As many readers here on PSB know, I've not been a big fan of genome-wide molecular profiling, preferring an oncogene addiction approach to drug development and targeted cancer therapies. However, every once in a while something comes along that stops you in your tracks and makes you think differently.
This morning I was reading the latest copy of the New England Journal of Medicine over coffee and was fascinated by a review article by Drs Lenz and Staudt at the NCI on the molecular genetics of diffuse large-B-cell lymphomas (DLBCL), which account for 30-40% of newly diagnosed lymphomas.
As the review article points out, it is well know that different subsets of diffuse large-b-cell lymphomas are associated with different overall survival rates after initial anthracycline based therapy. For example, it is more favourable in people with PMBL and the GCB subytype but less favourable in those with the ABC subtype. R-CHOP therapy has improved survival in people with ABC, but the cure rates are still lower than those with the GCB subtype. Gene expression signatures can help identify the subtypes and predict survival rates:
Current therapeutic treatment with chemotherapy has made headway in improved survival, but in order to make further headway, new approaches are very much needed. Targeted therapies have now begun to expand clinical trial options.
The article talks about numerous pathways, but I particularly liked this one, which details the Nuclear Factor kB (NFkB) signalling pathways in normal and malignant lymphocytes:
Essentially, signalling is initiated when a SRC family kinase ( SFK) phosphorylates tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMs) on B-cell subunits. SYK is then recruited to the ITAMs through the SH2 domains and becomes active. Many of you will remember SYK inhibition from previous posts on Rigel's fostamatinib, a SYK inhibitor. I think Celgene also mentioned a SYK inhibitor in early development at their recent R&D Day, although the Rigel-AZ is further ahead but more erratic in it's results, at least in immune disorders. A more recent paper in Blood looked promising in NHL and CLL, though. Companies are clearly starting to look at specific inhibitors in the downstream pathway for lymphomas and chronic lymphocytic leukemia.
What's interesting about the cartoon above is that you can also see that phosphatidylinositol-3-kinase (PI3-kinase) is activated in parallel, activating the mTOR pathway. These two targets are getting a lot of attention from Pharma in the clinic, especially in leukemias and lymphomas, and we may well see more of their latest development at AACR next week and ASCO in June. Exelixis and their partner, sanofi-aventis (a client), for example, have already announced 12 abstracts at ASCO, including 6 on their PI3K and mTOR inhibitors, but they are focusing on lung cancer, a much more difficult carcinoma, rather than NHL, where there is a strong rationale.
It's good see new treatment modalities being tested in leukemias and lymphomas and not just solid tumours, where most companies inevitably focus due to the larger population sizes. That said, the challenge in lymphoma is going to be identifying rational combinations that kill lymphoma cells synergistically. As we learn more about the underlying biology of the disease, targets and biomarkers, so more effective and less toxic solutions may evolve.
Lenz, G., & Staudt, L. (2010). Aggressive Lymphomas New England Journal of Medicine, 362 (15), 1417-1429 DOI: 10.1056/NEJMra0807082
Friedberg, J., Sharman, J., Sweetenham, J., Johnston, P., Vose, J., LaCasce, A., Schaefer-Cutillo, J., De Vos, S., Sinha, R., Leonard, J., Cripe, L., Gregory, S., Sterba, M., Lowe, A., Levy, R., & Shipp, M. (2009). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia Blood, 115 (13), 2578-2585 DOI: 10.1182/blood-2009-08-236471