HDAC1

Immunotherapy is one of the pillars in the fight against cancer and aims to enable the body's own immune system to fight a tumor. A recent study now shows that removing certain enzymes that regulate epigenetic processes from the so-called dentritic cells of the immune system influences their development and thus improves anti-tumor immunity. This finding could lead to new therapeutic strategies in immunotherapy. Immunotherapy is one of the pillars in the fight against cancer and aims to enable the body's own immune system to fight a tumor. A recent study now shows that removing certain enzymes that regulate epigenetic processes from the so-called dentritic cells of the immune system influences their development and thus improves anti-tumor immunity. This finding could lead to new therapeutic strategies in immunotherapy. The study by Cristiano De Sá Fernandes from Maria Sibilia's research group at the Center for Cancer Research and the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital was recently published in Cell Reports. Cancer cells are the body's own cells that do not divide and develop as intended and abandon their place and function in the body. The difficult thing about fighting them is that, as the body's own cells, the immune system cannot recognize them well and therefore cannot fight them. This is where immunotherapy kicks-in: It enables the patient's own immune system to identify the cancer cells and activate the body's own defenses. Dendritic cells (DCs) are important cells of the immune system that develop from precursor cells and can form different subgroups by changing their gene activity. These subgroups fulfill different functions in the immune system. However, it is not yet known exactly how certain epigenetic changes in chromatin (the material that makes up chromosomes) influence the development of DCs. In the study, the researchers inhibited two enzymes that regulate such epigenetic processes to see how this affects the development and function of DCs. They focused on the specific enzymes HDAC1 and HDAC2. Improved immune response Through multi-omics analyses, i.e. the analysis of several biological data such as gene expression and chromatin accessibility, the researchers found that the development of certain subgroups of DCs was impaired by the absence of HDAC1. This shows that HDAC1 plays a crucial role in their development. In the absence of HDAC1, DCs change their immune response, which improves tumor surveillance. Removing the enzyme HDAC2, on the other hand, had no major effect on the development of DCs. In summary, the study shows that the removal of HDAC1 influences the development of certain DC subsets and improves anti-tumor immunity. These findings could lead to new therapeutic strategies in cancer immunotherapy. This study was conducted as part of the FWF-funded PhD program DocFunds "Tissue Home," first author Cristiano de Fernandes was a PhD student.

First orphan drug designation for Nana-val granted in EBV+ solid tumors Seventh orphan drug designation for Nana-val globally; fifth granted by the FDA SAN DIEGO, Dec. 12, 2023 (GLOBE NEWSWIRE) -- Viracta Therapeutics, Inc. (Nasdaq: VIRX), a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide, today announced that the U.S. Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to Nana-val (nanatinostat in combination with valganciclovir), the company's all-oral investigational therapy targeting Epstein-Barr virus (EBV)-associated cancers, for the treatment of nasopharyngeal carcinoma (NPC). This represents the first ODD granted for Nana-val in Epstein-Barr virus-positive (EBV+) solid tumors and outside of EBV-associated lymphomas. The FDA previously granted Nana-val ODD for the treatment of T-cell lymphoma, post-transplant lymphoproliferative disorder, plasmablastic lymphoma, and EBV+ diffuse large B-cell lymphoma, not otherwise specified. "This orphan drug designation highlights the urgent need for new targeted treatment options for patients with rare diseases such as nasopharyngeal carcinoma, which is highly associated with EBV," said Mark Rothera, President and Chief Executive Officer of Viracta. "We are encouraged by the interim data from the Phase 1b/2 study of Nana-val in patients with recurrent or metastatic EBV-positive nasopharyngeal carcinoma, supporting the continued advancement of the study with a new split daily dosing regimen at higher doses. With sites open and enrolling the sixth dose cohort of the study, we are on track to expand into the Phase 2 portion in 2024. The growing clinical data in both the lymphoma and solid tumor settings, further validates the therapeutic potential of Nana-val to treat EBV-positive cancers, an underserved area of high unmet medical need.” The FDA’s Office of Orphan Products Development grants orphan status to drugs and biologics being developed to treat, diagnose, or prevent a rare disease or condition affecting fewer than 200,000 people in the U.S. ODD is designed to provide drug developers with various benefits to support the development of novel drugs, including the potential for seven years of market exclusivity upon FDA approval for the disease or condition for which the drug has ODD, eligibility for tax credits toward qualified clinical trial costs, exemptions from certain FDA application fees, reduced annual product user fees, clinical trial protocol design and drug development assistance, and potential qualification for expedited drug development programs. About the Phase 1b/2 Study of Nana-val in R/M EBV+ NPC and Other EBV+ Solid Tumors This Phase 1b/2 trial (NCT05166577) is an open-label, multinational clinical trial evaluating Nana-val alone and in combination with pembrolizumab. The Phase 1b dose escalation part is designed to evaluate safety and to select the recommended Phase 2 dose (RP2D) of Nana-val in patients with recurrent or metastatic (R/M) Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinoma (NPC). Along with the U.S. Food and Drug Administration’s Project Optimus initiative, at the start of Phase 2, up to 40 patients with R/M EBV+ NPC will be randomized to receive either the RP2D or a dose level below the RP2D in a dose-optimization cohort. Once the RP2D has been confirmed, up to 60 patients with R/M EBV+ NPC will be randomized to receive Nana-val at the RP2D with or without pembrolizumab to further evaluate antitumor activity, safety and tolerability, pharmacokinetics, and potential pharmacodynamic biomarkers. Additionally, patients with other advanced EBV+ solid tumors will be enrolled to receive Nana-val at the RP2D in a Phase 1b dose expansion cohort. About Nana-val (Nanatinostat and Valganciclovir) Nanatinostat is an orally available histone deacetylase (HDAC) inhibitor being developed by Viracta. Nanatinostat is selective for specific isoforms of Class I HDACs, which are key to inducing viral genes that are epigenetically silenced in Epstein-Barr virus (EBV)-associated malignancies. Nanatinostat is currently being investigated in combination with the antiviral agent valganciclovir as an all-oral combination therapy, Nana-val, in various subtypes of EBV-associated malignancies. Ongoing trials include a pivotal, global, multicenter, open-label Phase 2 basket trial in multiple subtypes of relapsed or refractory (R/R) EBV+ lymphoma (NAVAL-1) as well as a multinational Phase 1b/2 clinical trial in patients with recurrent or metastatic (R/M) EBV+ NPC and other EBV+ solid tumors. About EBV-Associated Cancers Approximately 90% of the world’s adult population is infected with EBV. Infections are commonly asymptomatic or associated with mononucleosis. Following infection, the virus remains latent in a small subset of cells for the duration of the patient’s life. Cells containing latent virus are increasingly susceptible to malignant transformation. Patients who are immunocompromised are at an increased risk of developing EBV-positive (EBV+) lymphomas. EBV is estimated to be associated with approximately 2% of the global cancer burden including lymphoma, nasopharyngeal carcinoma (NPC), and gastric cancer. About Viracta Therapeutics, Inc. Viracta is a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide. Viracta’s lead product candidate is an all-oral combination therapy of its proprietary investigational drug, nanatinostat, and the antiviral agent valganciclovir (collectively referred to as Nana-val). Nana-val is currently being evaluated in multiple ongoing clinical trials, including a pivotal, global, multicenter, open-label Phase 2 basket trial for the treatment of multiple subtypes of relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphoma (NAVAL-1), as well as a multinational, open-label Phase 1b/2 clinical trial for the treatment of patients with recurrent or metastatic (R/M) EBV+ nasopharyngeal carcinoma (NPC) and other advanced EBV+ solid tumors. Viracta is also pursuing the application of its “Kick and Kill” approach in other virus-related cancers. For additional information, please visit Forward-Looking Statements This communication contains "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding: the details, timeline and expected progress for Viracta's ongoing and anticipated clinical trials and updates regarding the same, the Company’s expectations of the significance and implications of the preliminary interim data from its clinical trials and preclinical studies disclosed herein, the Company’s expectations related to the FDA submission process and timelines and expectations regarding our target patient populations. Risks and uncertainties related to Viracta that may cause actual results to differ materially from those expressed or implied in any forward-looking statement include, but are not limited to: Viracta's ability to successfully enroll patients in and complete its ongoing and planned clinical trials; Viracta's plans to develop and commercialize its product candidates, including all oral combinations of nanatinostat and valganciclovir; the timing of initiation of Viracta's planned clinical trials; the timing of the availability of data from Viracta's clinical trials; previous preclinical and clinical results may not be predictive of future clinical results; the timing of any planned investigational new drug application or new drug application; Viracta's plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits, and market acceptance of Viracta's product candidates and Viracta's ability to manufacture or supply nanatinostat, valganciclovir, and pembrolizumab for clinical testing. If any of these risks materialize or underlying assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. Additional risks and uncertainties that could cause actual outcomes and results to differ materially from those contemplated by the forward-looking statements are included under the caption "Risk Factors" and elsewhere in Viracta's reports and other documents that Viracta has or will file, with the SEC from time to time and available at The forward-looking statements included in this communication are made only as of the date hereof. Viracta assumes no obligation and does not intend to update these forward-looking statements, except as required by law or applicable regulation. Investor Relations Contact: Ashleigh Barreto Head of Investor Relations & Corporate Communications Viracta Therapeutics, Inc. abarreto@viracta.com SOURCE Viracta Therapeutics, Inc.

Researchers discovered how anti-cancer drugs called HDAC inhibitors help treat pancreatic cancer by altering scar tissue (fibroblast) development. The findings suggest HDAC inhibitors could be powerful tools in fighting pancreatic cancer -- alone and in combination with other therapies. Pancreatic cancer is one of the deadliest cancers -- only about one in eight patients survives five years after diagnosis. Those dismal statistics are in part due to the thick, nearly impenetrable wall of fibrosis, or scar tissue, that surrounds most pancreatic tumors and makes it hard for drugs to access and destroy the cancer cells. Now, researchers at the Salk Institute have discovered how a class of anti-cancer drugs called HDAC inhibitors can help treat pancreatic cancer by modulating the activation of fibroblasts -- the cells that make up that wall of scar tissue. The new research was published in Nature Communications on December 6, 2023. "These drugs turn out to be hitting both the tumor itself as well as the fibrotic tissue around it. This could be a very effective way to treat pancreatic cancers, which have typically been very difficult to reach," says senior author Professor Ronald Evans, director of Salk's Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology. In response to a new pancreatic tumor, the pancreas typically activates fibroblasts -- the connective cells that support the structure of most organs. When flipped from a resting state to an active state, fibroblasts build a thick layer of scar tissue around the cancer. While this normal protective mechanism can help wall off a cancer and prevent its spread, fibroblasts also produce signaling molecules that the tumor itself takes advantage of to grow. "In the context of most pancreatic cancers, fibroblasts are acting as both good players and bad players," says Michael Downes, senior staff scientist and co-corresponding author on the paper. "It's a double-edged sword." In the new research, the team probed the effect on fibroblasts of an experimental class of cancer drugs known as histone deacetylase (HDAC) inhibitors. HDACs alter the three-dimensional structure of DNA inside cells, making some stretches of DNA easier or harder for other molecules to access and read. Targeting HDACs can therefore prevent cells from making large changes to their behavior, such as the out-of-control growth of cancer cells. But how the drugs work on all cell types is not well understood. In experiments on isolated cells, the researchers discovered that HDAC inhibitors prevented fibroblasts from becoming activated and tumor supportive. "Using HDAC inhibitors actually did two things -- it both turned down the growth signals from the fibroblasts to the cancer cells and it reduced the actual activation and accumulation of the fibroblasts," says Gaoyang Liang, first author and research associate in Evans' lab. In mice, the researchers found that one experimental HDAC inhibitor, entinostat, both reduced the activation of fibroblasts around pancreatic tumors and slowed tumor growth. When the researchers analyzed data from humans with pancreatic cancer, they discovered something similar: the higher the levels of HDAC1 in the fibrotic tissue around a patient's tumor, the worse their outcome. "This is in agreement with what we saw in cells and in mice," says Downes. "If you have more HDAC activities in the fibroblasts, you have a worse outcome. On the other hand, if you inhibit the HDACs, you have a better outcome." Since HDAC inhibitors work by preventing cells from activating certain genetic programs, the researchers wanted to know which stretches of DNA impacted by the drugs were most relevant for fibroblast activation. They identified several genes that HDAC inhibitors prevent from being expressed -- suggesting that new drugs could target those genes to keep fibroblasts from becoming activated and promoting cancer growth and fibrosis. "There have been some questions in the past about whether targeting fibroblasts is a good thing or a bad thing in pancreatic cancers, because people have shown that if you get rid of fibroblasts altogether it actually makes the cancers more aggressive," says Annette Atkins, co-author of the study and senior research scientist in Evans' lab. "But what our results suggest is that we don't have to get rid of them; just limiting their activation is beneficial." More work is needed to pinpoint how to best deliver HDAC inhibitors to the dense fibrotic tissue around pancreatic tumors, as well as how they might be most effectively combined with other cancer treatments. Other authors of the paper are Tae Gyu Oh, Nasun Hah, Yu Shi, Morgan L. Truitt, Corina E. Antal, Annette R. Atkins, Yuwenbin Li, Antonio F. M. Pinto, Dylan C. Nelson, Gabriela Estepa, Senada Bashi, Ester Banayo, Yang Dai, Ruth T. Yu, Tony Hunter, and Dannielle D. Engle of Salk; Hervé Tiriac of UC San Diego; Cory Fraser of HonorHealth Scottsdale; Serina Ng, Haiyong Han, and Daniel D. Von Hoff of The Translational Genomic Research Institute; and Christopher Liddle of the University of Sydney. The work was supported by grants from the Lustgarten Foundation (including award 552873), Don and Lorraine Freeberg Foundation, Ipsen Bioscience, a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16), a Ruth L. Kirschstein National Research Service Award (F32CA217033), a Life Sciences Research Foundation Fellowship, the Damon Runyon Cancer Research Foundation (DRG-2244-16), the National Institutes of Health (CA082683, 5T32CA009370), and the William Isacoff Research Foundation.