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...
