Re: follow up paper for those who saw Dr Talpaz online presentation

[Guest guest]

Here a short summary in layman words and a list of ideas and molecules

in in vivo test or in clinical trials :

How our current drugs works :

Our bugs is caused by a defect in the DNA of some blood stem cells

(the Ph+ chromosome) which adds a new gene, the BCR-ABL. In each of

our cells the DNA is a big recipe book with 1000s of recipes for

proteins. In the cml cells some pages of the book were torn and

changed place. A lot of the damage doesn't matter, but two recipes

(abl and bcr) got mixed in one that codes a protein (the p210 in the

pcr tests) that triggers our problems (cells divide too much, stay

alive too long, go to the wrong places). But in order to do its deed

the p210 protein has to be activated by some other compounds (it needs

fuel). One of them (the fuel) is the ATP molecule that binds into it,

without it the p210 protein is harmless. Gleevec and the 2 other

approved drugs work by making impossible (at least harder) for the ATP

to bind to p210, so it doesn't get fueled. Because the cml cells have

other DNA damage, without the p210 protein to help them become super

cells, they die quickly.

Why it not a cure :

First our drugs do not affect (or not enough) the progenitor cml cells

that do not divide (quiescent cells) so we keep a stock of sleeping

cml cells, and once in a while one wakes up and if we are not taking

the drug at that point the whole thing restarts.

Second the DNA in the cml cells is more fragile than in normal cells,

the recipe book is in bad shape and keeps degrading. When this extra

damage is in the same area than the bcr-abl, called the kinase domain,

it may makes things harder for our drug to find the spot where to stop

the ATP to bind to the p210 protein. The damage may also add recipes

that makes the cml cells divide faster than the drug can stop them.

Non ATP inhibitors :

To function the p210 protein needs other things than the ATP. A new

class of drugs that interferes with these other molecules are being

tested. I won't go into details but here a list of molecules :

GNF-2 : tested in vivo

DCC-2036 : works with most mutations, including T315i, but not with

P-loop mutations. Should be in trials soon, looks safe and is

available oraly.

ON012380 : works against T315i.

Genetic therapies :

Instead of trying to stop the p210 protein function, another way is to

stop its production. The DNA is decoded recipe by recipe, and each

recipe is copied in a messenger RNA, which is then used by other parts

in the cells to make the proteins. A new approach is to stop the

messengers carrying the BCR-ABL recipe from being used to make p210.

Several ways to do that are investigated, one of them is pretty much

like using correction fluid to mask the recipe. Lots of results in

vivo, but there's still a lot to do to figure out how to deliver the

correction without having to do it one cell at a time. I would bet we

ll see trials in the next 5 years.

Vaccination :

I won't go into that beside to say it is in trials for quite some time.

Other leads :

KOS-953 and KOS-1022 inhibit the heat shock protein HSP90, in clinical trials

Rapamycin, everolimus (RAD001), temsirolimus (CCI779), in clinical trials

Ftase inhibitors BMS214662, Sorafenib. BMS214662 seems to work against

all mutations and also against the quiescent cml cells.

MEK1 inhibitors PD98059, PD184352 and U0126.

[Guest guest]

Marcos, thanks so much for that very informative summary. It's so

exciting to see so much research being done!

Tracey

>

> Here a short summary in layman words and a list of ideas and

molecules

> in in vivo test or in clinical trials :

>

> How our current drugs works :

> Our bugs is caused by a defect in the DNA of some blood stem cells

> (the Ph+ chromosome) which adds a new gene, the BCR-ABL. In each of

> our cells the DNA is a big recipe book with 1000s of recipes for

> proteins. In the cml cells some pages of the book were torn and

> changed place. A lot of the damage doesn't matter, but two recipes

> (abl and bcr) got mixed in one that codes a protein (the p210 in the

> pcr tests) that triggers our problems (cells divide too much, stay

> alive too long, go to the wrong places). But in order to do its deed

> the p210 protein has to be activated by some other compounds (it

needs

> fuel). One of them (the fuel) is the ATP molecule that binds into

it,

> without it the p210 protein is harmless. Gleevec and the 2 other

> approved drugs work by making impossible (at least harder) for the

ATP

> to bind to p210, so it doesn't get fueled. Because the cml cells

have

> other DNA damage, without the p210 protein to help them become super

> cells, they die quickly.

>

> Why it not a cure :

> First our drugs do not affect (or not enough) the progenitor cml

cells

> that do not divide (quiescent cells) so we keep a stock of sleeping

> cml cells, and once in a while one wakes up and if we are not taking

> the drug at that point the whole thing restarts.

> Second the DNA in the cml cells is more fragile than in normal

cells,

> the recipe book is in bad shape and keeps degrading. When this extra

> damage is in the same area than the bcr-abl, called the kinase

domain,

> it may makes things harder for our drug to find the spot where to

stop

> the ATP to bind to the p210 protein. The damage may also add recipes

> that makes the cml cells divide faster than the drug can stop them.

>

> Non ATP inhibitors :

> To function the p210 protein needs other things than the ATP. A new

> class of drugs that interferes with these other molecules are being

> tested. I won't go into details but here a list of molecules :

> GNF-2 : tested in vivo

>

> DCC-2036 : works with most mutations, including T315i, but not with

> P-loop mutations. Should be in trials soon, looks safe and is

> available oraly.

>

> ON012380 : works against T315i.

>

> Genetic therapies :

> Instead of trying to stop the p210 protein function, another way is

to

> stop its production. The DNA is decoded recipe by recipe, and each

> recipe is copied in a messenger RNA, which is then used by other

parts

> in the cells to make the proteins. A new approach is to stop the

> messengers carrying the BCR-ABL recipe from being used to make p210.

> Several ways to do that are investigated, one of them is pretty much

> like using correction fluid to mask the recipe. Lots of results in

> vivo, but there's still a lot to do to figure out how to deliver the

> correction without having to do it one cell at a time. I would bet

we

> ll see trials in the next 5 years.

>

> Vaccination :

> I won't go into that beside to say it is in trials for quite some

time.

>

> Other leads :

> KOS-953 and KOS-1022 inhibit the heat shock protein HSP90, in

clinical trials

>

> Rapamycin, everolimus (RAD001), temsirolimus (CCI779), in clinical

trials

>

> Ftase inhibitors BMS214662, Sorafenib. BMS214662 seems to work

against

> all mutations and also against the quiescent cml cells.

>

> MEK1 inhibitors PD98059, PD184352 and U0126.

>