ABSTRACT
Apoptosis pathways 1565 BCL2 1565 BCL2 antisense (G3139, Genasense®) 1566 Apoptosis-targeting small molecules 1566 Conclusions for apoptosis-targeting therapy 1566 Cyclin inhibition 1566 Cell cycle dysregulation 1566 Targeting the cyclin-dependent kinases: 1567
flavopiridol – a CDK inhibitor Targeting cyclin D1 translation – mTOR inhibitors 1568 Proteasome inhibition 1568
The ubiquitin proteasome system 1568 Proteasome inhibition – bortezomib 1569 Targeting histones 1570 Histone acetylation 1570 Histone deacetylase inhibition 1571 Angiogenesis 1571 Inhibitors of angiogenesis 1572 Summary 1573 Key points 1573 References 1574
Therapy for lymphomas has entered a promising and potentially beneficial era. The understanding, development, and optimal application of such treatment are pivotal if we are to exploit it to the full benefit of patients with lymphoma. Rituximab has led the way but much more can be achieved by new agents, either alone or in logical combinations, based on the biological pathways of lymphoma cells. These pathways are often aberrantly activated by the altered molecular genetics of the lymphoma cell. Molecular therapy being developed is largely aimed at silencing these overexpressed pathways at either the DNA or RNA level, although quenching the protein product is also possible. All this builds logically on our greater understanding of the molecular and cellular biology of lymphoma and differs for each individual subtype of lymphoma. Primarily the new molecular therapies involve the apoptosis, cell cycle, angiogenesis, and proteasome pathways. Earlier new molecules such as antisense oligonucleotides showed that the paradigm for gene silencing was effective but not as beneficial as hoped, probably due to poor application and some naïvety of understanding for the molecule. In this chapter we will approach the new therapies available on a pathwaysdirected basis. The current emphasis is to modify lymphoma cell biology by pathway-silencing molecules, rendering
DNA-damaging treatment such as chemotherapy and radiation therapy. However, it is envisaged that in the future the combination of molecular therapies can be used in a more sophisticated manner as individualized medicine. This requires not only the therapeutic molecules, but also greater improvements in cellular diagnostics and biomarkers of response, which can be blamed in part for holding back the field. Recent technological developments will advance our application of the therapy outlined.
