ACSS2

Scientists demonstrate a double-acting mechanism for fighting a particularly aggressive, difficult-to-treat form of breast cancer. The research shows how silencing a certain gene, ACSS2, may improve existing treatments for patients. Zachary Schug, Ph.D., assistant professor in the Molecular and Cellular Oncogenesis Program of the Ellen and Ronald Caplan Cancer Center at The Wistar Institute, has published a new paper in the journal Nature Cancer. Schug's paper -- titled, "Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer" -- demonstrates a double-acting mechanism for fighting a particularly aggressive, difficult-to-treat form of breast cancer. Schug's research shows how silencing a certain gene, ACSS2, may improve existing treatments for patients. Triple-negative breast cancer, or TNBC, affects 10-15% of patients with breast cancer in the US. TNBC is called "triple-negative" because the cancer lacks an estrogen receptor, a progesterone receptor, and a HER2 (human epidermal growth factor) receptor. The absence of any of these receptors -- receptors that, when present in other forms of breast cancer, can be effectively targeted during treatment -- makes treating TNBC quite difficult, and patients with TNBC have limited treatment options. TNBC's notorious aggression makes the technical challenge of finding a reliably effective treatment target all the more serious: compared to other breast cancers, TNBC grows faster and resists treatment more stubbornly. All these factors contribute to the fact that TNBC patients suffer from worse prognoses. But Zachary Schug, Ph.D., and co-authors have demonstrated the efficacy of a double-acting concept: silencing the gene ACSS2 impairs TNBC metabolism while simultaneously boosting the immune system's ability to fight it. ACSS2 regulates acetate, a nutrient that cancer cells -- and TNBC cells in particular -- take advantage of to grow and spread. Schug and his team used two methods to de-activate ACSS2: CRISPR-Cas9 gene editing, and the compound VY-3-135, a potent ACSS2 inhibitor identified by Schug and his colleagues in 2021. The researchers found that targeting ACSS2 in this preclinical study not only hampered this aggressive cancer's ability to metabolize acetate and grow -- it also triggered the immune system to recognize and attack the cancer. Because cancer cells with inhibited ACSS2 can't process acetate very well, the tumor region becomes bathed in acetate, which alerts the immune system of something amiss. This process of guiding the immune system to the cancer -- called "immunosensitization" -- has confounded other TNBC researchers. But Schug's approach showed that ACSS2 inhibition immunosensitized against TNBC so well that tumor growth was drastically reduced, even to the point of wiping out the cancer completely in some experiments. "Basically, we've proved that the immune system can take advantage of acetate that the tumor can't process. It kicks the cancer while it's down," said Schug. "In fact, the immune system does this so well that it remembers how to attack TNBC in the future -- even if that tumor's ACSS2 gene is still active." Another group's different ACSS2-inhibiting approach is in human clinical trials, and Schug's research shows how ACSS2-inhibiting treatment might be able to improve outcomes for patients diagnosed with the infamous TNBC. By testing ACSS2 inhibitors alongside standard anti-breast-cancer chemotherapy, Schug et al. found that ACSS2 inhibition enhanced the treatment's effectiveness. "We knew that ACSS2 was a promising target for TNBC. Our research shows us how the immune effects of ACSS2 inhibition could eventually be used in for TNBC patients with limited treatment options," said Schug. "More research is needed, but by combining this approach with other cancer therapies, we expect to see big improvements in treating TNBC." Co-authors: Katelyn D. Miller, Seamus O'Connor, Katherine A. Pniewski, Toshitha Kannan, Reyes Acosta, Gauri Mirji, Sara Papp, Michael Hulse, Fabrizio Bertolazzi, Yellamelli V. V. Srikanth, Rahul S. Shinde, Daniel T. Claiborne, Andrew Kossenkov, Joseph M. Salvino and Zachary T. Schug of The Wistar Institute; Fabrizio Bertolazzi of the University of Bologna; and Steven Zhao and Kathryn E. Wellen of the University of Pennsylvania. Work supported by: This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute (NCI) DP2 CA249950-01, NIH NCI P01 CA114046, NIH R21 CA259240-01, the W.W. Smith Charitable Trust, Susan G. Komen CCR19608782 and the V Foundation for Cancer Research. This research and project is funded, in part, by a contract with the Pennsylvania Breast Cancer Coalition. The PBCC takes no part in and is in no way responsible for any analyses, interpretations or conclusions contained herein. We acknowledge funding from the NIH NCI T32 CA009171 and the American Cancer Society Rena and Victor Damone Postdoctoral Fellowship PF-20-1225-01-CCG. The Wistar Molecular Screening Facility and Genomics Facility are supported by NIH grant P30 CA010815. The Wistar Proteomic and Metabolomic Facility is supported, in part, by NIH grants R50 CA221838 and S10OD023586. The HIC is supported, in part, by NIH P30 AI045008 and P30 CA016520.

Company to receive over $250,000 in research funding to address condition affecting more than 14 million U.S. adults PHILADELPHIA, Sept. 13, 2022 /PRNewswire/ -- EpiVario, Inc., a biotech company developing novel therapeutics for memory-related psychiatric disorders, today announced it has been awarded a grant of nearly $260,000 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to advance research on its proprietary small molecule inhibitors designed to reduce alcohol craving responses and help people with alcohol use disorder prevent relapse. Alcohol Use Disorder (AUD) is characterized by an impaired ability to stop or control alcohol use despite clinically significant impairment, distress, or other adverse consequences. As one of the most common substance use disorders, it costs the U.S. healthcare system roughly $28 billion annually, and contributes to over 95,000 deaths each year. Moreover, alcohol use and misuse are thought to contribute to over 200 related diseases and health conditions globally, including cardiovascular disease, cancer, liver cirrhosis, and injuries1. The current standard of care for AUD is a combination of detoxification, psychotherapy, and community support programs, such as Alcoholics Anonymous. The limited number of pharmacotherapeutics available to supplement such treatments are not uniformly effective and are hampered by side effects, creating an urgent need for more effective treatments. EpiVario has developed an epigenetic approach to AUD that controls neuronal plasticity, inhibiting alcohol-related memory processes, which are known to play a large role in driving the disorder. The metabolic enzyme ACSS2 generates acetyl-CoA, a key cofactor for patterns of histone acetylation important for long-term memory2. EpiVario's co-founders, Drs. Shelley Berger and Philipp Mews, discovered that ACSS2 plays a critical role in alcohol-related learning by coordinating alcohol-induced histone acetylation and gene expression in the hippocampus, which converts alcohol-derived acetate to acetyl-CoA3. This supports the hypothesis that alcohol may exert its addictive properties via ACSS2-dependent histone acetylation. This novel gene regulatory mechanism presents an attractive therapeutic strategy via pharmacological inhibition of ACSS2 to interfere with alcohol-related learning that drives AUD. EpiVario's research will continue to evaluate the company's existing collection of small molecule inhibitors of ACSS2 for safety and efficacy in vivo, validate ACSS2 as a therapeutic target, and establish ACSS2 inhibition as a potential novel therapeutic strategy to treat AUD. "This award marks a significant milestone for both our company and the millions affected by alcohol addiction worldwide," said Thomas Kim, President & CEO of EpiVario. "We are one step closer to addressing the urgent need for a reliable and safe AUD pharmacotherapy with minimal side effects. We are excited to deploy this funding to advance our preclinical research and aspire to begin human trials by the first half of 2024." Dr. Howard Becker, Professor at the Medical University of South Carolina (MUSC), is widely recognized for his development of relevant animal models of AUD and their use in research on mechanisms and strategies for treating excessive, harmful drinking. In collaboration with MUSC, Dr. Becker was selected as Principal Investigator for EpiVario's six-month study. "I am honored to work with EpiVario on this truly innovative science," said Dr. Becker. "I have previously collaborated with EpiVario and its cofounder, Dr. Mews, and I am now most happy to collaboratively work on advancing EpiVario's drug development program that embraces a therapeutic strategy which is unlike any other AUD treatment available. It is exciting to take an active role in bringing this potentially life-changing therapy to market." The isolation and stress of the pandemic has only worsened alcohol addiction over the past few years, and it's estimated that binge drinking increased by 21% since 20204. Alcohol consumption changes due to COVID-19 are expected to cause 100 additional deaths and 2,800 additional cases of liver failure by 2023. While the number of affected people continues to rise, only approximately 7% of people who had AUD in the past year received any treatment. About EpiVario, Inc. EpiVario is a biotech company developing novel therapeutics to address a wide range of memory-related psychiatric disorders, including PTSD, Alzheimer's, and alcohol and drug addiction. EpiVario's strategy is to treat these psychiatric disorders at the source of the disease – the intrusive memories that often cause relapse. These memories are weakened via epigenetic regulation through the target enzyme acetyl-coA synthetase 2 (ACSS2), which regulates consolidation of fear and drug-craving memories. EpiVario's co-founders discovered that ACSS2 is a key metabolic enzyme that works directly within the nucleus of neurons to turn genes on when new memories are being established, and also when memories are recalled and then reconsolidated. For more information visit . Media Contact: Alyson Kuritz [email protected] (908) 892-7149 Burnette, E. M. et al. Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder. Drugs 82, 251–274 (2022). Mews, P. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546, 381–386 (2017). Mews, P. et al. Alcohol metabolism contributes to brain histone acetylation. Nature (2019) doi:10.1038/s41586-019-1700-7. The effect of COVID-19 on alcohol consumption, and policy responses to prevent harmful alcohol consumption. . SOURCE EpiVario Inc.

In vivo preclinical research findings from EpiVario and its co-founders describe a novel approach for reducing fear memories, which underly Post-Traumatic Stress Disorder PHILADELPHIA, Aug. 22, 2022 /PRNewswire/ -- EpiVario, Inc., an emerging biotech company developing novel therapeutics for memory-related psychiatric disorders, today highlighted preclinical research findings that could lead to a treatment approach for PTSD. Published in Proceedings of the National Academy of Sciences (PNAS), and co-authored by the academic co-founders of EpiVario, the study demonstrates that fear memories can be controlled through the enzyme acetyl-CoA synthetase 2 (ACSS2). The team also confirmed that a small molecule inhibitor against ACSS2 can block the epigenetic process required for the consolidation of stress and fear memories. Continue Reading In the study, published online August 5th in PNAS, the researchers identified the metabolic enzyme ACSS2 as a key regulator of fear memory, and showed that genetic deletion or pharmaceutical inhibition of ACSS2 greatly reduces the ability of mice and rats to form long-term memories of trauma events. The study demonstrates that fear memories can be controlled through the enzyme acetyl-CoA synthetase 2 (ACSS2). Tweet this The study was conducted at the Perelman School of Medicine at the University of Pennsylvania and was led by EpiVario Co-Founder Shelley Berger, PhD, Daniel S. Och University Professor and Director of the Penn Epigenetics Institute, and Co-Founder Philipp Mews, PhD, currently an Instructor at The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York, along with Tanya Corman, PhD, a postdoctoral scientist at University of Pennsylvania. Investigational small molecule compounds were provided by EpiVario, which is developing ACSS2 inhibitors as a therapeutic for memory related neuropsychiatric disorders. This work was further enabled through EpiVario collaborators Dr. Marcelo Wood at UC Irvine, and Dr. Hagit Cohen at Ben-Gurion University of the Negev, Israel. "These new results are exciting, as they validate our earlier discovery that ACSS2 is critical for activating genes during the creation of fear memories. Similarly, whenever we recall a traumatic event, these genes are activated in the same way, a process called reconsolidation, which is important in PTSD. In principle, reducing that reconsolidation by briefly blocking ACSS2, we expect to weaken trauma memories that underlie PTSD," said Dr. Mews. Previous research conducted in Berger's lab, and led by Dr. Mews, found that ACSS2 is a key metabolic enzyme that works within the nucleus of neurons to turn genes on when new memories are being established, and also after older memories are recalled (Mews et al., Nature 2017 & 2019). ACSS2 catalyzes the production of acetyl-coenzyme A (acetyl-CoA), a small molecule that serves as a cellular carrier of a chemical tag called acetyl group. Among its many actions, acetyl-CoA uses its acetyl payload to carry out a process called histone acetylation, which controls gene activity—including the gene activity needed to turn short-term memories into long-term memories. In the present study, the researchers investigated ACSS2's role in forming long-term fear memories in adult mice. The team first developed a line of mice in which the ACSS2 gene was disabled. They found that the absence of the gene did not impair ordinary, short-term working memory or other mouse activities, but did significantly reduce the strength of long-term memories, including fear memories. The researchers also confirmed a reduction of histone acetylation and gene activity changes normally associated with long-term memory consolidation. "These new findings support our approach of inhibiting ACSS2 as a therapeutic target to potentially reduce stress associated with traumatic memory," said Dr. Berger, senior author of the study. Next, the team injected normal mice and rats, immediately before and after fear-conditioning, with a compound that blocks ACSS2 activity for a brief period of time. Compared to untreated rodents, the treated animals showed significantly less freezing behavior when presented with shock-reminder cues. Importantly, the effect of the inhibitor was specific to gene activity during the treatment period—drug administered outside the consolidation window had no impact on the strength of memories formed. Lastly, the scientists used a rat model of PTSD, in which rats are exposed to a predator scent (cat urine) and tested a week later for heightened signs of anxiety when exposed to the scent. Here again, the presence of the ACSS2 inhibitor during the memory-consolidation window reduced subsequent anxiety signs in the treated rats, compared to control rats. "These research findings continue to encourage the team at EpiVario, since they provide significant additional in vivo validation of EpiVario's therapeutic approach, and further underscore the importance of ACSS2 as a target for attenuating fear memories, which we believe could be a transformative approach for the treatment of PTSD," said Thomas Kim, President and CEO of EpiVario. "It is exciting to see EpiVario's work progress through targeting fear-related neuroplasticity and the formation of fear memories," said Dr. John Krystal, EpiVario SAB member, and Chair of Psychiatry at Yale University. "We urgently need new treatments for PTSD, and need to explore innovative new therapeutic strategies, with ACSS2 inhibition representing a novel strategy that holds significant promise." EpiVario exclusively in-licensed the intellectual property related to this work from the University of Pennsylvania. In addition to their current work on the development of a treatment for PTSD, EpiVario is developing small molecule therapeutics for alcohol and substance use disorders, which, akin to the roots of PTSD, emerge from learned behaviors embedded in memory. University of Pennsylvania financial disclosure Dr. Berger is a Penn faculty member, as well as a scientific collaborator, advisor, and co-founder of EpiVario. As such, she holds an equity stake in the company, her laboratory at Penn receives sponsored research funding from EpiVario, and as an inventor of certain Penn intellectual property that is licensed to Epivario, she and Penn may each receive additional financial benefits in the future. Penn also holds a founder's equity stake in the company. About EpiVario, Inc. EpiVario is an emerging biotech company developing novel therapeutics to address a wide range of memory-related psychiatric disorders, including PTSD, Alzheimer's, and alcohol and drug addiction. EpiVario's strategy is to treat these psychiatric disorders at the source of the disease – the intrusive memories that often cause relapse. These memories are attenuated via epigenetic regulation through the target enzyme acetyl-coA synthetase 2 (ACSS2), which regulates consolidation of fear and drug-craving memories. EpiVario's co-founders discovered that ACSS2 is a key metabolic enzyme that works directly within the nucleus of neurons to turn genes on when new memories are being established, and also when memories are recalled and then reconsolidated. For more information visit . Media Contact: Thomas Kim [email protected] 215-400-0133 SOURCE EpiVario Inc.