AACR 2002 - Day 4 - Tuesday 9 April 2002 Report: Why singlemindedness is a mistake in apoptosis-based therapy Investigator: Aaron Schimmer Tuesday Apr 9th, 2002 by Rabiya S. Tuma In the late-breaking abstracts session, one scientist presented compelling evidence that drugs designed to target only one branch of the apoptosis pathway are likely to fail in hard-to-treat acute myeloid leukemia (AML) cases. A full 20% of AML patients are resistant to treatment at the time of diagnosis. Data from tissue-culture experiments hint that this failure to respond is likely due to defects in the apoptosis pathway, but researchers find only a weak correlation between apoptosis protein levels and disease outcome in clinical trials, says Aaron Schimmer from the Burnham Institute in La Jolla, California.He surmises that these attempts to correlate prognosis with information about a single protein fail because they portray a static image in a very dynamic system. Instead, he suggests, if researchers want a more accurate picture of what occurs in a cancer cell, they need to look at the whole apoptosis pathway. External and internal signals can activate the apoptosis pathway, but the two signal types work through distinct intermediaries, creating a forked, semi-independent pathway. These independent branches converge at caspase-3, the actual apoptosis effector protein. Many drugs currently in development, such as TRAIL and antisense BCL-2, are designed to act on only one or the other branch of the pathway. When Schimmer looked in primary leukemia cells from 24 AML patients (12 sensitive to treatment and 12 resistant), he found that 21 had defects in apoptosis. Furthermore, 8 of these patients have blocks in both branches of the signaling pathway, meaning that apoptosis cannot be activated by either external or internal stimuli. This doubly blocked phenotype was more common in the patients with treatment refractory disease than in those with drug-sensitive disease. Upon further examination, Schimmer found that the problem in these doubly blocked cells was an excess of an inhibitor of caspase 3, called XIAP. That means that even if the pathways carrying the signal to caspase-3 are intact, the effector protein was prevented from doing the work the signal was telling it to do. In other words, no matter how many signals the cell sends out, caspase-3 can't bring about programmed cell death - an obvious advantage for a tumor cell. These data, says Schimmer, are important for several reasons. Any drug developed to target the pathway prior to caspase-3 will fail in the patients who are most in need of new treatment methods. With this in mind, says Schimmer, drugs need to be developed that either target XIAP, or caspase-independent mechanisms of cell death. Finally, he said "only the simultaneously blocked pathway was a predictor for treatment failure." This result, says Schimmer, implies that clinicians should really be looking at multiple proteins for prognostic indicators, rather than the single protein assays they are currently trying to develop Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.