67IN - IMIDS: Multiple pathways but how does it really work?

Date 30 September 2012
Event ESMO Congress 2012
Session Molecular targets in malignant lymphomas: From basic science to clinical practice
Topics Lymphomas
Pathology/Molecular Biology
Presenter Gareth Morgan
Authors G. Morgan
  • The Institute of Cancer Research, SM2 SNG - London/UK

Abstract

The mechanism of action of IMiD® compounds has been the subject of much recent research which has highlighted the dual effects of these drugs, with both direct tumoricidal effects and immunomodulatory activity. Lenalidomide exerts its tumoricidal effects through a number of mechanisms, including decreased production of cytokine and growth factors causing disruption of stromal support, induction of tumor suppressor genes leading to cell cycle arrest and activation of caspases triggering tumor cell apoptosis. A recent study showed that IMiD® compounds increase p21 expression by a novel epigenetic mechanism. Lenalidomide also provides sustained disease control by improving immune function, resulting in continued tumour killing. Lenalidomide exerts immunomodulatory effects via enhanced antigen-specific CD8+ T-cell cytolysis and by increasing natural killer (NK)-cell expression of death effector molecules. Lenalidomide and pomalidomide have greater tumoricidal effects than thalidomide. Lenalidomide also has a more potent effect on the immune system. Both thalidomide and pomalidomide have potent anti-angiogenic properties. Evidence now indicates that clinical benefit can be gained in thalidomide-treated and refractory patients. In this respect cereblon has been identified as an intracellular imid binding moiety which is responsible for the teratogenic effects of these agents loss of which can mediate resistance to imids.It is possible to build combinations which improve the activity of Imid drugs. Co-administration of dexamethasone may synergistically improve the tumoricidal effects of lenalidomide but during maintenance the inhibition of the immune-enhancing effect of lenalidomide may impair its activity. There are a number of antibodies, including elotuzomab, which may be combined with lenalidomide. In view of the effects of lenalidomide on the epigenetic upregulation of tumour suppressor genes combination with other epigenetic agents such as HDAC inhibitors and demethylating agents may be useful. As research continues, additional insights into the mechanism of action of Imid drugs which may help to further maximize the use of lenalidomide and subsequently pomalidomide in the treatment of MM.

Disclosures

All authors have declared no conflicts of interest.