BRD2

Gladstone researchers find new evidence against using BET inhibitors to treat COVID-19 SAN FRANCISCO, July 19, 2022 /PRNewswire/ -- A while ago, some researchers had suggested that blocking a set of proteins, known as bromodomain and extraterminal (BET) proteins, might be a way to fight COVID-19. However, in a surprising study, scientists at Gladstone Institutes and UC San Francisco (UCSF) discovered that BET proteins are actually crucial for the body to fight the infection. In fact, the SARS-CoV-2 virus itself blocks the proteins to try to gain an advantage and continue to spread. Gladstone Graduate Student Irene Chen (right) is first author of a new study showing that BET proteins both enable and fight off COVID-19. Shown here in the lab with Tongcui Ma (left). Photo: Michael Short/Gladstone Institutes The new research, published in the journal Cell Reports, found that BET proteins have two distinct roles that affect how SARS-CoV-2 interacts with human cells: they give the virus a window into cells while also helping our cells defend themselves. These opposing functions explain the mixed results of previous experiments studying of the effect of targeting BET proteins on SARS-CoV-2 infection. "Our study shows how complex and nuanced interactions between virus and host cells can be," says Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and co-senior author of the new paper. "Even though blocking some BET proteins before viral exposure can help prevent infections, blocking other BET proteins actually plays right into the hands of the virus." The study's other co-senior author is Danica Galonić Fujimori, PhD, a professor of cellular and molecular pharmacology at UCSF. Directions from a Map In 2020, Nevan Krogan, PhD, a senior investigator at Gladstone Institutes and director of the Quantitative Biosciences Institute at UCSF, assembled a detailed map showing which SARS-CoV-2 proteins directly interact with which proteins in infected human cells. When they perused Krogan's results, Ott and Fujimori were surprised by one pairing: the virus's envelope protein bound to BRD2 and BRD4, two members of the BET family of proteins. Scientists thereafter discovered that one of the genes turned on by these BET proteins is ACE2, the same protein that SARS-CoV-2 relies on to get into cells. Indeed, it had been shown that completely blocking BET proteins prior to exposure to the virus could protect cells from infection. But Ott's lab had already been studying BET proteins in the context of HIV infection, and knew that they also control activation of genes related to inflammation, immunity, and cancer. They wondered how and why SARS-CoV-2 would be directly interacting with BRD2 and BRD4 given their known roles in cellular responses to invading pathogens. New Insight into BETs In this study, Gladstone graduate student Irene Chen and the rest of the team discovered that, in SARS-CoV-2 infected cells, the BET proteins turn on genes that ward off viruses—this is in addition to turning on the gene ACE2, which lets SARS-CoV-2 enter human cells. When the researchers blocked the BET protein BRD4 in mice already infected with COVID-19, rather than before infection, the mice's symptoms grew worse and they experienced more severe disease. These results suggested that BET proteins play a role in both enabling and fighting off COVID-19, yet still didn't explain why or how the virus was directly binding to BRD2 or BRD4. But a close look at SARS-CoV-2 revealed that the envelope protein has a small section that closely resembles human histones, which are complexes of proteins found along DNA. With additional experiments, the researchers revealed that SARS-CoV-2 was able to engage the BRD4 protein at the periphery of the cell nucleus by mimicking the histones that BET proteins naturally bind to—and this, in turn, prevented BRD4 from activating antiviral genes. "This is an example of a viral protein that can actually mimic one our own proteins to fool our cells and prevent them from activating immune defenses that would kill the virus," says Chen, who is a co-first author of the new paper along with James Longbotham, PhD, a former postdoctoral fellow at UCSF. A Target for Treatment The new findings indicate that existing drugs that simultaneously block all BET proteins likely won't be effective in treating COVID-19—at least in patients who are already infected. However, the new study also confirmed that different BET proteins play different roles in the infection cycle, which could lead to future therapeutics that target only specific BET proteins, or parts of these proteins. More research is also needed to understand how the timing of such treatment with an infection could work. "It's clear from our results that the BET drugs currently available are not suitable for COVID-19," says Ott. "But certain elements of these drugs could be adapted for future drug development." About the Research Project The paper "Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2" was published in the journal Cell Reports on July 19, 2022. Other authors are Sarah McMahon, Rahul K. Suryawanshi, Mir M. Khalid, Taha Y. Taha, Takako Tabata, Jennifer M. Hayashi, Frank W. Soveg, and Nevan Krogan of Gladstone; Jared Carlson-Stevermer, Jennifer Oki, and Kevin Holden of Synthego; Meghna Gupta, Meng Yao Zhang, Victor L. Lam, Yang Li, Zanlin Yu, Erron Titus, and Amy Diallo of UCSF. The work was supported by the National Institutes of Health (NCI R01CA250459, NIAID R01AI137270, NIAID R37AI083139, and F31 AI164671-01), the Tobacco-Related Disease Research Program (T30DT1006), a UCSF Discovery Fellowship, philanthropic support from Quantitative Biosciences Institute COVID-19 Research Group donors, and the James B. Pendleton Charitable Trust. About Gladstone Institutes To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco. CONTACT:Gladstone Institutes: Julie Langelier | [email protected] | 415.734.2019 SOURCE Gladstone Institutes

SEATTLE, April 05, 2021 (GLOBE NEWSWIRE) -- SEngine Precision Medicine , a precision oncology company revolutionizing cancer therapies by pre-testing drugs on patient-derived tumor organoids, announced today that the PARIS® Test was utilized in a study to identify novel drug targets and combinations to combat ovarian clear cell carcinoma (OCCC). The study, “Targeting BET proteins BRD2 and BRD3 in combination with PI3K-AKT inhibition as a therapeutic strategy for ovarian clear cell carcinoma,” was recently published in American Association for Cancer Research’s Molecular Cancer Therapeutics and was co-authored by researchers from the Fred Hutchinson Cancer Research Center, SEngine Precision Medicine, Weill Cornell Medicine, and the University of Washington. Ovarian clear cell carcinoma, a relatively uncommon subtype of ovarian cancer, has historically been treated with the same platinum-based chemotherapies as patients with high grade serous carcinoma. However, clear cell carcinoma patients typically display a poorer response to chemotherapies, which leads to lower overall survival for these patients. In this study, researchers identified BET proteins BRD2 and BRD3 as novel targets against ovarian clear cell carcinoma, which could lead to more effective targeted therapies for this subtype. Additional drug sensitivity screening identified the combination of BET protein and PI3K-AKT pathway inhibitors as a promising therapeutic path for further investigation. SEngine’s PARIS® Test, a high-throughput drug sensitivity assay using patient-derived tumor organoids, was utilized in this study to validate the drug-response findings on ovarian cancer cell models. In addition to the PARIS® Test already being utilized as a clinical tool guiding oncologists’ treatment decisions for patients with ovarian cancer, this study demonstrates the power of SEngine’s functional drug sensitivity assay to identify novel therapeutic targets and drug synergies to combat hard-to-treat ovarian cancers. "We are excited to share these new findings that identified two novel BET proteins as candidate therapeutic targets for OCCC and suggest a potential drug combination therapeutic strategy for OCCC,” said Shogo Shigeta, MD, PhD, current Research Associate in the department of gynecology at the Tohoku University Graduate School of Medicine and lead author of the study. “The validation of our study with organoids derived from patient samples will help enable rapid clinical translation." “In this study, SEngine’s PARIS® Test was applied to patient derived tumor cells to identify new therapeutic strategies for hard-to-treat cancers. This is yet another example of the benefit that functional testing brings to oncologists seeking novel treatment options,” commented Carla Grandori, MD, PhD, co-founder and Chief Executive Officer of SEngine Precision Medicine. About PARIS® Test The PARIS® Test is based on the capability to propagate patient-specific cancer cells as organoids outside the body and is applicable to all solid tumors including colon, breast, lung, ovarian and pancreatic cancer. Organoids are cancer-derived cells grown in 3D outside the body, which maintain the functionality of the original tumor as well as its genomic characteristics. For cancers where a treatment path is not clear, such as many metastatic and recurrent cancers, the PARIS® Test provides crucial information to treating physicians to match the right drug to the right patient. About SEngine Precision Medicine SEngine Precision Medicine Inc. is a precision oncology company revolutionizing cancer therapies by pre-testing drugs on patient-derived organoids grown ex-vivo utilizing patient specific tumor cells. As a spin-out from the world-renowned Fred Hutchinson Cancer Research Center, SEngine is leveraging over two decades of R&D in diagnostics and drug discovery. The Company is commercializing the PARIS® Test, a next generation diagnostic test that predicts drug responses integrating knowledge of cancer genomics with organoids, robotics, and AI-driven computational tools. SEngine’s CLIA certified PARIS® Test generates predictive drug sensitivity reports for patients with solid tumors. SEngine is also pursuing drug discovery via strategic collaborations with biopharmaceutical / pharma companies leveraging its precision oncology platform. Discover more at SengineMedicine.com and follow the latest news from SEngine on Twitter at @SEngineMedicine and on LinkedIn . Contact: Stephanie Carrington stephanie.carrington@westwicke.com 646-277-1282