INOSINE

Inosine can be derived from dietary sources including oily fish, and widely available as a supplement. Its research has been mainly in neurodegenerative diseases such as Parkinsons but lately has emerged in cancer studies with some impressive early results. Higher levels of inosine have been linked to increased response levels in patient records from immunotherapy treatment. A recent pilot phase trial has confirmed these higher responses in a trial environment, and some significantly longer progression free periods In particular for lung cancer with immunotherapy where response rates are substantially improved to a variety of immunotherapy drugs, whilst side effects are reduced.

The underlying mechanism by which inosine decreases tumor resistance to immunotherapy is reportedly common in lung, triple negative breast cancer and melanoma. Overall gene analyses show this UBA6 upregulation increasing progression risks in several cancers that also include glioblastoma and pancreatic cancer. And, in treatment for early phase prostate cancer, relatively higher levels of gut microbiota such as akkermansia, and resulting higher levels of inosine, are also linked to lower progression risks in case data.

Researchers have recently found that recurrence levels in breast cancers are reduced following use of inosine stimulating probiotics. A healthy diverse microbiome is a crucial factor in patient case records. This has led to an ongoing phase II trial with replased patients receiving chemotherapy for advanced triple negative breast cancers. https://ctv.veeva.com/study/inosine-reverse-chemo-resistance-in-triple-negative-breast-cancer

 

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

YES
ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

Highlighted Studies

In this trial, the median PFS in the inosine group was 2.6 months longer than that in the non-inosine group and the risk of disease progression was reduced by 37%. The median OS was not reached in the inosine group and was 29.67 months in the non-inosine group. The ORR of the inosine group was higher than that of the non-inosine group, although the difference was not statistically significant. Inosine had a tendency to enhance the efficacy of ICIs and reduced immunotherapy-related adverse...

Link

Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and ...

Link

This article reviewed a microbiota-dependent immune-modulating system that can enhance or reduce antitumor immunity and may be an adjuvant in cancer immunotherapy. Inosine may aid in anticancer treatment by giving energy to T cells in a glucose-restricted environment, such as the tumor microenvironment, and acting as a signaling molecule (59). Consequently, inosine might enhance antitumor immune responses through a variety of mechanisms. Future basic research is required to improve the safety...

Link

INO [inosine] induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platf...

Link
BACK TO INDEX

TABLE OF REFERENCES

Help grow the evidence. Login and use the form, or try Feedback and Ideas below.

URLRatingHighlightHighlight 2Visuals (click)
https://onlinelibrary.wiley.com/doi/10.1002/cam4.701434Human study - adjunctIn this trial, the median PFS in the inosine group was 2.6 months longer than that in the non-inosine group and the risk of disease progression was reduced by 37%. The median OS was not reached in the inosine group and was 29.67 months in the non-inosine group. The ORR of the inosine group was higher than that of the non-inosine group, although the difference was not statistically significant. Inosine had a tendency to enhance the efficacy of ICIs and reduced immunotherapy-related adverse reactions in clinical applications.In terms of safety, Grades 3 and 4 adverse reactions were observed in 25 (29%) and 31 (36%) patients in the inosine and non-inosine groups, respectively, and inosine likely reduced immunotherapy-related adverse reactions. The results of this trial suggest that, compared with that in the non-inosine group, the mPFS was significantly prolonged in the inosine group. Inosine combined with PD-1/PD-L1 inhibitors has a synergistic effect that will provide a new option for overcoming immunotherapy resistance. Inosine tablets have been used clinically as a long-term adjuvant treatment for hepatitis, is safe and economical, and will not impose a huge economic burden on the patient. In the subgroup analysis, the median PFS for lung cancer and digestive system malignancies tended to increase in the inosine group.Lung cancer ICI plus inosine
https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00008-41Lab studyINO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.In summary, these data demonstrate that INO is a potent inducer of T cell stemness that dramatically modulates T cell metabolism, augments function and induces epigenetic programming. INO can be used to manufacture cell products with enhanced potency compared to standard glucose-based media. While many approaches are under development to inhibit Ado generation or signaling, our data suggest that approaches designed to metabolize Ado in the TME and generate INO may prove to be more effective in augmenting antitumor immunity.Adosine inosine mouse model
https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-021-01028-71Notably, dietary BL [barley leaf] supplementation resulted in the enrichment of microbiota-derived purine metabolite inosine, which could activate PPARγ signaling in human colon epithelial cells. Furthermore, exogenous treatment of inosine reproduced similar protective effects as BL to protect against DSS-induced colitis through improving adenosine 2A receptor (A2AR)/PPARγ-dependent mucosal barrier functions. Given the pivotal role in the modulation of intestinal homeostasis, PPARγ has been recognized as an important target for the treatment of inflammatory bowel disease. For instance, troglitazone and rosiglitazone are the two PPARγ synthetic ligands that can dramatically reduce disease severity in experimental colitis models and in patients with ulcerative colitis
https://www.mdpi.com/2076-2607/12/8/16531Supplementing AKK metabolite inosine could alleviate intestinal barrier damage and reduce serum LPS level, ultimately inhibiting castration resistance via the LPS/NF-κB/AR axis. Finally, we constructed a predictive model for CRPC combining gut microbiota and clinical information (AUC = 0.729). This study revealed the potential mechanism of gut microbiota on CRPC and provided potential therapeutic targets and prognostic indicators.In summary, we found that the increased AKK abundance and serum inosine level were associated with the more sensitive response to ADT in PCa. AKK secreted inosine to alleviate intestinal barrier damage and reduce serum LPS level, thereby inhibiting castration resistance through the LPS/NF-κB/AR axis. Furthermore, we established a predictive model for CRPC combining AKK and clinical indicators. In summary, this study revealed the pathological mechanism and provided potential therapeutic targets and prognostic indicators for CRPC.

Help grow the community

Join the Pubmedders subscriber base

Get our monthly email newletter – designed so you can give us your opinions, thoughts and feedback…

ALL contributions are invested into growing the site to help others.