Researchers at the University of Notre Dame have identified how a gene called Pygo2 makes some prostate cancers resistant to treatment with immunotherapy.
This new study, published in Science Immunology, expands on previous work by Xin Lu, John M. and Mary Jo Boler Associate Professor in Biological Sciences. In the paper, researchers in the Lu Lab showed that Pygo2 is an oncogene, meaning that it promotes cancer progression, and that it is found in high levels in advanced prostate cancer tumors.
"Prostate cancer has the highest incidence and is the second leading cause of cancer death for American men,” said Lu, who is affiliated with the Harper Cancer Research Institute and the Boler Parseghian Center for Rare and Neglected Diseases. “Immunotherapies for prostate cancer have largely failed so far. By showing that targeting Pygo2 dramatically enhanced immunotherapy in prostate cancer animal models, our study illuminates a path to improve prostate cancer patients' outcomes."
Lu began this project during his postdoctoral research nearly a decade ago. He screened several hundred genes looking for those that caused tumors to grow, called tumor progression. Out of these genes, he found that cancerous prostate tumors had much higher levels of Pygo2 compared to non-cancerous samples, and that reducing the amount of Pygo2 expression in models of human cancer slowed tumor progression, or metastasis.
More than half of the samples from men with prostate cancer had higher levels of Pygo2 compared to people without it, suggesting that it might be an important target in treating this resistant form of cancer.
Lu calls his first Pygo2 manuscript “humble”, because although he identified Pygo2 as being important for cancer metastasis, he did not understand how it caused progression of the disease. His graduate student from the Integrated Biomedical Sciences program at Notre Dame, Yini Zhu, read that paper and wanted to further investigate how Pygo2 contributed to prostate tumor resistance to immunotherapy.
Using both mouse and cell culture models, Zhu and other lab members found that genetically knocking out levels of Pygo2 allowed a type of immune cell that kills cancer cells, cytotoxic T lymphocytes (CTLs) to enter into prostate tumors. This finding was crucial because a common type of immunotherapy, adoptive cellular therapy, involves treating patients with isolated CTLs.
Furthermore, the team found that loss of the Pygo2 gene enhanced the ability of CTLs to infiltrate prostate tumors, making them more amenable to treatment. This friendlier environment for T-cells also enhanced the ability of another therapy to work well. The therapy, immune checkpoint blockade, is approved to treat melanoma but presents challenges when treating prostate cancer.
“This is an exciting finding because most immunotherapies try to activate T cells. However, most advanced prostate tumors are ‘cold’, meaning that they have very few T cells inside them,” Lu said, noting that this is likely because the tumors express too much Pygo2.
In the future, finding ways to reduce the amount of Pygo2 in these tumors could greatly improve how well immunotherapy works by turning the tumors from “cold” to “hot”.
While it is possible to knock out genes like Pygo2 in mouse models, in humans it is impractical, and even dangerous to do so without harming healthy cells.
But Lu’s team found a single paper that identified a small molecule that inhibited PYGO2’s function, and decided to synthesize the compound with Brian Blagg, the director of the Warren Family Research Center for Drug Discovery and Development and professor in the Department of Chemistry and Biochemistry. The Lu lab found that treatment of fast-growing prostate tumors with that compound significantly reduced tumor growth and enhanced tumor response to immunotherapy.
Lu said that although this inhibitor does not behave enough like a drug for the purposes of clinical trials, his team is working on finding better PYGO2 inhibitors through a collaboration with Olaf Wiest, a professor of chemistry and biochemistry affiliated with the Warren Center for Drug Discovery. Since the publication of their study, they have identified additional, more effective inhibitors that may be suitable for clinical trials in the future. Lu is hopeful that these inhibitors will allow for more effective treatments for patients with advanced prostate cancer.
Other Lu lab members who contributed to this work include Yun Zhao, Jiling Wen, Tianhe Huang, Xiaoxia Peng, Hawraa Al Janabi, Gang Huang, Jackson Mittlesteadt, and Xuemin Lu. Notre Dame Professor Brandon Ashfield also contributed to this study. This work was supported by grants to Lu from the National Institutes of Health, the Department of Defense, the Elsa U. Pardee Foundation, Indiana CTSI, and the Boler Family Foundation Endowment at University of Notre Dame.
A link to download a copy of the paper will be provided on the Lu lab website.