BACH1

Vitamin C and other antioxidants stimulate the formation of new blood vessels in lung cancer tumors, a new study shows. The discovery corroborates the idea that dietary supplements containing antioxidants can accelerate tumor growth and metastasis. Vitamin C and other antioxidants stimulate the formation of new blood vessels in lung cancer tumours, a new study from Karolinska Institutet published in The Journal of Clinical Investigation shows. The discovery corroborates the idea that dietary supplements containing antioxidants can accelerate tumour growth and metastasis. "We've found that antioxidants activate a mechanism that causes cancer tumours to form new blood vessels, which is surprising, since it was previously thought that antioxidants have a protective effect," says study leader Martin Bergö, professor at the Department of Biosciences and Nutrition and vice president of Karolinska Institutet in Sweden. "The new blood vessels nourish the tumours and can help them grow and spread." Antioxidants neutralise free oxygen radicals, which can damage the body, and are therefore commonly found in dietary supplements. But overly high doses can be harmful. "There's no need to fear antioxidants in normal food but most people don't need additional amounts of them," says Professor Bergö. "In fact, it can be harmful for cancer patients and people with an elevated cancer risk." Previously unknown mechanism Professor Bergö's research group has previously shown that antioxidants like vitamin C and E accelerate the growth and spread of lung cancer by stabilising a protein called BACH1. BACH1 is activated when the level of free oxygen radicals drops, which happens, for example, when extra antioxidants are introduced via the diet or when spontaneous mutations in the tumour cells activate endogenous antioxidants. Now the researchers have been able to show that the activation of BACH1 induces the formation of new blood vessels (angiogenesis). While low oxygen levels (hypoxia) are known to be required for angiogenesis to occur in cancer tumours, the new mechanism identified by the researchers demonstrates that tumours can form new blood vessels in the presence of normal oxygen levels as well. The study also shows that BACH1 is regulated in a similar way as the HIF-1α protein -- a mechanism that was awarded the 2019 Nobel Prize in Physiology or Medicine and that allows cells to adapt to changes in oxygen levels. HIF-1α and BACH1 work together in the tumours, the new research shows. Hoping for more effective drugs "Many clinical trials have evaluated the efficacy of angiogenesis inhibitors, but the results have not been as successful as anticipated," says Ting Wang, doctoral student in Professor Bergö's group at Karolinska Institutet. "Our study opens the door to more effective ways of preventing angiogenesis in tumours; for example, patients whose tumours exhibit high levels of BACH1 might benefit more from anti-angiogensis therapy than patients with low BACH1 levels." The researchers used a range of cell-biological methods and concentrated most of their work on lung cancer tumours by studying organoids -- small cultivated microtumours from patients. But they also studied mice and samples of human breast and kidney tumours. Tumours in which BACH1 was activated, either via ingested antioxidants or by overexpression of the BACH1 gene, produced more new blood vessels and were highly sensitive to angiogenesis inhibitors. "The next step is to examine in detail how levels of oxygen and free radicals can regulate the BACH1 protein, and we will continue to determine the clinical relevance of our results," says Ting Wang. "We'll also be doing similar studies in other cancer forms such as breast, kidney and skin cancer." The study was conducted in close collaboration with KI researchers Susanne Schlisio, Staffan Strömblad and Eckardt Treuter and researchers at the First Affiliated Hospital of Zhengzhou University. The research was financed primarily by grants from the Swedish Cancer Society, the Swedish Research Council, the Sjöberg Foundation, the Knut and Alice Wallenberg Foundation, the Centre for Innovative Medicine (CIMED) and Karolinska Institutet. There are no reported conflicts of interest.

TOKYO, Dec. 1, 2021 /PRNewswire/ -- Astellas Pharma US, Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") today announced the presentation of new investigational data in acute myeloid leukemia (AML) and sickle cell disease at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place December 11-14, in Atlanta, Ga. Astellas' largest ASH showing to date includes 11 AML abstracts, including four oral presentations. "Research being presented at this year's ASH meeting investigates gilteritinib across the FLT3-mutation-positive AML disease continuum," said Ahsan Arozullah, M.D., M.P.H., Vice President, Medical Sciences-Oncology, Astellas. "Several presentations highlight data for gilteritinib in a wide range of patients – from newly diagnosed to relapsed or refractory patients, and in varying combination regimens." Presentations will include results from two Phase 3 trials: three abstracts from LACEWING, a clinical trial which included patients with newly diagnosed FLT3 mutation-positive (FLT3mut+) AML who were ineligible for first-line intensive induction chemotherapy; and one from COMMODORE, a trial of gilteritinib versus salvage chemotherapy in patients with FLT3mut+ relapsed or refractory AML conducted in China, Malaysia, Thailand, Singapore, and Russia. Astellas will also present research based on patients' perspectives of AML symptoms, life impact and treatment. "A deeper understanding of patient experiences is vital as we seek better treatment approaches in all stages of AML," said Erhan Berrak, M.D., Vice President of Medical Affairs, Oncology, Astellas. "For example, one study to be presented at this year's ASH meeting investigated the patient experience after a stem-cell transplant, shedding light on both symptoms and emotional impact, which can inform efforts to better serve patients post-transplant." In addition, Astellas plans to present new preclinical data on sickle cell disease (SCD) for ASP8731, a novel BACH1 inhibitor that potentially induces fetal hemoglobin (HbF). The data show potential to increase expression of antioxidant and HbF genes and reduce SCD-related pathophysiology. This may result in the reduction of hemolysis, inflammation, and vaso-occlusive pain crises in patients living with the condition. "We are pleased to have the opportunity to present our preclinical data supporting further development of ASP8731, our BACH1 inhibitor," said Itsuro Nagase, Ph.D., D.V.M., Vice President and Primary Focus Lead, Mitochondrial Biology, Astellas. "These data further support our focus on mitochondrial disease research and the advances we are making across the Astellas research pipeline to develop novel therapies for patients with unmet medical needs." Oral Presentations Title: Symptoms and Impacts Reported by Patients with Acute Myeloid Leukemia (AML) in Remission Post-Stem Cell Transplant (Abstract 278). Presenting author: Thomas Leblanc, M.D., M.A., Department of Medicine, Duke University School of Medicine, Durham, N.C., USA Session Date/Time: Saturday, Dec. 11, 2:15 p.m. ET Title: Phase 3, Open-Label, Randomized Study of Gilteritinib and Azacitidine vs Azacitidine for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in Patients Ineligible for Intensive Induction Chemotherapy (LACEWING) (Abstract 700). Presenting author: Eunice S. Wang, M.D., Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., USA Session Date/Time: Monday, Dec. 13, 3:30 p.m. ET Title: Gilteritinib Versus Salvage Chemotherapy for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Phase 3, Randomized, Multicenter, Open-Label Trial in Asia (COMMODORE) (Abstract 695). Presenting author: Jianxiang Wang, M.D., State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China Session Date/Time: Monday, Dec. 13, 3:45 p.m. ET Title: Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 Mutation in Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia (Supported by AbbVie, Astellas and Genentech) (Abstract 691). Presenting author: Naval Daver, M.D., Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Session Date/Time: Monday, Dec. 13, 2:45 p.m. ET Title: ML-0207/ASP8731: A Novel BACH1 Inhibitor That Induces Fetal Hemoglobin in Treatment of Sickle Cell Disease (Abstract 854). Presenting author: Greg Vercellotti, MD, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minn., USA Session Date/Time: Monday, Dec. 13, 6:30 p.m. ET Poster Presentations Title: A Phase 1, Dose-Escalation Study of Gilteritinib Combined with Chemotherapy in Patients Aged 6 Months to <21 Years with FLT3 Internal Tandem Duplication-Positive Relapsed or Refractory AML (Abstract 2315). Presenting author: Philip Connor, M.B.B.S., Department of Pediatric Hematology/Oncology, Noah's Ark Children's Hospital for Wales, Cardiff, Wales, UK Session Date/Time: Sunday, Dec. 12, 6-8 p.m. ET Title: Impact of FLT3 Mutation Clearance After Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: Results from the Phase 3 LACEWING Trial (Abstract 3445). Presenting author: Eunice S. Wang, M.D., Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., USA Session Date/Time: Monday, Dec. 13, 6-8 p.m. ET Title: Patient Reported Outcomes in Patients with Newly Diagnosed FLT3mut+ Acute Myeloid Leukemia Ineligible for Intensive Induction Chemotherapy From LACEWING: A Randomized Phase 3 Trial of Gilteritinib and Azacitidine Versus Azacitidine Alone (Abstract 3058). Presenting author: Eunice S. Wang, M.D., Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., USA Session Date/Time: Sunday, Dec. 12, 6-8 p.m. ET Title: First Salvage Therapy for Relapsed or Refractory Acute Myeloid Leukemia: Associated Health Care Resource Use and Costs (Abstract 1936). Presenting author: Lori Muffly, M.D., M.S., Division of Blood and Marrow Transplantation, Stanford University, Stanford, Calif., USA Session Date/Time: Saturday, Dec. 11, 5:30-7:30 p.m. ET Title: Gilteritinib Can Be Safely Combined with Atezolizumab for The Treatment of Relapsed or Refractory FLT3-Mutated AML: Results of a Phase 1 Study (Abstract 2343). Presenting author: Jessica K. Altman, M.D., Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Feinberg School of Medicine, Chicago, Ill., USA Session Date/Time: Sunday, Dec. 12, 6-8 p.m. ET Title: Patient and Physician Preferences for Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) in Patients Not Candidates for Intensive Chemotherapy (Abstract 4047). Presenting author: Mo Zhou, Ph.D., Analysis Group, Boston, Mass., USA Session Date/Time: Monday, Dec. 13, 6-8 p.m. ET Online-Only Publication Title: Real-World Use of FLT3 Tyrosine Kinase Inhibitors in Patients with Relapsed/Refractory FLT3 Mutation-Positive Acute Myeloid Leukemia in the United States (Abstract 5033). About Acute Myeloid Leukemia (AML) Acute myeloid leukemia (AML) is an aggressive cancer that affects the bone marrow and blood, and its incidence increases with age.1,2 Of patients newly diagnosed with AML and tested for FLT3 mutations, approximately one-third have an alteration to the FLT3 gene. FLT3-ITD mutations have been associated with worsened disease-free survival and overall survival, and a higher risk of getting the disease more than once. FLT3 mutation status can change over the course of AML treatment, even after relapse.3-6 About Gilteritinib Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor with demonstrated activity against FLT3-ITD, a common driver mutation that presents with a high disease burden and poor prognosis, and FLT3-TKD mutations.7 It was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global development, commercialization and manufacturing rights to gilteritinib.8 United States Gilteritinib Full Prescribing Information For more information about gilteritinib please see the U.S. Full Prescribing Information at: About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at . ASP8731 and Primary Focus Mitochondria Biology The mission of Primary Focus Mitochondria Biology – part of Astellas' Focus Area Approach – is to become the global leader in discovering, developing and bringing to market mitochondria biology-based medicine that provides clear value for patients, clinicians and healthcare systems. The BACH1 inhibitor ASP8731, which can modulate mitochondrial biology, was discovered by researchers at Mitobridge and tested in models of sickle cell disease at the University of Minnesota. Mitobridge was acquired by Astellas in 2018. Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. References American Cancer Society. What Is Acute Myeloid Leukemia (AML)? Available at: . Last accessed November 16, 2021. American Cancer Society. Key Statistics for Acute Myeloid Leukemia (AML). Available at: . Last accessed November 16, 2021. Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. 2010; 116(18), 3622-3626. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res. 2001; 61(19), 7233-7239. Visser O. et al. Incidence, survival and prevalence of myeloid malignancies in Europe. Eur J Cancer (2012) 48, 3257–3266. Warren M, et al. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012;25(10):1405-12. Daver N, Schlenk RF, Russel NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 2019; 33, 299-312. Data on file. Northbrook, Ill. Astellas Pharma US Inc. Company Codes: Tokyo:4503, OTC-PINK:ALPMY

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. A study in mice by The National Institutes for Quantum Science and Technology in Japan found that a low protein diet can accelerate brain degeneration in an Alzheimer’s mouse model. But more significantly, they found that a supplement with seven specific amino acids called Amino LP7, appeared to slow brain degeneration and dementia development in the animals. They published their research in Science Advances. “In older individuals, low protein diets are linked to poor maintenance of brain function,” said Makoto Higuchi, one of the lead scientists of the study. “Amino acids are the building blocks of proteins. So, we wanted to understand whether supplementation with essential amino acids can protect the brains of older people from dementia, and if yes, what mechanisms would contribute to this protective effect.” Mice on a low protein diet had accelerated brain deceleration as well as poor neuronal connectivity. But the effects were reversed after receiving Amino LP7, which suggested those seven specific amino acids might inhibit brain damage. They then studied how Amino LP7 affects different types of brain degeneration in their model. For example, untreated mice had high levels of progressive brain degeneration, but Amino LP7 suppressed neuronal death, which decreased brain degeneration, even though the mice brains still had Tau aggregates. Tau plaques are characteristic of Alzheimer’s. They also analyzed the gene-level changes caused by Amino LP7, which suggested the supplement decreased brain inflammation and prevented kynurenine an inflammation inducer, from entering the brain. “These results suggest that essential amino acids can help maintain balance in the brain and prevent brain deterioration,” said Hideaki Sato and Yuhei Takado, both contributors to the research. “Our study is the first to report that specific amino acids can hinder the development of dementia. Although our study was performed in mice, it brings hope that amino acid intake could also modify the development of dementias in humans, including Alzheimer’s disease.” Lab-Grown Mini Brains, ALS and Frontotemporal Dementia Researchers at the University of Cambridge developed “mini brains” that can be used to study amyotrophic lateral sclerosis, which often overlaps with frontotemporal dementia (FTD). And for the first time, they’ve managed to grow these organoids for almost a year. The team used stem cells from patients with ALS/FTD to grow brain organoids. They are similar to parts of the human cerebral cortex in terms of embryonic and fetal developmental milestones, 3D architecture, cell-type diversity and cell-cell interactions. This has been done before, but what was new was they were able to grow them for so long; and they had the most common genetic mutation in ALS/FTD. The published research has them growing for 240 days, but an unpublished manuscript shows they have grown for 340 days. Malaria Drug Might Help Fight COVID-19 A study published in the journal ACS Infectious Diseases evaluated the potential of atavaquone against the Wuhan wildtype strain of SARS-CoV-2 and other variants of concern. The study tested the drug in cell cultures infected with several different strains of COVID-19. The data showed a dose-dependent block in the infectivity. Anecdotal evidence from 17 patients in Quebec and Ontario, Canada, had suggested that malarone/atovaquone might have a preventive effect. So the researchers decided to test the drugs in cell cultures to evaluate the antiviral potential. They found that it “potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model.” Two clinical trials were initiated in the U.S. in 2020 to evaluate atovaquone alone or in combination with azithromycin, but the results have still not been reported. This new study suggests that the drug may be a strong antiviral against COVID-19. Blocking Bach1 Protein Slows Deterioration of Brain Cells in Parkinson’s Investigators at the Medical University of South Carolina (MUSC) identified a novel role for the regulatory protein Bach1 in Parkinson’s disease. They found that Bach1 levels were higher in postmortem Parkinson’s disease-affected brains, while cells without Bach1 seemed to be protected from the damage that accumulates in Parkinson’s. Working with vTv Therapeutics, they identified a drug, HPPE, which is a potent inhibitor of Bach1. This seems to protect cells from inflammation and the buildup of toxic oxidative stress when given before or after the onset of Parkinson’s symptoms. They believe this is the first evidence that Bach1 is dysregulated in Parkinson’s disease. Many of the inflammation and toxic oxidative stress pathways are controlled by two proteins, Nrf2 and Bach1. Nrf2 turns on the expression of more than 250 genes involved in protecting cells from these stressors, while Bach1 prevents the genes from being activated. In mouse studies, HPPE appeared to alleviate symptoms of Parkinson’s and to protect neurons from destructive pathways by switching on antioxidant genes and switching off pro-inflammatory genes. Type 1 Diabetes Might Be More Than a Single Disease New research from the international The Environmental Determinants of Diabetes in the Young (TEDDY) study added support to the theory that type 1 disease is not just one disease. The study found that the cause of autoimmune diabetes seems to vary in genetically high-risk children. The study, which was published in Diabetologica by Jeffrey Krischner, director of the Health Informatics Institute at the University of Southern Florida Health Morsani College of Medicine, compared the traits of type 1 diabetes diagnosed in children before and after the age of 6. Type 1 diabetes is an autoimmune disease where the immune system attacks the person’s pancreatic beta cells, which are the cells that produce insulin. Four specific autoantibodies directed against beta cells are the most reliable biological indicators of early type 1 diabetes before symptoms are observed: glutamic acid decarboxylase autoantibody (GADA), insulin autoantibody (IA), insulinoma-associated-protein-2 autoantibody (IA2-2A), and zinc transporter 8 autoantibody (ZnT8A). But not all children who test positive for one or more of those antibodies end up diagnosed with type 1 diabetes. Their research found out more about the order, timing and type of autoantibodies, which can help predict which children are most likely to be diagnosed with type 1 diabetes as they get older. “Our results underscore the importance of taking into account the age at development of multiple autoantibodies when evaluating risk factors for progression to a diabetes diagnosis,” said Krischner. “When the changing picture of autoantibody presentation is considered, it appears type 1 diabetes at an early age is a more aggressive form of the disease.”