|
|
|||||
| ALCL | RESEARCH GROUPS | FEATURED PUBLICATIONS | TOOLS | ||
Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma that affects mainly children but also adults. ALCL is further sub-divided into two disease entities based on expression of the Anaplastic Lymphoma Kinase (ALK) oncogene, ALCL, ALK+ and ALCL, ALK-. The former category has a relatively good prognosis with a 5 year survival rate approaching 80% in comparison to 48% for the latter diagnostic entity. However, disease relapse is common (approximately 30% of cases) and whilst these patients remain sensitive to chemotherapy, treatment is often limited by its toxic side-effects.
The picture on the right shows activated molecular pathways within ALCL and indicates potential sites of action of present and future ALCL therapeutics.
Whilst the lack of a defining oncogene in ALCL, ALK- and the relative rarity of this disease has hampered progress, by comparison the expression of hyperactive ALK in ALCL, ALK+ has enabled some important discoveries with immediate impact on the therapy of this disease. For example, compounds designed to interfere with the activity of ALK have been shown to induce tumour cell death and hence are promising drug candidates. Indeed, Crizotonib, an ALK and c-Met inhibitor has entered clinical trial for the treatment of other ALK-related malignancies to date has proven extremely efficacious in inducing patient responses. However, it is known from experience with other drugs with target specific hyperactive kinases that mutant forms of the protein will evolve which are resistant to the inhibitor. It is therefore essential that we understand more concerning the activity of hyperactive ALK in order that we can design other drugs which will act synergistically with ALK inhibitors and work together to prevent disease recurrence. Hence, another or additive approach is the inhibition of one of the many ALK-activated downstream pathways like PI3K/Akt1/mTOR (6;7), JAK/Stat3 (8;9) and RAS/ERK (77). Several inhibitors are known to directly act on members of these pathways (PF-956980, JAK3-inhibitor; S3I-201, STAT3-inhibitor; ABT-737 and ABT-263, BH-3 mimetics inhibiting Bcl-2 and Bcl-xl; GGTI-298 (geranylgeranyltransferase inhibitor-298) and FTI (farnesytransferaseinhibitor), Ras-inhibitors; rapamycin and temsirolimus, mTOR inhibitors; diverse Akt-inhibitors). It may also be possible to reactivate pathways silenced by hyperactive ALK in order to induce tumour regression. For example, in ALCL tumours in which wild-type p53 is retained, MDM2 antagonists have been shown to reactivate p53 and induce cell death. In contrast, ALCL, ALK- patients may benefit from other treatment options which target proteins common to this disease.. One of those may be the monomethyl-auristatin E (MMAE) coupled CD30 antibody SGN-35 (Seattle Genetics) targeting CD30, a molecule commonly expressed on the cells of ALCL, ALK+ and ALK-. Alternativey, oncogenic microRNAs that are specifically over-expressed, for example the miR-17-106 cluster in ALCL, ALK+ or miR-155 in ALCL, ALK- may represent novel molecular targets for future ALCL therapies.