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Description
Pancreatic cancer (PC), which accounts for 95% of all pancreatic cancers, is a devastating disease that has a 4-5% five-year survival rate and the outcomes remain unchanged for the last 50 years. Thus, it is important to further analyze the pathogenesis of PC and develop new treatment strategies.
Recently, a new generation of drugs targeting immune checkpoint proteins (PD-1/PD-L1) has been successful in treatment of various human cancers. Although response rates vary and unwanted side effects have been reported, it opens new possibilities for PC treatment in selected patients. The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that enhances cell proliferation, tumorigenicity and immunosuppression by increasing PD-1/PD-L1 expression. AHR also modulates the RNA-binding protein ELAVL1 signaling pathway leading to cytoprotection and inhibition of apoptosis thereby increasing chemoresistance. In addition, overexpression of ELAVL1 is known to inhibit immune cell-mediated cytotoxicity and modulate monocyte function. Here we seek to identify known and develop new low-molecular weight drug candidates to improve anti-PD-1/PD-L1 therapy by inhibition of AHR activity.
We hypothesize that inhibition of AHR activity alone or in combination with PD-1/PD-L1 inhibitors will result in enhanced anti-tumor immune response, and increased cancer cell susceptibility to chemotherapy via the ELAVL1 pathway. We will use in vitro and in vivo models, including patient-derived xenografts, to evaluate the potential of AHR inhibition in PC therapy. Ultimately, we will assess the activities of AHR and ELAVL1 pathways in PC patients, to determine the subsets of patients who would benefit most from AHR inhibition, thereby enabling a more personalized approach in future PC therapy.
Collectively, this preclinical study will provide new knowledge about the AHR and ELAVL1 pathways in PC and provide novel drug candidates for future clinical studies.
Summary of project results
The pancreatic cancer (PC) is a big problem in the medicine. Thus, it is important to further analyze the pathogenesis of PC and develop new treatment strategies. Recently, a new generation of drugs targeting immune checkpoint proteins (PD-1/PD-L1) has been successful in treatment of various human cancers. Project aim was to identify known and develop new low-molecular weight drug candidates to improve anti-PD-1/PD-L1 therapy by inhibition of aryl hydrocarbon receptor (AHR) activity.
Project team hypothesized that modulation of ligand-dependent transcription factor AHR activity alone or in combination with immune checkpoint proteins (PD-1/PD-L1) results in enhanced anti-tumor immune response and increased cancer cell susceptibility to chemotherapy via the RNA-binding protein ELAVL1 pathway. There were used patient tissue samples, in vitro and in vivo models to evaluate the potential of Kyn-AHR-ELAVL1 modulation in PC therapy. Project also assessed the AHR and ELAVL1 pathways in PC patients, to determine the subsets of patients who would benefit most from AHR inhibition, thereby enabling a more personalized approach in future PC therapy. This task was tackled by the international team of molecular biologists, chemists, biochemists, biotechnicians and physicians capable of obtaining and analyzing human cancer tissue samples, and blood cells, developing knock-out cancer cells using the CRISPR-CAS gene editing, developing and testing new drug precursors and prototypes in vitro and in vivo models.
The project team developed new low-molecular weight drug candidates and showed that in experimental settings the targeted modulation of Kyn-AHR-ELAVL1 signaling pathway slows down the growth and dissemination of malignant cells, restores the cancer suppressing function of the immune cells and increases cancer cell susceptibility to chemotherapy. Thus, the findings of this study could directly impact the outcomes of the treatment of PC patients and allow for more personalized precision medicine application in the future.
Summary of bilateral results
The cooperation among Norway, Lithuanian, and Estonian as well as input from the Latvian partners regarding potentially identifying novel small molecule inhibitors for AHR and PARP7 that could be used in future studies and would complement the genetic approaches was indispensable for the success of these studies. Each partner contributed with their unique expertise, enabling the project to move forward and seamlessly adjust in response to changes observed during the execution of the work.