CD38

[pjoshea13]

It has been some hours since TottenhamMan & Dexy1234 posted the recent PCa/CD38 news [1] & [2] without a single response, so I thought I would try a different angle.

"CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells." [3]

CD38 & Multiple Myeloma. [4] {Stay with me.}

"CD38 is a protein that is primarily found on the surface of multiple myeloma cells. Other cells carry CD38, including red blood cells, although at lower levels. The protein’s strong association with multiple myeloma cells is what makes CD38 a treatment target.

"CD38 inhibitors are antibodies, which are produced by the immune system to recognize and eliminate harmful invaders such as viruses and bacteria. They bind specifically to one part of a particular protein. CD38 inhibitors are synthetic antibodies designed to bind to the CD38 protein. When they bind to CD38 on myeloma cells, they block the cells’ growth and induce their death."

"Darzalex (daratumumab), marketed by Janssen, is an FDA-approved CD38 inhibitor that may be used as a monotherapy in multiple myeloma patients who already tried at least three other therapies, including a proteasome inhibitor and an immunomodulatory agent."

"Isatuximab, developed by Sanofi, targets a particular region on the CD38 protein to trigger apoptosis (programmed cell death) and an immune response. It has been granted orphan drug status as a potential multiple myeloma therapy by the FDA and the European Medicines Agency (EMA). A biologics license application requesting its approval for people with hard-to-treat (relapsed/refractory) multiple myeloma is under FDA review with a decision expected around late April 2020."

***

CD38 as the Good Guy.

(2018, Wake Forest, U.S.) [5]

CD38 Inhibits Prostate Cancer Metabolism and Proliferation by Reducing Cellular NAD+ Pools

Nicotinamide Adenine Dinucleotide (NAD+)

"Tumor cells require an available pool of NAD+ for appropriate metabolic control and post-translational protein modification, among other functions, to support survival and proliferation."

"NAD+ turnover in cancer cells is dramatically increased relative to non-proliferating healthy cells, making NAD+ metabolism an attractive therapeutic target.

"NAD+ levels can ... be modulated by enzymatic consumption. ... CD38 is the primary NAD’ase in mammalian cells"

CD38 drives down NAD+, &, hence, the proliferation rate.

"Although we and others have demonstrated that CD38 expression is reduced in PCa, the mechanism by which CD38 expression is decreased is unknown."

"... the data suggest that strategies to induce CD38 expression could be one mechanism to decrease NAD+ in PCa and perhaps affect therapeutic response and hint that there are epigenetic or other elements in CD38 that regulate its expression."

(2015, U.S.) [6]

Low CD38 Identifies Progenitor-like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome

CD38 as the Bad Guy.

(2021, International. Lead authors drom The Institute of Cancer Research, London, UK & The Royal Marsden - as in the recent posts) [7]

This study looked at CD38 in the context of regular PCa epithelial cells & tumour-infiltrating immune cells (TIICs)

"Since CD38 depletes NAD+, it can also impair downstream NAD+-dependent enzymatic and metabolic processes, thereby constraining cellular proliferation ..."

"CD38 upregulation on tumour-infiltrating immune cells (TIICs) has been reported in gastrointestinal malignancies, but not in PC. The growing body of evidence implicating CD38 in tumour immune evasion led us to hypothesise that CD38 expression on prostate TIICs contributes to PC progression and may serve as an important immunotherapeutic target. Indeed, studies in patients with multiple myeloma have shown that anti-CD38 antibodies can deplete immunosuppressive lymphoid and myeloid cells to allow the expansion of effector T cells. Given the availability of several anti-CD38 antibodies, with daratumumab routinely used for the treatment of multiple myeloma, there is an urgent clinical need to elucidate the expression, function, and impact of CD38 in PC. The primary objective of this study was to quantify the expression and clinical impact of CD38+ prostate TIICs as tumours progressed from being castration sensitive to castration resistant, with the long-term goal of repurposing CD38-directed therapies for mCRPC treatment."

"This is the first study to characterise the expression and potential clinical impact of CD38, a druggable ectoenzyme, on PC epithelial cells and prostate TIICs, with the goal of evaluating CD38 as a prognostic biomarker in lethal PC and repurposing CD38-directed therapies to abrogate the potential deleterious effects of CD38+ TIICs. We show that CD38 is highly expressed on phenotypically diverse prostate TIICs and these cells are independently associated with worse OS."

***

So what we have is important news where we don't have to wait ten years to see if it pans out.

CD38 is both, good guy & bad guy, but perhaps more so bad guy for many in this group.

Perhaps we will be hearing more about Daratumumab ( Darzalex). [8]

-Patrick

[1] healthunlocked.com/advanced...

[2] healthunlocked.com/advanced...

[3] en.wikipedia.org/wiki/CD38

[4] myelomaresearchnews.com/cd3...

[5] ncbi.nlm.nih.gov/pmc/articl...

[6] ncbi.nlm.nih.gov/pmc/articl...

[7] sciencedirect.com/science/a...

[8] en.wikipedia.org/wiki/Darat...

[pjoshea13]

Nal,

Yes, our friend J-O-H-N has noted that my clarifications send him running for ice cream.

Clarification should mean fewer words?

I shall rewrite using nothing but Swedish emojis!

-Patrick

[MateoBeach in reply to pjoshea13]

My Indian traditional birth-star horoscope is Vishaka. Says I have the ability to make the complicated simple, and the simple complicated. So true! Perhaps you have the same star? 🙏

[pjoshea13 in reply to pjoshea13]

I did actually locate a site with Swedish emojis.

The one I chose had a skeletal figure with a scythe, together with a chess piece.

An Ingmar Bergman reference & quite appropriate IMO.

I pasted into the above post, but HU edited it out.

I will try this (1480 - Albertus Pictor - Täby Church, Täby Municipality, Stockholm County, Sweden):

en.wikipedia.org/wiki/Death...

-Patrick

[TheTopBanana in reply to pjoshea13]

Trevligt trevligt!! Eller 🏴‍☠️☠️ som vi säger på svenska.

[pjoshea13 in reply to TheTopBanana]

Thankyou!

Here's a bonus:

youtube.com/watch?v=f4yXBIi...(Not working as expected?)

Best, -Patrick

[SeosamhM in reply to pjoshea13]

I vote NOT to change your style, PJ. I love the headache and the reality that we have to wade through heavy science to earn (or temper) our hopes. You give enough summary within your narrative - we CANNOT lose sight that what we are going through is complicated and idiosyncratic.

[pjoshea13 in reply to SeosamhM]

Thanks! The minority view, but much appreciated.

17 years ago PCa studies were such that they could be explained to the average high school graduate IMO. But gradually, researchers have delved deeper and deeper into the inner workings of the PCa cell. There seems to be no end to it. But, like you, I want to keep up - & I want to try to explain why something new might be important.

Best, -Patrick

[cigafred in reply to pjoshea13]

There are a lot of us in that "minority."

[cesanon]

"we need to try to simplify for the 95%+ of our readers, when we present new scientific data that might be useful for Pca. so they can get a basic understanding"

1. Emphatically agree.

Except I would change 95% to 99%.

Actually, people don't need to make major changes to their favored style of communication.

All they need to do is to follow the ditty:

"Tell them what you are going to tell them

Tell them

Then tell them what you told them"

And just add the front and then end to what they were going to post anyway.

And then assume almost all readers will only read the "Tell them what you are going to tell them" part.

That's only if you want the broadest audience to listen and understand.

2. Acronyms

I would also add if you really want to help others, especially newbies, lay off the cryptic acronyms.

Spell it out the first time in a post before using.

Though frankly it seems the people most drawn to do this are the freshmen newbies and especially the sophomore newbies.

[pjoshea13 in reply to cesanon]

Way too many word - lol.

Also:

"Tell them what you are going to tell them

Tell them

Then tell them what you told them"

means you have to tell them 3 times? Too many words.

[Hidden in reply to pjoshea13]

Agreed with the simplification. I don't think this is above the understanding of most of us here. But time is a precious resource.

Me for example. I'm going to lunch in 15 minutes. When I get back I have more plans. So I'll have an hour or so to devote to cancer research. I have a lot to do and far too little time.

[Boywonder56 in reply to Hidden]

I agree ....i have a life...it may end....sooner than i like.....

[Hidden in reply to Boywonder56]

Go pound nails....oh wait...you do pound nails...

[Hidden in reply to Boywonder56]

So I have a porter gable 2.5 gallon compressor with the stapler, braid nailer and finisher nailer...I recently added the 32 framing nailer....main..is that fun...

I'm redoing a bathroom at a shore house I need to rebuild a wall...overkill with the framing nailer but I'm doing it myself so it makes it so much easier...

question for you....do you do tile work? I have a question about sealing around the diverter and the water flow valve...

[cesanon in reply to pjoshea13]

That's the trick. It's hard work to summarize with a low word count.

But among communication professionals, following that ditty is considered the gold standard of communication.

This is basically a fundamental law of physics for professional communicators.

It has been around a whilte. It is originally attributed to Aristotle.

“Tell them what you’re going to tell them, tell them and tell them what you’ve told them” – Aristotle

It definitely is Aristotle's formula, I don't think it was ever captured as succinctly in Greek as this English "translation" would imply.

[Hidden in reply to pjoshea13]

I find your posts very informative and I read every one (or scan them). One thing I would add upfront: "note, this is actionable and will probably not be provided by your oncologist" or "note, this is not actionable but informative" or "note, this is actionable and your oncologist will likely inform you"

etc.

[Currumpaw in reply to pjoshea13]

Hey pjoshea13!

The 'three tells'---standard part of college courses on public speaking or courses that include public speaking.

Currumpaw

[pjoshea13 in reply to Currumpaw]

My long-ago boss was big on the 3 tells, but I couldn't bring myself to do it. In those days, I was communicating with people who already knew a lot about the topic. Not here, of course.

Many men on ADT have brain fog, & age itself is not kind to brain function, so perfect communication with everyone in the group all the time is unlikely.

On the other hand, there are a lot of smart guys here (& smarter women - lol) who have no problem with most of the topics. I wouldn't class CD38 as an easy topic. Note that Dexy & Tottenham got one response between them (if you can call it that.)

26 words in the 1st sentence of the 3rd para. Something else I wasn't able to do:

- keep sentences short

- keep paragraphs short

- keep memos short (one page or less!)

How about we keep posts to under 100 characters? lol

-Patrick

[MateoBeach in reply to cesanon]

😆 Yes, that is the instructors manual for Marine drill instructors to give teaching lectures for boot camp recruits. And it works pretty well. I like the curated research that starts off with a “Take home lessons” first, then dives into the deep end.

[MateoBeach]

Oh! Cyclic ADP ribose hydrolase, now I recognize it. 😆Curious about the relationship to NAD+ reserves in relation to CD38 mechanisms and TIICs.?

Particularly re supplementing NMN and similar. Good or bad in this context?

[kaptank]

Thanks Patrick. I appreciate the effort that went into your summary and the scrupulous intent to get it right. Yes its a hard read but not incomprehensible.

[RonnyBaby]

Thanks for sharing and explaining - I think enough of us can make some sense out of it and expands our knowledge somewhat about some of the science and obstacles to overcome through research.

There is hope (again) that more of us will survive PCa given enough time and success from the ongoing efforts to get some answers.

[Jennifer1800]

Appreciate the information. As I understand, there is no approved treatment using daratumumab for prostate cancer in the US. It seems as though it may be approved in Great Britain? Thoughts on time frame for approval in US? Are any doctors using it off label for pc in the US?

[pjoshea13 in reply to Jennifer1800]

This is all rather new & approval may take some time. If a doctor were to prescribe it 'off-label', the patient would need to be willing to spend a lot of money, because Medicare wouldn't pay for it right now.

Of couse, for men unfortunate enough to also have multiple myeloma ...

-Patrick

[fmenninger]

Yes, let’s use the KISS (keep it simple stupid) approach is always best in this forum. Thanks Patrick !!

[Faith1111]

Let’s just call it the readers digest version. Do you remember readers digest? We want the soup not the whole recipe 😂

[j-o-h-n]

Your clarifications send me running for ice cream, Chocolate Chip (two scoops)...

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 05/09/2021 11:06 PM DST

[pete-ginger in reply to j-o-h-n]

j-o-h-n,

chocolate understands.

moke

[kaptank]

Another summary: icr.ac.uk/news-archive%2Fne...

[Jack02]

I wish I could understand all the no and letters, but everything even research you may do for eg, trials, meds, injection types are all short hand, and so hard to understand any off it, and sometimes I can find my self getting frustrated as I want to understand every word of it, so I can have more knowledge on everything to do with the diagnosis in order to help my pars journey and better his treatment x