Interesting read!

[P-O-T-S]

Structure of protein pair provides a blueprint for future drugs

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wehi.edu.au/news/structure-...

[mhos61]

Thanks for the link Barry. It all sounds very promising. It’s always good to know of all the different research taking place.

Mary x

[Paul123456]

I don’t understand how this can be a ‘cure’? Certainly sounds very a encouraging breakthrough but is it not limited to the JAK2 mutation? Whilst inhibiting JAK2 is clearly good news, it’s identifying the ‘driver’ mutation that is the Holy Grail.

What is it that causes progression in JAK2 -ve MPN patients? And presumably this same mutation affects all of us.

[P-O-T-S in reply to Paul123456]

I guess I still have much to understand as I am very new to this subject being only recently diagnosed. How it affect those with a negative mutation I’m not sure! As I understood it, progression comes from an ever increasing allel burden due to random cloning. Statistically eventually the mutated number of receptors are going to increase but how quickly is set by pure chance. By reducing the burden allows the receptors that are unaffected to grow increase again over time by cloning allowing for better regulation of blood counts controlled by the Jak stat pathway.

Or maybe I’m just rambling now!

[Paul123456 in reply to P-O-T-S]

Thanks, that’s my basic understanding. The higher the AB, the greater the risk of progression/more mutations.

However this is only part of the story. When JAK2 was discovered c. 12 years ago, a lot of research went into JAK inhibitors. It is now clear that this is not enough.

Have you seen a very promising new drug, RG7388. I’ll post a link to a Presentation later. Currently in Phase 2 trials after very exciting Phase 1, especially when combined with Peg.

Basically it’s a MDM2 inhibitor. The logic goes (my very limited understanding) is that high AB stimulates MDM2 which then inhibits p53. Since p53 is fighting new mutations/slowing progression, this is bad news!

The Presentation will explain properly.

Best Paul

[P-O-T-S]

Thanks for replying Paul, I look forward to seeing the article sounds very interesting!

[Paul123456]

Hope this works

youtu.be/w-Rj_R-zwW8(Not working as expected?)

[Ovingite in reply to Paul123456]

Thanks for posting this Paul. It's far too much for my addled brain to fully take in ( I am filled with admiration for those that can), but it is great to see just how much research is being conducted on behalf of members of the MPN Club - and at a global level too. I tend to be of a 'glass half full' disposition and the progress that is being made inspires me with confidence that science will soon unearth a way of bringing MPNs under control; not with a big bang discovery but by the aggregation of many small discoveries that combine to slay the MPN dragon.

John

[P-O-T-S in reply to Paul123456]

Thanks for the post Paul, looks interesting although I’ll have to watch it at weekend as I’m away with work and the diagrams are tiny on my phone!

Cheers

Barry

[Paul123456]

Barry

This is much more user friendly (5 mins and no slides!) Presentation describing roles of MDM2 and p53 and how MDM2 inhibits p53 (p53 helps stop us developing cancers/mutations). From memory the other Presentation claims that INF upregulates (boosts) p53 which may explain why INF effective at slowing progression for some patients.

Ie a battle between our disease boosting MDM2 which in turn makes p53 less able to combat mutations versus INF which boosts p53? Add RG7388 into the mix and we take the brakes of p53. Is that your reading?

cancernetwork.com/ash-stree...

RG7388 looks very promising, I assume for MF as well. Especially combined with Ropeginterferon. Perhaps two years time.....

Best Paul

[Bluetop]

Thanks P-O-T-S and Paul for both the information and the explanations. It does seem that new treatment options are in the pipeline.

[P-O-T-S]

Paul,

Thanks for posting both of these and apologies in getting back to you so late. The new drug seems to offer promise for PV patients especially when taken in conjunction with Interferon but sadly doesn't seem to apply to MF Patients as far as I currently understand it. I have to say it was a very intense watch and would require much research to fully understand all that was said as opposed to just some of it.

Thanks for posting

barry