PD-1 antibody "new partner" - ENPP1 inhibitor

Source: Pharmaceutical Rubik's Cube Pro Cancer cells have chromosomal instability, and as cancer cells divide, DNA fragments and even entire chromosomes can be repeated, mutated, or completely lost.
the more unstable the chromosome, the more likely it is that DNA fragments will appear in unseeded places, such as cytestics floating outside the nucleosphere.
cells identify these free DNA fragments as evidence of viral invasion, triggering alarms inside the cells, triggering inflammation and recruiting immune cells to launch immune attacks on tumor sites.
, however, it appears that cancer cells can cause immune cells to kill from fragments of DNA scattered in the cytones, but in reality cancer cells can still efficiently evade the surveillance of the immune system, metastasis and spread.
at the Memorial Sloan Kettering Cancer Research Center explained the phenomenon.
molecule on the outside of cancer cells destroys immune cells before warning signals reach them, the study was published on December 28, 2020 in Cancer Discovery.
cGAS-STING is an early warning system within a cell with which cGAS binds the DNA of a virus or cancer cell chromosome into the cytoste, forming a cGAMP molecule that acts as a warning signal to activate the STING path path in the cell.
addition, a large number of cGAMP can also alert neighboring immune cells outside the cell, activate the STING path of immune cells, and launch immune attacks against virally infected cells or cancer cells.
In the new study, researchers found that cancer cells have a scissor-like protein, ENPP1, which is clipped when cGAMP appears outside the cell, preventing signals from reaching immune cells, a process that also releases the immunosuppressive molecular adenosine, which also relieves inflammation.
researchers conducted a series of experiments in mouse models of breast, lung and colorectal cancer, which showed that ENPP1 acted like a control switch for immunosuppression and metastasis.
can suppress the immune response, increase metastasis, close it immune response restrictions lifted, reducing the metastasis of cancer cells.
the ENPP1 switch can also increase the sensitivity of many types of cancer to checkpoint inhibitors.
researchers also studied ENPP1 in human cancer samples and found that the expression of ENPP1 was associated with increased metastasis and resistance to immunotherapy.
ENPP1 is located on the surface of cancer cells, making it less difficult to target blocking drugs.
most tissues in healthy individuals are inflamed, so cancer cells are more susceptible to ENPP1 targeted drugs.
addition, target suppression ENPP1 will also play a "one arrow, two carvings" role.
" levels of cGAMP outside cancer cells increased, activating the STING path path of adjacent immune cells and preventing the production of immunosuppressive adenosine.
Samuel Bakhoum, author of the paper, explains.
it is worth mentioning that the research around STING agonists has been very hot, compared to STING's direct pharmacological activation, ENPP1 inhibition has many advantages.
For example, STING excitants activate STING in cancer cells and host cells indistinguishable, while ENPP1 tilts the relative balance of STING activation from cancer cells to host cells, playing a role in enhancing anti-tumor immunity.
And ENPP1 in metastatic and chromosomal instability of tumor cells selectively increased, ENPP1 inhibitor systemic drug delivery can interfere with the spread of tumor cells on the evasive ability to immune surveillance, avoiding the STING astigist tumor in the technical difficulties of delivery.
several companies are currently developing ENPP1 inhibitors for cancer, with Mavupharma (acquired by AbbVie in 2019) and Stingray Therapeutics in the process.
: 1 s Jun L, Mercedes A Duran, Ninjit Dhanota, et al. Metastasis and immune evasion from extracellular cGAMP hydrolysis. Cancer Discovery (2020). 2# Marcus A, Mao A J, Lensink-Vasan M, et al. Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response. Immunity (2018) 3 s taking the STING Out of Cancer: Discovery How How Cancer Cells Immune Defenses Inspires New Treatment Approach (Source: Memorial Sloan Kettering Cancer Center)