Monday, November 05, 2007

Hope for p53 mutants

The worst cases of CLL are those with reduced or absent p53 function. There are two reasons for this. p53 is known as ‘the guardian of the genome’. I like to think of it as a sort of bumble bee buzzing up and down the DNA seeking out mistakes. When it finds them, it puts the cell into stasis and instructs the DNA repair enzymes to put the matter right. If they cannot do so, it instructs the cell to commit suicide – apoptosis, or programmed cell death. If this doesn’t happen and the cell continues to multiply the mistake is perpetuated and more accumulate. Characteristically, cells with a defunct p53 molecule develop a complex karyotype with many mistakes. Without p53 the cell gets progressively more malignant.

In addition p53 is needed by most cytotoxic drugs to kill the cells. They don’t work by committing murder, but by inducing p53 to tell the cell to commit suicide. Thus cells with aberrant p53 tend to be drug resistant.

CLL cells can be defective in p53 either by losing the part of chromosome 17 on which it is located, or by a molecular mistake so that the DNA sequence that codes for p53 has an error in it (ie a mutation). There is a third way that diminishes the effectiveness of p53. The ATM gene of chromosome 11q23 codes for an enzyme that adds a phosphate group to p53 which makes it much more active, so no ATM and your p53 is a bit effete, weak and watery. That’s not as bad as having no p53, but it will do for you in the end.

A poster at the IWCLL from the Royal Marsden confirmed what most of us had suspected. 85% of those with deleted p53 on one chromosome had a mutated p53 on the other one. Since they did not look at the complete length of the gene it is likely that the true figure is 100%. Interestingly, this was only true for those with >20% cells with the del 17p, lesion. In those with <20% the mutation rate was only 7%. This confirms the finding of the LRF CLL4 trial that only those with >20% del 17p had a very poor prognosis.

I have already written about Nutlin-3, a molecule that antagonises MDM-2, a natural inhibitor of p53 and about PARP-1 inhibitors, chemicals that enhance the effect of ATM, but here I want to introduce you to two other ways of putting right defective p53.

RITA (2.5-bis (5-hydroxymethyl-2-thienyl) furan) binds to the p53 N-terminal domain and preventing the p53-HDM2 interaction which leads to the accumulation of p53 in tumour cells lines, increasing its half-life. Of course there must be some normal p53 present for it to work, but it may have a use in del 11q CLLs where the p53 is there but not very strong.

PRIMA-1 (2,2-bis(hydroxymethyl)-1-azabicyclo[2,2,2]octan-3-one)is a low-molecular-weight compound that can restore wild-type conformation of mutant p53 and specific DNA binding, consequently triggering apoptosis in tumor cells carrying mutant p53.

Look forward to seeing papers reporting the use of these two molecules in early clinical trials.


Anonymous said...

As CLL progresses, there is a tendency for genetic mishaps to accumulate. 11q is one of the genetic abnormalities which may make a late appearance.

That tendency is much more apparent in unmutated CLL, if I understand correctly.

Patients with mutated somatic hypermutation status can live for many years (even decades) with CLL and die from another cause.

Patients with unmutated CLL have a shorter survival.

1) Why do 17p and 11q pop up more in long-term unmutated survivors, and,

2) Does it make sense to go for a deep remission in unmutated patients, and treat mildly those patients with mutated status? (I do know there are patients with discordant markers, particular somatic mutations, etc. that do muddy up the picture). But in general, is that the evolving thinking?

Terry Hamblin said...

del 11q turns up more frequently in unmutated cases because in these cases the cells divide more rapidly. Every cell division exposes it to the risk of a copying error.

I'm not sure that starting slow is the evolving thinking. It's my idea but there are not many takers.