Genetic and Molecular Targets in Lymphoma
Genetic and Molecular Targets in Lymphoma
The NF-κB family regulates the transcription of proteins mediating cell proliferation and survival in lymphocytes. Constitutively activated NF-κB pathway enhances the survival of malignant cells by inhibiting apoptosis and creating a clone of cells resistant to chemotherapy. High NF-κB expression is noted in several B- and T-cell lymphomas. Various agents, including lenalidomide, curcumin and proteasome inhibitors such as bortezomib, have demonstrated the ability to target NF-κB in vivo and in vitro. Since lenalidomide has been discussed earlier, the focus of this section is about advances made through proteasomal inhibition in lymphomas.
Under normal circumstances, NF-κB proteins are bound to Ikβα (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, α) and are protected from degradation by the proteasomal complex. In lymphomas, there is constitutive activation of the NF-κB pathway, due to breakdown of IKβα by ubiquitination-associated proteasomal degradation. Ikβα breakdown leads to the release of free NF-κB in the cytoplasm which then enters the cell nucleus and induces the production of antiapoptotic genes. Bortezomib is a ubiquitin-proteasomal inhibitor and exerts its action by inhibiting Ikβα degradation by the proteasomal complex and keeping NF-κB bound to Ikβα, thereby preventing the transcription of antiapoptotic proteins. Based on this rationale, bortezomib has been used to treat r/r B-cell lymphomas and showed encouraging activity specifically in cohort of patients with MCL. The excellent single agent activity of bortezomib in patients with r/r MCL was further confirmed in a subsequent study (ORR 33%; median time to progression (TTP) 6.2 months) and led to its FDA approval for this indication. Other studies have explored combinations of cytotoxic or other biological agents with bortezomib in indolent and aggressive lymphomas, with the most promising activity seen in lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL/WM) and T-cell NHL. Many other ongoing clinical trials are also exploring the optimal combination of proteasome inhibitors with chemotherapy drugs.
NF-κB Pathway
The NF-κB family regulates the transcription of proteins mediating cell proliferation and survival in lymphocytes. Constitutively activated NF-κB pathway enhances the survival of malignant cells by inhibiting apoptosis and creating a clone of cells resistant to chemotherapy. High NF-κB expression is noted in several B- and T-cell lymphomas. Various agents, including lenalidomide, curcumin and proteasome inhibitors such as bortezomib, have demonstrated the ability to target NF-κB in vivo and in vitro. Since lenalidomide has been discussed earlier, the focus of this section is about advances made through proteasomal inhibition in lymphomas.
Under normal circumstances, NF-κB proteins are bound to Ikβα (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, α) and are protected from degradation by the proteasomal complex. In lymphomas, there is constitutive activation of the NF-κB pathway, due to breakdown of IKβα by ubiquitination-associated proteasomal degradation. Ikβα breakdown leads to the release of free NF-κB in the cytoplasm which then enters the cell nucleus and induces the production of antiapoptotic genes. Bortezomib is a ubiquitin-proteasomal inhibitor and exerts its action by inhibiting Ikβα degradation by the proteasomal complex and keeping NF-κB bound to Ikβα, thereby preventing the transcription of antiapoptotic proteins. Based on this rationale, bortezomib has been used to treat r/r B-cell lymphomas and showed encouraging activity specifically in cohort of patients with MCL. The excellent single agent activity of bortezomib in patients with r/r MCL was further confirmed in a subsequent study (ORR 33%; median time to progression (TTP) 6.2 months) and led to its FDA approval for this indication. Other studies have explored combinations of cytotoxic or other biological agents with bortezomib in indolent and aggressive lymphomas, with the most promising activity seen in lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL/WM) and T-cell NHL. Many other ongoing clinical trials are also exploring the optimal combination of proteasome inhibitors with chemotherapy drugs.
