Friday, June 02, 2006

Nutlin

We have all heard of p53, usually in a negative way. We know that cancer patients whose p53 has gone missing have bad news disease. It is the gene that is most commonly disrupted in cancer. In CLL deletion of 17p13, where the p53 gene is located, or mutation of the gene so as to make it non-functional, leads to poor prognosis, drug-resistant disease. So what does p53 do?

It is often called the Guardian of the Genome, meaning that it's role is to guard against copying errors in the DNA. The idea is that it recognizes when a mistake is made, puts the cell into stasis to see if it can be repaired, and if it can't, orders the cell to kill itself. It's a dangerous molecule to have around; kept on a leash doing what it's told it serves an essential function; let loose, like the dogs of war, it could cause untold damage.

One of the ways of controlling p53 is through the molecule MDM2 (it stands for Murine Double Minute - a reference to the mouse chromosome it is found on). In humans mdm2 is on the short arm of chromosome12. MDM2 is the master regulator of p53. (By the way, if you are getting confused by the use of italics, the covention is that the gene is in italics and small letters whereas the protein is not italicized and often capital letters are used. p stands for protein and the 53 refers to the molecular weight in kiloDaltons. there are other important molecules called p21 and p16 etc.)

MDM2 controls p53 in several ways, including blocking its transactivation domain so that it blocks its ability to activate transcription, also by aiding the nuclear export of p53 and by acting as a ubiquitin ligase to promote p53 degradation by proteosomes. Normally a cell has very low levels of both p53 and MDM2. It has been well demonstrated that disruption of p53-MDM2 interaction leads to activation of p53 and tumor suppression, but until recently disrupting this interaction has been very difficult. The breakthrough came from examining the crystal structure of MDM2 which showed that there is a relatively deep hydrophobic (= water repelling) pocket in the molecule which raised the possibility that small molecular weight molecules might be able to block the interaction with p53. Scientists at Roche have been screening molecules that might do this. They hit upon a series of molecules called cis-imidazolines (Chaya will understand precisely what this means) which they named Nutlins. The name puzzled me for a while until I realized that the Roche Research Institute is based at Nutley, New Jersey. Thus Nutley inhibitors.

The nutlins have been shown to activate the p53 pathway and to have anti-tumor effects in tumor cell lines, especially in those that over-express MDM2. and including some cell lines derived from acute myeloid leukemia and myeloma. In fresh CLL cells the nutlins activate the p53 pathway and induce apoptosis. They synergize with fludarabine and chlorambucil and they are much less toxic to noemal T cells.

They seem to have great promise in CLL; they are orally available and they penetrate cell membranes. Of course they have yet to be tried out in patients, but it can't be long before they are in clinical trials. In order to act they require an intact p53 pathway, so they will of no use in drug resistant CLL, but nevertheless to have a non-toxic agent in CLL that works will be a great boon.

15 comments:

Anonymous said...

I read this from my desk at Roche in Nutley

Anonymous said...

For those not named 'Chaya', "cis-" refers to the orientation of atoms in a molecule.

A molecule is composed of atoms. A molecule can be described by the numbers and types of atoms it is composed of. An example would be H2O, which of course is water. It can be described as:

H
\
O
/
H

Some molecules can consist of the same atoms, but be different because they are oriented differently.

This can happen in a double carbon-carbon bond or in a ring structure.

A double bond resists rotation around that bond, so the cis- form of a molecule would have the atoms present on the same of the molecule. The opposite form would be the "trans-" form, where the atoms would be on the opposed side of a molecule.

H H H CH3
\ / \ /
C=C C=C
/ \ / \
CH3 CH3 CH3 H

cis-but-2-ene trans-but-2-ene

The same situation (i.e. permanent orientation of atoms on an isomer) can be present in a ring structure. That is what cis-imidazoline is.

There are a number of agents including nutlin-3a which can disrupt the mdm2-p53 bond, and show potential for use as anti-cancer agents for the reasons shown in the Hamblin post.

It is unknown to this poster whether this agent has been used in animal trials as of yet. Human trials would be some time off, if ever.

Anonymous said...

Unfortunately, the spaces in the cis- and trans- form of the molecule did not come out at all when I posted.

There are hydrogen atoms above each carbon atom in the first molecule, and a hydrogen atom and a CH3 group above each carbon atom in the second molecule.

There are two CH3 groups on the bottom of the first molecule and a CH3 and a hydrogen atom on the second.

The cis- form of this molecule is:

.H.....H
..\.../
...C=C
../...\
CH3....H

Perhaps these periods will serve as place holders. Just ignore them to see the correct cis-but-2-ene molecule.

Anonymous said...

I picked up on Nutlins in Nutley New Jersey too. :-) And used to live nearby working with a bunch of telecommunications research types who also had a great, sometimes unexpected sense of humor.

bernard adler said...

Terry:
I am a constant reader of your blog and appreciate you as a considerate human being with great insight, as well as being a GREAT doctor.

I will be 81 in Sept and have not been treated since I dx in 1993. My onc is concerned that my platelets, which is 46, will require low dose tx of Rituxan shortly.

I am a U.S. Navy vet of WWII, Korean War and Viet Nam. Met many Brits on the many Pacific islands I called home.

Thank you again, for just being Terry.

Bernard Adler, Savannah, Georgia

Anonymous said...

I searched for ubiquitin protein information for a paper and found your article. thanks! also, I you may be interested in Science Magazine's current webinar: Science Magazine's Webinar: The Ubiquitin-Proteasome Pathway

Anonymous said...

Great post. As an update, my wife will start on the first human clinical trial of the MDM2 / Nutlin drug that Roche developed in two weeks. I thought it might be interesting for everyone to know that it has indeed made into trials. She has liposarcoma with shows the over expression of MDM2 in 90% of cases. Wish us (and all the others with cancer this might help) the luck we need :)

Anonymous said...

my husband, too, began human trial of MDM2, Nutlin, in august and we are so excited. He also has liposarcoma (dedefferianted-stage 4) I wish the gentleman's wife good luck and will pray for her. Many thanks for your blog.

Elsa D. said...

I also have a liposarcoma and I am trying to get to the Nutlin trial. Great blog. Thank you. :)

Anonymous said...

I wonder what the name of this trial using nutlin? Thanks

Gail said...

Thank you so much for such an informative blog. I'm hoping your personal battle will continue in a positive manner... prayers added to those supporting you at this time.

As with the other posters, I'm curious about the clinical trials underway for the Nutlin 3a drug. My husband is also dealing with liposarcoma, and all information is vital to making knowledgeable decisions.

If the posters who have indicated they're involved with clinical trials could share more information, I'd certainly appreciate and value that! Thanks.

Anonymous said...

Can anyone give me some updated info on Nutlin-3? My brother has liposarcoma which has returned since a 35lb tumor was removed in May. They want him to start chemo again next week and he is undecided if he wants to accept treatment. He is in his early 30s and I don't want to lose him!

Terry Hamblin said...

There is a guy blogging about it at http://livingwithasarcoma.blogspot.com/2009/08/r7112-and-alencar.html

Note that nutlin has a different number here. R7112.

Details of all liposarcoma trials can be found here:

http://clinicaltrials.gov/ct2/results?term=liposarcoma

Try ringing Roche Pharmaceuticals to find out what is happening with Nutlin

Anonymous said...

I am currently taking Nutlins, and have had promising results, blood counts are very good, and have seen a small reduction in size of my tumors, liver function is way down, and bone marrow show little signs of lukiemia, I have been in the trial for almost a year, and have had no side effects, too soon to tell if this is the silver bullet, but my life quality is great.

Anonymous said...

I am on the R7112 trial. I have experienced side effects including hair loss, rash/allergy , nausea, diahrea, lowered white blood cell count. However, the drug has shrunk my tumor. Would love to hear from anyone else still on this trial.