Histone H3

UCLA Health has announced the launch of a clinical trial to tackle aggressive brain tumours in adolescents and young adults using a personalised cancer vaccine. Researchers from the UCLA Health Jonsson Comprehensive Cancer Center, supported by the Department of Defence, will evaluate the safety of a personalised cancer vaccine in young patients living with diffuse hemispheric glioma (DHG), a serious form of paediatric brain cancer. According to the National Institutes of Health, primary brain tumours are estimated to be responsible for 80,000 new cases every year in the US. In the study, the cancer vaccine being developed at the UCLA Human Gene and Cell Therapy Facility will be evaluated to target H3 G34-mutant DHG, a highly aggressive brain tumour that is commonly found in adolescents and young adults and is primarily characterised by a particular mutation of the H3-3A gene, beginning with patients aged 18 years and over. The H3-3A gene encodes an important regulatory component on histone H3, that influences RNA processing, cancer behaviour and response to treatment. Aiming to improve survival rates and provide new insights into how the immune system responds to primary brain cancers and whether these targets lead to a lasting anti-tumour immune response, the vaccine is designed to arm a patient’s dendritic cells, an activator in the body’s immune system, to target products of the altered RNA regulation that defines this cancer type. Once activated, the patient’s dendritic cells are injected back into them. Designed to stimulate the immune system to attack the cancer, dendritic cell vaccination has previously shown promise in treating other forms of cancer, including glioblastoma, extending years of life for a subset of patients with the disease. Dr Linda Liau, chair of neurosurgery, UCLA Health, commented: “This clinical trial represents a novel and potentially transformative approach to treating high-grade gliomas in children and young adults. “We are optimistic that this research could lead to more advanced studies and eventually a new standard of care for this challenging subtype of brain cancer.” The study will later be expanded to include patients as young as five years old who have a confirmed diagnosis of H3 G34-mutant DHG.

Researchers have revealed the mechanism of the drug valemetostat shown to be effective in treating certain types of cancer by targeting a protein modification (histone methylation) silencing the expression of tumor suppressor genes and restoring their function. The researchers also demonstrated in clinical trials the efficacy of the drug in treating blood cancers by reducing tumor growth. The findings could lead to sustainable, longer-term treatments for the disease, as well as therapies for other types of cancer with similar underlying causes. Researchers have revealed the mechanism of a drug shown to be effective in treating certain types of cancer, which targets a protein modification silencing the expression of multiple tumor suppressor genes. They also demonstrated in clinical trials the efficacy of the drug in reducing tumor growth in blood cancer. The findings could lead to longer-term treatments for the disease and therapies for other types of cancer with similar underlying causes. A team of researchers from the University of Tokyo and their collaborators focused on therapies targeting H3K27me3, a modification on a DNA-packaging histone protein, which plays a large role in regulating gene expression. The modification occurs when methyl groups, each consisting of three hydrogen atoms bonded to a single carbon atom (CH3), are added to the protein in a process called methylation. The modification, also referred to as being epigenetic (a heritable change in gene function that occurs without altering the sequence of the DNA), has been tied to the repression, or reducing the expression, of tumor suppressor genes, with the accumulation of the methylated histones around the genes. Because of its effects on repressing genes, H3K27me3 is being targeted by therapies to correct some of the disordered gene expression observed in cancer cells. While this therapy is effective for some cancers, the mechanism of H3K27me3 therapies on tumor cells was not yet known. The research team conducted a study characterizing the effects of H3K27me3 on cancer cells by treating patients who have adult T-cell leukemia/lymphoma (ATL), a rare type of blood cancer, with valemetostat. The drug prevents the methylation of histone H3 by inhibiting the histone-modifying enzymes EZH1 and EZH2, which increase H3K27 and have been found to be abnormal in cancers. Treating patients with valemetostat decreased H3K27me3 and the condensation of DNA, opening up several tumor-suppressor genes for expression in cancer cells. "Before H3K27me3-inhibitor therapies were developed, no effective treatments for blood cancers with accumulated genetic abnormalities existed, and new treatments needed to be developed," said Makoto Yamagishi, first author of the paper and associate professor at the Graduate School of Frontier Sciences at the University of Tokyo. "Once we established that these therapies were effective against some types of cancer, understanding the therapeutic mechanisms of these drugs became extremely important." The team established that valemetostat treatment decreased tumor size and produced a durable clinical response to therapy in the clinical trial of patients with ATL, an aggressive cancer with many genetic mutations. The patients were able to safely remain on valemetostat treatment for more than two years. "In blood cancers with poor prognosis due to genetic abnormalities, epigenetic mechanisms mediated by methylated histones can be targeted therapeutically," said Professor Kaoru Uchimaru, also of the Graduate School of Frontier Sciences and last author of the study. "Valemetostat can restore expression of many tumor suppressor genes and sustainably inhibit tumor cell growth." Characterizing the mechanism of valemetostat therapy in patients with ATL is a huge step forward for epigenetic cancer treatments that target the expression of genes in cancer cells. The team recognizes, however, that many challenges remain. Cancers can become resistant to H3K27me3-inhibitor therapies if patients are treated for long periods of time, allowing cancer to recur. In some cases, cancer cells had acquired new mutations that interfered with valemetostat's effectiveness over time and reduced long-term patient response to the drug. "EZH1/2 inhibitors are effective treatments, but a mechanism of resistance to long-term treatment has also been identified," said Yamagishi. "Based on this mechanism of resistance, it is important to continue to improve treatment methods and develop combination therapies that provide longer-term therapeutic effects."

GELEEN, Netherlands, Jan. 30, 2024 /PRNewswire/ -- Matisse Pharmaceuticals B.V., a clinical stage company developing a medicinal product for the treatment of sepsis, today announced topline results from the HistoSeps trial evaluating the safety, tolerability and pharmacokinetics of intravenously (IV) administered M6229 in critically ill sepsis patients. According to the WHO, sepsis is the leading cause of death. Currently, there is no effective treatment against sepsis. Matisse's platform technology is based on the discovery that in most patients suffering from sepsis, proteins called histones are released by the innate immune system and apoptotic and/or necrotic cells into the blood stream, where they are toxic to other cells. Due to this self-enforcing cascade, people may die from organ failure within one or two days. Preclinical results have shown that by neutralizing the toxic histones with Matisse's product M6229, the negative cascade is inhibited by neutralization of cationic histones by highly anionic M6229. In this first in human clinical study, performed at the intensive care unit (ICU) of the Amsterdam University Medical Center, in total 10 critically ill patients in ICU setting received a six-hour IV infusion of M6229. This study met its primary objectives, showing favorable safety and tolerability as well as close to dose-proportional pharmacokinetics of IV administered M6229 in critically ill patients with sepsis. Preliminary semi-quantitative plasma histone H3 (H3) analysis executed by the University of Maastricht, showed a pharmacodynamic effect of M6229 by assessing plasma levels of extracellular histones in the study patients, before and at different time-points after M6229 administration. A decrease in SOFA (Sequential Organ Failure Assessment) score was found for 70% of the patients following the three days after the infusion day. Further quantitative analyses on plasma histones H3 and H2b are ongoing. Based on available data, it is concluded that the treatment infusion with M6229 should be started as soon as possible after patients are diagnosed with sepsis to be most effective. Matisse Pharmaceuticals is preparing for a Phase IIb clinical study in which critically ill sepsis patients will receive an IV infusion which should last until discharge from ICU, or organ support free for 24h, or severe adverse events, or the maximum allowed duration of infusion is reached. The recently closed funding round will allow Matisse to effectively continue its preparation for the large scale phase IIb study in sepsis patients. In the course of 2024, Matisse aims to conclude an additional funding round which should cover the full execution of the phase IIb clinical trial, the production scale up to a commercial level and to progress on a number of R&D projects, thereby also further strengthening the organization. "We are very pleased with the results confirming strong progress in the development of our lead compound M6229, as the first effective treatment for sepsis. The current data give strong guidance to us in the design of a successful phase 2b study, which we expect to run in the US and Europe," according to Kees Groen, Chief Development Officer at Matisse Pharmaceuticals. About M6229 Matisse claims to have identified an elegant solution for treating sepsis by using its lead compound M6229 to neutralize toxic circulatory histones. Matisse's platform technology is based on the discovery that in most patients suffering from sepsis, proteins called histones are released by the innate immune system and apoptotic and/or necrotic cells into the blood stream, where they are toxic to other cells. Due to this self-enforcing cascade, people may die from organ failure within one or two days. Preclinical results have shown that by neutralizing the toxic histones with Matisse's product M6229, the negative cascade is inhibited by neutralization of cationic histones by highly anionic M6229. Currently, there is no effective treatment against sepsis. According to the WHO, sepsis is the leading cause of death. From the 49 million patients globally suffering from sepsis every year, more than 20% die. According to a study by Buchman et al., published in the Journal of Critical Care Medicine, sepsis is the most common cause of in-hospital deaths, costing over $62 billion annually in the USA alone. About Matisse Pharmaceuticals Matisse Pharmaceuticals BV was founded in 2014 in Geleen, the Netherlands. Matisse targets life-threatening inflammation by neutralizing cytotoxic components of the inflammatory system. Its main development program is the development of a medicine to fight sepsis and septic shock. This study has been financed by the Dutch Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships. Logo: SOURCE Matisse Pharmaceuticals B.V.