Myelofibrosis potential development

[MFBMT2011]

One of my MF buddies in New Zealand sent me the link below about a discovery relating to a potential ’fix’ for Myelofibrosis. Early days, but who knows?

Chris (Princess Leia version with lady stem cells)

abc.net.au/news/2022-03-25/...

[kevinbros]

Afternoon

Thanks for that , interesting read !!

[Whitehair51]

Do you think this drug might work on all MPNs?

[EPguy]

The protein they are fixing is calreticulin, we know also as CALR, <<As we were making an antibody to try and understand how calreticulin protein worked >>

See reference below. My guess is the patient was PMF with CALR mutation. So it might not apply to the other mutations, but maybe is relevant to CALR ET.

But could be a much broader implication. Much more detail is needed to know what they are up to, but seems quite a good advance.

<<(...CALR). This mutation was detected in patients with PMF and ET>>

<<The CALR gene encodes the calreticulin protein,>>

pubmed.ncbi.nlm.nih.gov/273...

[Rem31 in reply to EPguy]

I haven’t tried to read it yet but does this help?

embopress.org/doi/epdf/10.1...

[EPguy in reply to Rem31]

It points to a similar idea, CALR may be subject to antibody treatment while Jak 2 is not:

<<Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR-dependent myeloproliferation.>>

My take is the top post article should apply to ET and post ET MF mostly or only with CALR.

I recall seeing elsewhere that CALR exposes the mutation on the cell surface more visibly than Jak2 and thus CALR may be subject to more types of treatments that Jak2 hides from. In this way CALR may be more similar to other conventional cancers where the bad cells are more discoverable.

A side note, as I understand it, INF causes jak2 mutants to "unhide" so that the body's immune system can discover and kill them. Good jak2's get killed too, but more slowly so that as the marrow manufactures fresh Jak2 batches the jak2's slowly become normal. Maybe someone can figure an agent that works with INF to nail the un-hidden jak2 alleles more quickly.

[FG251 in reply to EPguy]

Are you referring to increased ‘tumor surveillance’ with IFN? If so, I wouldn’t be at all surprised if the drug they’re developing could be tweaked to recognise JAK2. Serendipity is an amazing thing - just when some major figures in the haematology-oncology world say they don’t expect any great changes to treatment modalities any time soon.

[EPguy in reply to FG251]

Thanks for the proper word, I believe that is the means for un-hiding. Agree on the broader use in this context, they do say:

<<Researchers hope the unexpected find can lead to treatments for more than just myelofibrosis. Similar peptide fragments like the one used to generate the new antibody can also be found in other types of cancers>>

The "found" part here may be what INF helps with.

Your comment on there being nothing new is similar to an apocryphal quote from late 1800's "everything that can be invented has been invented." As an inventor, I see nothing but newness in what came from the past.

[FG251 in reply to EPguy]

Good quote!

Of course, as you know, it’s post-ET MF with JAK2 that I’d love to see a curative treatment for. I would imagine that, if this works for CAL-R, they’d want to make it work for JAK2, too, though maybe that will be a distinct possibility if we’ve been on IFN and the mutation is no longer ‘hidden’. Early days, but most certainly promising.

[Hidden]

I saw another report on this a month ago – sounds fantastic. Couldn't find any details, though, and no sign of published research on it. Looking forward to reading when he publishes... Might have postponed my November BMT and gotten myself to Adelaide if I'd known about it a year ago...

[Maisie10]

Thank you for sharing. This is brilliant news. Take care x

[FG251]

Please do keep us abreast of updates - thanks for sharing this wonderful news.

[welshhuw]

Thank you for posting this information. I was diagnosed with CALR E.T. (Type 2 - 5BP ins) A few years ago, so it’s very encouraging to see such positive research. Fingers crossed the clinical trial outcomes prove to be just as positive and will pave the way to cancer cures. Thanks again.

[Meatloaf9]

Thank you for posting. Fingers crossed.

[Thankfulone]

Thanks for the info. It's something to watch and see how it goes!

[CanadaG]

thank you for sharing this Chris. This is a very interesting and promising development that I will follow.

Did you hear about Galecto’s Mylox trial which aims to reduce the bm fibrosis? A link is provided below:

globenewswire.com/en/news-r...

[EPguy in reply to CanadaG]

This is neat, reducing the more adverse type fibrosis (collagen) is a big accomplishment.

Half of the 16 pts discontinued therapy bec of tolerance, 5 still on therapy are at 6 months and had the good fibrosis results.