Release Date: 25-Jan-2023
A lot of cancers exploit immune checkpoint deregulation as a defensive measure to evade immune surveillance and proceed towards malignancy. Immune checkpoint blockade enhances clinical results in some cancer patients whose conditions were previously thought to be largely incurable. We now have another protein whose role has emerged in several cell-related biological processes that aid in cancer growth and spreading. However, new treatment targets and novel molecules/strategies are constantly under study in order to further increase the number of individuals that respond towards the treatment.
The STAT family of proteins, which includes the signal transducer and activator of transcription-3 (STAT3), is involved in a wide variety of biological activities, including cell division, survival, and angiogenesis. As a result, cellular signaling disruption has become a novel therapeutic strategy that is currently being intensively researched by academics and pharmaceutical businesses worldwide. Peptides, non-peptides, oligonucleotides, and small molecule inhibitorsandmdash;the most well-known of them allandmdash;as well as other approaches can be used to directly and indirectly inhibit the STAT3 protein.
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These domains serve as simple targets for direct protein inhibition since they are necessary for the protein to interact with its ligands. PY*LKTK, a phosphopeptide, and its tripeptide derivatives namely PY*L and AY*L, were the first STAT3 inhibitors known to exist. They bound to the SH2 domain of the STAT3 and effectively inhibited both its biochemical activity and biological function. Being a first-generation STAT3 inhibitor, PY*LKTK is frequently employed in research investigations even now.
Targeting the protein's upstream stimulators or its downstream signal carriers could result in indirect inhibition of the protein, which would block the aforementioned biological processes. For this, JAK kinase inhibitors and IL-6, the upstream STAT3 activators, have been widely researched. For instance, Xeljanz, an approved JAK protein inhibitor, has been observed to change STAT3 signaling, causing regression in endometrial lesions, suggesting the possibility of treating the condition. Similar to how Abrocitinib, a recently approved JAK inhibitor, inhibits STAT3 by preventing it from being phosphorylated, which is a necessary step in the formation of the activated STAT3 dimer.
It has also been observed that immunosuppression is brought on by the over activity of STAT3 in tumor-infiltrating immune cells (TIICs), which suppresses the responses of both innate and adaptive immunity by encouraging the production of suppressive molecules like VEGF, IL-6, and IL-10 in tumor cells. In other words, increased STAT3 signaling in innate immune cell subtypes may suppress antigen presentation, reduce the synthesis of pro-inflammatory mediators like IFN-andgamma;, and prevent effector cells from destroying tumors. The interaction between tumor cells and their immune milieu can be propagated by atypically activated STAT3, which can result in tumor-induced immunosuppression.
As in the case of other immunotherapies, combination therapy has been gaining momentum for cancer treatment involving STAT3 inhibition. It has been demonstrated that increased expression of immune checkpoint proteins such PD-1 and CTLA-4 helps tumor immune escape. Accumulating evidences have that STAT3 can control these immune checkpoints either directly or indirectly by interacting with their promoters as a transcription factor, and boosting the protein expression of these genes. Combination of cancer immunotherapies that target both STAT3 and other checkpoint proteins can improve anti-tumor effects and also lower drug resistance. Additionally, the use of STAT3 inhibitors in combination with CAR-T cells can lessen CAR-T cell overgrowth and treat cytokine release syndrome (CRS), which lowers the likelihood of immune-related side effects.
The pipeline of STAT3 inhibitors is quite robust with many pharmaceutical companies like Tvardi Therapeutics, AstraZeneca and Otsuka Pharmaceuticals having STAT3 inhibitors in clinical or developmental phases. Apart from cancer, the role of STAT3 is also emerging in other indications such as rheumatoid arthritis, which will help broaden its usage in the future as more companies show interest in the protein. At present, even though a variety of small molecule inhibitors can successfully block STAT3 signaling, additional research will be required to creatively design new drugs and therapy strategies to enhance clinical outcomes.
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