasomal activity and promoting apoptosis by enhancing activities of the extrinsic (death receptors, Trail, Fas) and intrinsic (caspases, Bax, Bcl2, p53, nuclear factor-kappa B, p27) cell death programs. (Suh K S, et al. The role of the ubiquitin proteasome system in lymphoma[J]. Critical reviews in oncology/hematology, 2013, 87(3): 306-322.)

Drug Targets Histone deacetylases for Lymphoma Cancer with Approved Drugs

Drug targets Cancer drugs Company
HDAC1, HDAC2, HDAC3, HDAC4,
HDAC5, HDAC7, HDAC8, HDAC9
Romidepsin Gloucester Pharmaceuticals
vorinostat Merk

Histone deacetylases (HDACs) play an important role in the regulation of gene expression. In addition to histones, HDACs can modulate the function of many other proteins involved in the regulation of cell survival and proliferation, angiogenesis, inflammation, and immunity. Deregulated HDACs have been shown to be commonly associated with many types of cancer, and are considered promising targets for cancer therapy. Several HDAC inhibitors are in clinical trials as monotherapies or in combination with other anticancer agents, but only two such inhibitors -- vorinostat (suberoylanilide hydroxamic acid) and romidepsin (depsipeptide) -- have been approved by the US Food and Drug Administration for treating relapsed cutaneous T-cell lymphoma. Other HDAC inhibitors, such as belinostat (PXD101), mocetinostat (MGCD0103), entinostat (SNDX-275), and panobinostat (LBH589), are currently in clinical development. (Lemoine M, Younes A. Histone deacetylase inhibitors in the treatment of lymphoma[J]. Discovery medicine, 2010, 10(54): 462-470.)

Drug Targets BTK for Lymphoma Cancer with Approved Drugs

Drug target Cancer drugs Company
BTK Ibrutinib Abbvie

Constitutive activation of B-cell receptor signaling appears to be essential for the survival and proliferation of malignant B cells, an observation that has led to the design of inhibitors of B-cell receptor–associated kinases. Bruton's tyrosine kinase (BTK) has been identified as an essential component of the B-cell–receptor signaling pathway. An antigen-driven origin of mantle-cell lymphoma has been suggested, and genomic and expression profiling of samples from patients with mantle-cell lymphoma has identified proteins upstream of BTK, such as the spleen tyrosine kinase Syk, as important contributors to the growth and survival of mantle-cell lymphoma cells.Ibrutinib (PCI-32765) is an oral covalent inhibitor of BTK that significantly reduced the tumor burden in a rodent treatment and prevention model of mantle-cell lymphoma. (Wang M L, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma[J]. New England Journal of Medicine, 2013, 369(6): 507-516.)

Drug Targets P110δ for Lymphoma Cancer with Approved Drugs

Drug target Cancer drugs Company
P110δ Idelalisib Gilead Sciences, Inc.

p110δ is expressed in leukocytes, thymus, and breast tissue, and is essential for B- and T-cell development and B-cell receptor signaling. Mouse embryonic knockout of p110δ is nonlethal but results in a substantial decrease in B cell number and function. As a result, p110δ is preferentially targeted in B-cell malignancies, including many kinds of lymphoma. (Westin JR. Status of PI3K/Akt/mTOR Pathway Inhibitors in Lymphoma. Clinical lymphoma, myeloma & leukemia. 2014;14(5):335-342.)

Drug Targets CD20 for Lymphoma Cancer with Approved Drugs

Drug target Cancer drugs Company
CD20 Rituximab Roche
CD20 Obinutuzumab Genentech
CD20 Ofatumumab GlaxoSmithKline
CD20 Ibritumomab tiuxetan IDEC Pharmaceuticals

The CD20 antigen is restricted to B cells: its expression starts at the pre-B stage of B cell ontogeny and continues until the immunoblast stage; importantly, CD20 is not expressed on either precursor lymphoid cells or in the vast majority of plasma cells. CD20 antigen expression on malignant B cells corresponds to the ontogenetic stage at which the malignancy is assigned: thus, non-Hodgkin's lymphomas (NHL) are CD20-positive in over 90% of cases. Certain characteristics make the CD20 antigen an appealing target for monoclonal antibody therapy; it is present on the surface of mature B cells and has been noted in approximately 93% of patients with B cell lymphoma. (Kosmas C, et al. Anti-CD20-based therapy of B cell lymphoma: state of the art[J]. Leukemia, 2002, 16(10): 2004.)

Drug Targets CD52 for Lymphoma Cancer with Approved Drugs

Drug target Cancer drugs Company
CD30 Brentuximab vedotin Seattle Genetics, Inc.

Initially termed Ki-1, this antigen was clustered as CD30 showing a very strong expression on the malignant cells in Hodgkin's lymphoma. Importantly, only a few activated lymphocytes and eosinophils physiologically express this antigen and there is very little cross-reactivity with vital organs. Shortly thereafter, CD30 was also found on the malignant cells of anaplastic large cell lymphoma (ALCL) and other malignant lymphomas. Brentuximab vedotin (formerly SGN-35), the antibody-drug conjugate consists of a humanized monoclonal antibody targeting CD30 that is linked via a protease-sensitive dipeptide to monomethyl-auristatin-E, a potent cytostatic tubulin inhibitor. Upon binding to the target antigen, brentuximab vedotin is internalized and subsequently degraded within the lysosomal compartment. This mechanism of action explains the high specific potency of this construct, both in preclinical in-vitro models as well as in animals bearing human Hodgkin's and other CD30-positive xenografts. (Engert A. CD30-positive malignant lymphomas: time for a change of management?[J]. 2013.)

Drug Targets PD-1 for Lymphoma Cancer with Approved Drugs

Drug target Cancer drugs Company
PD-1 Nivolumab Bristol-Myers Squibb

PD1 is specifically expressed by germinal center associated T cells in reactive lymphoid tissue and shows a varying distribution in defined lymphadenopathies. It has been shown that the distribution of PD1+ cells in nodular lymphocyte predominant Hodgkin lymphoma is not random but that PD1+ cells form rosettes around the neoplastic B cells in all analyzed cases. It has also been shown that PD1 is a highly specific marker for tumor cells in angioimmunoblastic T cell lymphoma (AITL) and can serve as a diagnostic marker in this entity. PD1 has also been proposed to be expressed and to serve as a diagnostic marker in chronic lymphocytic leukemia (CLL). Finally, there is evidence suggesting a prognostic importance of the amount of PD1positive tumor infiltrating lymphocytes, analogous to other tumor microenvironmental components, like FOXP3 positive tumor infiltrating lymphocytes, in follicular lymphoma (FL) and in classical Hodgkin lymphoma. (Muenst S, et al. Diagnostic and prognostic utility of PD-1 in B cell lymphomas[J]. Disease markers, 2010, 29(1): 47-53.)

Drug targets for Lymphoma cancer: Related Information