Roles Of Prostaglandin E Receptor in Tumor Microenvironment And Its Potential Application in Cancer Therapy Ⅱ

2 Application of EP4 in tumor treatment

Normal inflammatory response activates the immune environment, but it is ineffective in TME. Since PGE2-EP4 signaling is a regulatory node connecting inflammatory response and immunosuppression in TME, the rational development and use of appropriate EP4 antagonists and agonists may play a role in regulating inflammatory response in the immune microenvironment or TME to improve the therapeutic effect of the disease. Since COX inhibitors and NSAIDs have anti-tumor effects and side effects, EP4 is a key downstream receptor of the COX/PG pathway. Blocking EP4 signaling to enhance immune surveillance of tumors has become a new strategy for cancer immunotherapy.

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2.1 Drugs

2.1.1 EP4 antagonists

EP4 antagonists have been shown to be effective against a variety of cancers in basic research. The EP4 receptor selective antagonist RQ-15986 has been shown to have anti-tumor effects in colorectal cancer and breast cancer［29-30］. In addition, the new EP4 antagonist ASP7657 showed good pharmacokinetic properties in oral doses in human and mouse experiments [31], and further clinical trials are needed. The new EP4 inhibitor L001 may have a therapeutic effect on patients with metastatic pancreatic cancer [32].
E7046 was confirmed in a phase I clinical study to be well tolerated by patients with advanced malignant tumors and had a certain anti-cancer effect, but no side effects [33]. ONO-4578, which entered human studies for the first time, has been confirmed to be well tolerated in patients with advanced or metastatic solid tumors, including monotherapy and combination therapy with nivolumab [34].
The newly designed selective EP4 antagonist will be a candidate drug for the treatment of cancer and inflammatory diseases, and further development and verification will be carried out in the clinic.

2.1.2 Combination therapy

The PGE2-EP4 pathway can regulate the therapeutic effect of immune checkpoint blockade in the TME. PD-1 is currently the most widely used immune checkpoint in clinical practice. EP4 antagonist MF-766 combined with anti-PD-1 therapy can enhance anti-tumor activity by regulating the collaboration of various immune cells [35].

EP4 inhibitor ONO-AE3-208 combined with anti-PD-1 therapy can reduce tumor metabolism, including glycolysis, fatty acid oxidation and oxidation, and enhance the therapeutic effect [36]. Therefore, EP4 receptor inhibitors can also regulate tumor occurrence and progression by indirectly affecting tumor metabolism.

2.1.3 EP4 agonists

EP4 receptor agonists also have important therapeutic effects in tumors. For fulminant hepatitis induced by liver cancer treatment, EP4 receptor agonist PGE2R-A can show a protective effect on liver cells by inducing overexpression of anti-apoptotic protein Bcl-xL [37]. In the study of hematological tumors, EP4 agonists or combined effects with several drugs can help inhibit the progression of malignant B cell lymphoma [38]. However, currently EP4 receptor agonists are mainly new targets for the development of drugs for immune system diseases such as osteoarthritis and the treatment of non-tumor diseases such as anti-thrombotic therapy［39-40］.

2.2 EP4 antagonists are important for reversing drug resistance/improving drug efficacy

The use of EP4 antagonists has an inhibitory or reversal effect on drug resistance in a variety of tumors. In the study of colorectal cancer resistant to immune checkpoint blockade (ICB), the new EP4 antagonist TP-16 blocked the function of IMCs (M2 macrophages and MDSCs) and enhanced CD4+ cell-mediated elimination of colorectal cancer in vivo, enhancing the responsiveness of colorectal cancer ICB anti-PD-1 therapy [41].
Clinical trials on the combination of EP4 antagonist AN0025 and atezolizumab (anti-PD-L1) for the treatment of patients with advanced solid tumors are ongoing (NCT04975958). Knockout of the PGE2 upstream synthase PTGES can re-sensitize HT29 cells (OXR) resistant to oxaliplatin, indicating that selective EP4 receptor antagonists will improve the resistance of colon cancer to oxaliplatin after long-term use [42].
On the other hand, PGE2 increases intracellular cAMP through EP4 receptor activation, enhances glucocorticoid-induced gene expression, and makes human T cell acute lymphoblastic leukemia sensitive to dexamethasone [43], thereby improving the resistance of childhood acute lymphoblastic leukemia to dexamethasone.
Currently, breakthroughs in engineered cell therapy have provided more means for tumor immunotherapy. Chimeric antigen receptor T cell (CAR-T) therapy is based on the successful application of antigen chimeric technology transformation of T cells.
At present, CAR-T cell therapy has achieved great success in clinical application in hematological malignancies [44]. However, in solid tumors, due to the existence of TME, its clinical application effect needs to be improved. Recent experiments by Akbari et al. [45] showed that activation of PGE2 signaling through EP2 and EP4 receptors can inhibit the proliferation and anti-tumor function of mesoCAR T cells; dual blockade of EP2 and EP4 receptors can reverse the inhibition of PGE2 on mesoCAR T cells. Therefore, inhibiting the PGE2-EP2/4 signaling pathway can enhance the efficacy of CAR-T cells in complex TME and provide a better solution for solving CAR-T cell resistance in solid tumors such as pancreatic cancer. Antagonism of EP4 can also improve chemoradiotherapy, thereby reducing tumor recurrence. Studies have shown that radiation-induced breast cancer cells express high levels of the marker SCA-1, showing enhanced migration and metastasis activity. After using COX2 inhibitors and EP4 antagonists, radiation-induced cancer metastasis is deeply inhibited [46].
In addition, EP4 antagonist treatment can enhance the efficacy of chemotherapy by inducing the transformation of cancer stem cells into non-cancer stem cells and reducing the number of breast cancer stem cells [47]. Treatment with EP4 antagonists or celecoxib (COX2 inhibitor) can lead to increased sensitivity of bladder cancer cells to cisplatin treatment [48].
In addition, regarding neoadjuvant treatment, a phase Ib clinical trial of EP4 antagonist E7046 combined with radiotherapy/chemoradiotherapy (RT/CRT) for preoperative treatment of rectal cancer subjects showed good tolerability [49].
In summary, research on EP4 receptor targeted drugs can provide new ideas and technologies for chemoradiotherapy.

2.3 EP4 can be used as a marker for early cancer screening and prognosis for tumor diagnosis

Cancer has a very high recurrence rate due to its high invasiveness and high metastasis. The unlimited proliferation and invasion and metastasis of tumor cells are the most difficult treatment difficulties. Therefore, early cancer screening and treatment are effective measures to reduce cancer mortality and are of great significance to the prevention and control of cancer.
EP4, as a new prognostic factor, helps in the treatment of malignant tumors. EP4 expression in uterine leiomyoma can be used to identify patients at risk of chemotherapy resistance [50]. EP4 is also a negative prognostic factor for vulvar cancer [51]. At present, research on lung malignant lesions based on DNA methylation biomarkers and radiological feature models is constantly developing. Based on epigenetic research on the gene encoding the EP4 receptor, PTGER, the methylation of PTGER can also be used as a basis for cancer diagnosis. Studies have shown that the detection of PTGER4 methylation in plasma DNA can be used as a biomarker to support clinical decision-making for patients with chronic obstructive pulmonary disease and benign lung disease in high-risk lung cancer screening [52].
Combined detection of blood markers can increase the diagnosis rate of lung cancer [53]. In addition, tissue-specific DNA methylation indicators of PTGER4 and ZNF43 are helpful for prognosis judgment and timely intervention of invasive colorectal cancer [54]. Whether PTGER4 has the potential to become a relevant marker for cancer prognosis requires further study of its performance in various tumors.

3 Summary

Based on the diverse progress of cell engineering technology and combined therapy, people need to further explore the mechanisms related to tumor immunity. EP4 is currently an ideal tumor-related therapeutic target, and its impact on tumor diagnosis, treatment, and prognosis is significant and worthy of attention. The current limitation is how to overcome or reverse the immunosuppression of TME by targeting prostaglandins and their downstream signals, thereby enhancing the efficacy of immunotherapy. The long-term safety of various EP4 inhibitors/agonists still needs more clinical trials to evaluate. In addition, the efficacy of EP4 antagonists/agonists may vary due to individual differences, and the regulatory effects on different tumors and non-tumor diseases are worthy of further study. Combination therapy with other methods is also a direction worthy of further study in the future.

References:

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