DGAT1

Pictured: Illustration depicting a damaged liver/iStock, Mohammed Haneefa Nizamudeen A Phase II clinical trial of Ionis Pharmaceuticals’ metabolic dysfunction-associated steatohepatitis drug candidate has hit its primary endpoint, the company said Wednesday. Investigators randomized 160 people with metabolic dysfunction-associated steatohepatitis (MASH), the liver disease formerly known as nonalcoholic steatohepatitis, to receive placebo or one of three doses of ION224 subcutaneously once a month. Ionis designed the ligand-conjugated antisense medicine to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. After 51 weeks, the proportion of patients who had MASH histologic improvement without worsening of fibrosis was significantly higher in the top two dose cohorts than in the placebo group. The significant differences caused the trial to meet its primary endpoint. Ionis shared the p values for the successful 90-mg and 120-mg doses—0.015 and less than 0.001, respectively—but is yet to provide a closer look at the primary endpoint data. Subgroup analyses found patients with both F2 and F3 fibrosis, the middle scores on a four-point scarring severity scale, improved after taking ION224. The biotech published some secondary endpoint data. ION224 beat placebo on an endpoint that looked at MASH resolution without worsening of fibrosis, as measured by biopsy. At the highest dose, 44% of patients had a 50% or greater relative reduction in liver steatosis, as measured by imaging, while 3% of people on placebo experienced such an improvement. Ionis also saw a trend favoring ION224 for a liver scarring endpoint. In the high-dose arm, 32% of people had at least a one stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of their peers in the placebo cohort. The FDA asks sponsors to show a one stage improvement in fibrosis with no worsening of MASH or the resolution of MASH with no worsening of fibrosis in Phase III clinical trials. The first wave of MASH assets failed to clear that bar but recent studies have fared better, with Madrigal Pharmaceuticals hitting both the endpoints in Phase III. The FDA is set to decide whether to approve Madrigal’s resmetirom by Thursday. The success of resmetirom, a THR-β agonist, in clinical trials is part of a series of events that suggest Ionis will face competition if it delivers its own pivotal study victory and brings ION224 to market. Companies are working on MASH molecules against a range of targets, from Boehringer Ingelheim’s glucagon/GLP-1 receptor dual agonist survodutide to Akero Therapeutics’ FGF21 analog efruxifermin. Other companies are interested in Ionis’ MASH target, DGAT2. Pfizer axed one DGAT2 inhibitor after Phase I but still has another candidate, PF-06865571, in mid-stage development. Data from the Phase II clinical trial are imminent, according to ClinicalTrials.gov. Other companies including Sinew Pharma and Viking Therapeutics are working on DGAT1 inhibitors. Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn.

A new drug could potentially replace the current standard for treating brain cancer by sensitizing the cancer cells to radiotherapy BUSAN, South Korea, Jan. 19, 2023 /PRNewswire/ -- Glioblastoma (GBM) is a WHO grade IV brain tumor with dismal prognosis. Although post-surgical radiation chemotherapy combined with temozolomide is the standard line of treatment, GBM cells surviving radiotherapy contribute to tumor progression and recurrence even more aggressively. Researchers have now unveiled the mechanism of radioresistance in GBM cells, identifying therapeutic targets to overcome radioresistance. Moreover, the team has discovered a clinical drug that sensitizes GBM cells to radiotherapy and could replace temozolomide. Continue Reading Researchers from Korea and USA unveil the mechanism of radioresistance, or resistance to chemotherapy, in glioblastoma (brain cancer) cells, identifying potential therapeutic targets and a clinical drug, cladribine, that could potentially revolutionize the current treatment strategy for glioblastoma. Post-surgical radiotherapy and temozolomide, a chemotherapeutic drug, targeting post-cell division is the current standard of care for glioblastoma (GBM) – the most prevalent and lethal primary tumor of the central nervous system. An aggressive form of brain tumor, GBM is highly resistant to current therapies with high mortality and frequent recurrence. Moreover, GBM cells are highly radioresistant and contribute to tumor progression and recurrence even more aggressively when surviving radiotherapy. Thus, there is an urgent need to revise the standard treatment strategy and develop a new therapy to overcome the radioresistance of GBM cells. To this end, a team of researchers from Korea and USA led by Professor BuHyun Youn from Pusan National University in Korea has now unveiled a plausible mechanism underlying the radioresistance of GBM cells that involves regulating an internal steady state of lipid within the cells, known as "lipid homeostasis." "Put simply, radioresistant GBM cells prefer to stock up on fatty acids instead of utilizing them as an energy source in order to reduce mitochondrial reactive oxygen species that may cause damage to their DNA, RNA, and proteins, and, in turn, cell death," explains Prof. Youn. In their study published in Cell Reports Medicine, the researchers derived GBM stem cells from patients and established radioresistant cells for investigation. They showed that diacylglycerol kinase B (DGKB), a regulator of the intracellular level of diacylglycerol (DAG), was significantly suppressed in radioresistant GBM cells. This, in turn, increased DAG accumulation and decreased fatty acid oxidation, reducing mitochondrial lipotoxicity (harmful lipid accumulation in non-adipose tissues) in GBM cells and contributing to their radioresistance. Further, the team showed that the ionizing radiation induced an increase in the level of diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the formation of triglycerides from DAG. Armed with this understanding, the researchers further demonstrated that the genetic inhibition of DGAT1 suppresses radioresistance. In addition, they discovered that cladribine, a clinical drug, activates DGKB and inhibits DGAT1. This action sensitized GBM cells to radiotherapy both in vitro and in vivo ( in mouse models). "Our research has revealed cladribine as a radiosensitizer for GBM treatment by drug repurposing, which can offer multiple advantages," says Prof. Youn. "As an FDA-approved oral drug, the side-effects of cladribine are quite manageable and it has been well evaluated for pharmacokinetics. Additionally, the clinical trial period will be considerably shorter than that required for new drug development. In this regard, cladribine could become a standard future treatment for GBM." Taken together, this study demonstrates that DGKB and DGAT1 are potential therapeutic targets for overcoming GBM radioresistance. Moreover, drugs like cladribine could potentially replace existing treatment options with a new and more effective strategy. Reference Title of original paper: DGKB Mediates Radioresistance by Regulating DGAT1-dependent Lipotoxicity in Glioblastoma Journal: Cell Reports Medicine DOI: Media contact: Jae-Eun Lee [email protected] 82 51 510 7928 SOURCE Pusan National University

Glioblastoma (GBM) is a WHO grade IV brain tumor with dismal prognosis. Although post-surgical radiation chemotherapy combined with temozolomide is the standard line of treatment, GBM cells surviving radiotherapy contribute to tumor progression and recurrence even more aggressively. Researchers have now unveiled the mechanism of radioresistance in GBM cells, identifying therapeutic targets to overcome radioresistance. Moreover, the team has discovered a clinical drug that sensitizes GBM cells to radiotherapy and could replace temozolomide. Glioblastoma (GBM) is a WHO grade IV brain tumor with dismal prognosis. Although post-surgical radiation chemotherapy combined with temozolomide is the standard line of treatment, GBM cells surviving radiotherapy contribute to tumor progression and recurrence even more aggressively. Researchers have now unveiled the mechanism of radioresistance in GBM cells, identifying therapeutic targets to overcome radioresistance. Moreover, the team has discovered a clinical drug that sensitizes GBM cells to radiotherapy and could replace temozolomide. Post-surgical radiotherapy and temozolomide, a chemotherapeutic drug, targeting post-cell division is the current standard of care for glioblastoma (GBM) -- the most prevalent and lethal primary tumor of the central nervous system. An aggressive form of brain tumor, GBM is highly resistant to current therapies with high mortality and frequent recurrence. Moreover, GBM cells are highly radioresistant and contribute to tumor progression and recurrence even more aggressively when surviving radiotherapy. Thus, there is an urgent need to revise the standard treatment strategy and develop a new therapy to overcome the radioresistance of GBM cells. To this end, a team of researchers from Korea and USA led by Professor BuHyun Youn from Pusan National University in Korea has now unveiled a plausible mechanism underlying the radioresistance of GBM cells that involves regulating an internal steady state of lipid within the cells, known as "lipid homeostasis." "Put simply, radioresistant GBM cells prefer to stock up on fatty acids instead of utilizing them as an energy source in order to reduce mitochondrial reactive oxygen species that may cause damage to their DNA, RNA, and proteins, and, in turn, cell death," explains Prof. Youn. In their study published in Cell Reports Medicine, the researchers derived GBM stem cells from patients and established radioresistant cells for investigation. They showed that diacylglycerol kinase B (DGKB), a regulator of the intracellular level of diacylglycerol (DAG), was significantly suppressed in radioresistant GBM cells. This, in turn, increased DAG accumulation and decreased fatty acid oxidation, reducing mitochondrial lipotoxicity (harmful lipid accumulation in non-adipose tissues) in GBM cells and contributing to their radioresistance. Further, the team showed that the ionizing radiation induced an increase in the level of diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the formation of triglycerides from DAG. Armed with this understanding, the researchers further demonstrated that the genetic inhibition of DGAT1 suppresses radioresistance. In addition, they discovered that cladribine, a clinical drug, activates DGKB and inhibits DGAT1. This action sensitized GBM cells to radiotherapy both in vitro and in vivo ( in mouse models). "Our research has revealed cladribine as a radiosensitizer for GBM treatment by drug repurposing, which can offer multiple advantages," says Prof. Youn. "As an FDA-approved oral drug, the side-effects of cladribine are quite manageable and it has been well evaluated for pharmacokinetics. Additionally, the clinical trial period will be considerably shorter than that required for new drug development. In this regard, cladribine could become a standard future treatment for GBM." Taken together, this study demonstrates that DGKB and DGAT1 are potential therapeutic targets for overcoming GBM radioresistance. Moreover, drugs like cladribine could potentially replace existing treatment options with a new and more effective strategy.