bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2025–09–14
sixteen papers selected by
Brett Chrest, Wake Forest University
  1. An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
  2. β-Hydroxybutyrate promotes chemoresistance and proliferation in breast cancer cells.
  3. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  4. Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
  5. L-5-[11C]-glutamine PET of breast cancer: Preclinical studies in mouse models.
  6. Prospects of the therapeutic approaches of ketogenic diet on the clinical outcomes of cancer: A scoping review.
  7. Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
  8. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
  9. Optimization of 13C stable isotope labeling for the study of tricarboxylic cycle intermediates in mouse models.
  10. Oncologists' Perspectives on Ketogenic Diets in Pediatric Brain Cancer: Potential, Challenges, and the Path Forward.
  11. ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.
  12. Absolute measurement of fast and slow neuronal signals with fluorescence lifetime photometry at high temporal resolution.
  13. Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.
  14. Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
  15. Efficacy of Venetoclax Combined with Azacitidine in Elderly Patients with Relapsed Acute Myeloid Leukemia.
  16. CF10 Displayed Improved Activity Relative to 5-FU in a Mouse CRLM Model Under Conditions of Physiological Folate.
  1. Nat Metab. 2025 Sep 08.
    An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Rachel 'Rae' J House, Althea Waldhart, Kelly H Sokol, Samuel R Daniels, Cameron J Lee, Joseph Longo, Amy Johnson, Vincent J Sartori, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse KrasG12D; Trp53-/- pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.
    DOI:  https://doi.org/10.1038/s42255-025-01366-y
  2. Biochem Biophys Rep. 2025 Dec;44 102217
    β-Hydroxybutyrate promotes chemoresistance and proliferation in breast cancer cells.
    Milad Mashinchian, Somayeh Vandghanooni, Amir Reza Karamibonari, Morteza Eskandani.
      Breast cancer is the most prevalent cancer among women, posing significant challenges due to its heterogeneity. Recent studies suggest that the ketogenic diet (KD) may enhance chemotherapy efficacy by modulating cancer cell metabolism, particularly through the elevation of ketone bodies like β-hydroxybutyrate (BHB). This study investigates the effects of BHB on breast cancer cells using both 2D and 3D culture models, focusing on its role in developing resistance to fluorouracil (5-FU). We utilized CF41.Mg canine mammary gland cancer cells and MCF7 human breast cancer cells to assess BHB's effects as a pre-treatment and post-treatment under varying glucose conditions. The findings indicated that BHB notably increased cell viability, proliferation, and migration. Pre-treatment resulted in a 52.94 % increase in viability for CF41.Mg cells and a 54.73 % increase for MCF7 cells after 48 h, compared to treatment with 5-FU alone. This enhancement persisted at 72 h, indicating BHB's potential to promote resistance to 5-FU. In 3D spheroid models, which better mimic the tumor microenvironment, BHB pre-treatment significantly increased spheroid size and conferred resistance to 5-FU in both cell lines. Additionally, BHB pre-treatment elevated the expression of proliferation markers such as Ki-67 and tumorigenic markers like MUC-1 (Mucin 1), while showing no significant impact on mesenchymal markers like N-cadherin and vimentin. These findings suggest that BHB significantly increases resistance to 5-FU, indicating that BHB may enable cancer cells to evade chemotherapy-induced stress. Our findings raise important questions about the potential dual role of BHB and KD in promoting cancer cell survival while potentially complicating treatment outcomes.
    Keywords:  Breast cancer; Fluorouracil; Ketogenic diet; Tumorigenesis; β-Hydroxybutyric acid
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102217
  3. Nat Metab. 2025 Sep 10.
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1038/s42255-025-01363-1
  4. Int J Mol Sci. 2025 Aug 30. pii: 8466. [Epub ahead of print]26(17):
    Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
    Melvin Li, Sarah R Amend, Kenneth J Pienta.
      Metabolism is a tightly controlled, but plastic network of pathways that allow cells to grow and maintain homeostasis. As a normal cell transforms into a malignant cancer cell and proliferates to establish a tumor, it utilizes a variety of metabolic pathways that support growth, proliferation, and survival. Cancer cells alter metabolic pathways in different contexts, leading to complex metabolic heterogeneity within a tumor. There is an unmet need to characterize how cancer cells alter how they use resources from the environment to evolve, spread to other sites of the body, and survive current standard-of-care therapies. We review key techniques and methods that are currently used to study cancer metabolism and provide drawbacks and considerations in using one over another. The goal of this review is to provide a methods' guide to study different aspects of cell and tissue metabolism, how they can be applied to cancer, and discuss future perspectives on advancements in these areas.
    Keywords:  13C-metabolic flux analysis; Seahorse metabolic flux analysis; cancer metabolism; fluorescent probes; genetically encoded fluorescent biosensors; isotope tracing; untargeted metabolomics
    DOI:  https://doi.org/10.3390/ijms26178466
  5. Nucl Med Biol. 2025 Aug 30. pii: S0969-8051(25)00101-5. [Epub ahead of print]150-151 109092
    L-5-[11C]-glutamine PET of breast cancer: Preclinical studies in mouse models.
    Christopher T Hensley, Prashanth Padakanti, Raheema Damani, Christina Dulal, Hoon Choi, Shihong Li, Jianbo Cao, Hsiaoju Lee, Austin Pantel, Elizabeth Li, David Mankoff, Rong Zhou.
       BACKGROUND: Glutamine is an important metabolic substrate in many aggressive tumors, with comparable importance to glucose metabolism. Utilizing human breast cancer mouse xenograft models, we studied the kinetics of the PET imaging agent, L-5-[11C]-glutamine ([11C]glutamine or [11C]GLN) a biochemical authentic substrate for glutamine metabolism, to further characterize the metabolism of glutamine and downstream labeled metabolites. Studies were performed with and without inhibition of the enzyme, glutaminase (GLS), the first step in glutamine catabolism that generates glutamate, and key target for therapy directed to glutamine-metabolizing cancers.
    METHODS: The study used xenograft mouse models for two breast cancer cell lines, HCC1806, a highly glutaminolytic triple-negative cell line, and MCF-7, a hormone receptor positive line with only low levels of glutaminolysis. Mice were injected with [11C]glutamine and either underwent metabolite analysis or dynamic PET imaging. The contributions of individual metabolites to the total 11C-activity signal in blood and tumor tissue were measured at 10, 20, and 30 min via HPLC. We measured fractional activity in the form of [11C]glutamine versus labeled metabolites, focusing on L-5-[11C]-glutamate ([11C]glutamate or [11C]GLU), and any activity in the other metabolite small molecules labeled with 11C (11C-other or 11C-OTH). Additionally, the contribution of [11C]CO2 to total 11C-activity was measured. Together with image-based uptake curves, this generated estimated time activity curves for [11C]glutamine and downstream metabolites in both xenograft models treated with vehicle or GLS inhibitor (CB-839).
    RESULTS: We found that, out to 30 min post-injection, the majority of radioactivity in highly glutaminolytic tumors (HCC1806) was in the form of [11C]glutamine and [11C]glutamate, with relatively low amounts of radioactivity in metabolites downstream of glutamate including [11C]CO2. In HCC1806 tumors, [11C]glutamate was retained in the large cellular glutamate pool leading to a majority fraction of total radioactivity in tumor tissue that is greater than the fraction within the blood, with this tumoral fractional pattern reversing with CB-839. This phenomenon leads to a total tumor time-activity curve that is only marginally different before and after CB-839. The radioactivity patterns of MCF-7 tumors after vehicle treatment were similar HCC1806 tumors after CB-839 treatment.
    CONCLUSION: Our studies on [11C]glutamine in breast cancer models show significant retention of 11C-activity in the form of [11C]glutamate in tumors with high GLS activity that confounds non-invasive inference of GLS activity. This suggests limited utility for [11C]glutamine PET for inferring tumor GLS activity and its specific antagonism by drug inhibitors. Our analysis of labeled metabolites in mouse models does, however, yield insights that include the retention of glutamate generated by GLS-mediated catabolism in a large cellular pool and also provide data that is the basis for a compartmental model of glutamine metabolism that is the subject of a companion paper.
    Keywords:  Cancer; Glutaminase; L-5-[(11)C]-glutamate; L-5-[(11)C]-glutamine; Metabolism
    DOI:  https://doi.org/10.1016/j.nucmedbio.2025.109092
  6. Bull Cancer. 2025 Sep 05. pii: S0007-4551(25)00332-7. [Epub ahead of print]
    Prospects of the therapeutic approaches of ketogenic diet on the clinical outcomes of cancer: A scoping review.
    Anmar Al-Taie, Jouwana Elmasri.
      The scientific community has become more enthusiastic about ketogenic diet (KD) to improve the outcomes in medical conditions, including cancer by exploiting the reprogramed metabolism of cancer cells, making the diet a promising candidate as an adjuvant cancer therapy. From this perspective, the aim of this study was to provide a broad overview covering the therapeutic effects, evaluating the clinical evidence of clinical studies underlying the implementation of the KD in the context of cancer treatment and prognosis. A scoping literature search between the years 1990 and 2023 was carried out by using PRISMA guidelines and searching through different databases of the clinical studies supporting the effectiveness and benefits of KD in various carcinomas that could provide findings of evidence on the prognosis and clinical outcomes of cancer treatment. A total of 23 cancer-related publications were included, 12 of which focused on brain cancer particularly glioblastoma multiforme (GBM), 4 on both breast and ovarian cancers, and 3 on pancreatic cancer. A total of 10 publications were reported as clinical trials regarding cancers of the brain (4 studies), breast (2 studies), and ovarian (4 studies). Case report studies were reported in 3 publications for brain cancer, and 2 publications for breast cancer. Nearly almost of the studies found that there was a potential role of KD in the prognosis of cancer treatment. The current review suggests that cancer patients may get favorable effects from the implementation of KD to support clinical outcomes of cancer treatment.
    Keywords:  Brain cancer; Breast cancer; Cancer; Glioblastoma multiforme; Ketogenic diet
    DOI:  https://doi.org/10.1016/j.bulcan.2025.05.012
  7. J Biol Chem. 2025 Sep 08. pii: S0021-9258(25)02545-1. [Epub ahead of print] 110693
    Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
    Oliver J Newsom, Eric Zheng, Lucas B Sullivan.
      Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS. Here, we use a combination of live-cell imaging and quantitative lipidomics to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation, with serum metal and lipid components serving as crucial metabolic resources. Despite access to a wide range of lipid classes available in serum, we find albumin-bound lipids are the primary species consumed by cancer cells. Furthermore, we find that supplementing with additives that contain necessary metals and any of the albumin-associated lipid classes can obviate the FBS requirement for cancer cell proliferation. Using this defined system, we investigated cancer cell lipid consumption dynamics, finding that albumin-associated lipids are primarily consumed through a mass-action mechanism with minimal competition within or amongst lipid classes. We also find that lipid scavenging is a dominant lipid acquisition route and is necessary for cancer cell proliferation. This work therefore identifies metabolic contributions of serum and provides a framework for building defined culture systems that sustain cell proliferation without the undefined contributions of serum.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110693
  8. Nat Metab. 2025 Sep 09.
    Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
    Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.
      The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01358-y
  9. Methods. 2025 Sep 10. pii: S1046-2023(25)00201-4. [Epub ahead of print]
    Optimization of 13C stable isotope labeling for the study of tricarboxylic cycle intermediates in mouse models.
    Jarrod Laro, Monica Ness, Joseane Godinho, Randy Coats, Laura-Isobel McCall.
      The tricarboxylic acid cycle (TCA), also known as the Krebs Cycle or the citric acid cycle, is an essential metabolic pathway involved in energy production that is often impacted by disease, making it of key interest to identify effective, affordable, and simple ways to monitor the impact of disease on TCA metabolism. 13C-based stable isotope labeling is a useful technique to track pathway alterations in living hosts. However, infusion-based methodologies are slow and expensive despite achieving steady-state labeling. Bolus-based methods are cheaper, faster, and compatible with biohazardous models, but require optimization to achieve maximum labeling. Herein, we performed bolus-based stable isotope labeling experiments in mouse models to identify the optimal dosage amount, label administration length, fast length prior to label administration, 13C-labeled precursor, and route of administration for the TCA cycle in the esophagus, heart, kidney, liver, plasma, and proximal colon. 13C-glucose at a concentration of 4 mg/g administered via intraperitoneal injection followed by a 90 min label incorporation period achieved the best overall TCA labeling. For most organs, a 3 h fast prior to label administration improved labeling, but labeling in the heart was better with no fasting period, showcasing the need to optimize methodology on an organ-by-organ basis. We also identified that bolus administration of glucose provided little impact on metabolism compared to vehicle control. The experiments outlined here provide critical information for designing in vivo stable isotope labeling experiments for the study of the TCA cycle.
    Keywords:  Bolus; Carbon-13; Fasting; Glucose; Labeling; Mice; TCA cycle
    DOI:  https://doi.org/10.1016/j.ymeth.2025.09.004
  10. Nutrients. 2025 Aug 31. pii: 2843. [Epub ahead of print]17(17):
    Oncologists' Perspectives on Ketogenic Diets in Pediatric Brain Cancer: Potential, Challenges, and the Path Forward.
    Hanan AlMutairi, Madhumita Dandapani, Khawar Siddiqui, Fiona McCullough.
      Background/objectives: Treating pediatric brain tumors remains challenging due to the limitations of conventional therapies, which often damage healthy cells. Ketogenic diets (KDs)-high in fat and low in carbohydrates-have emerged as potential adjunct therapies by limiting glucose availability and offering ketones as an alternative energy source proposed to hinder tumor growth. However, due to limited awareness, there is hesitancy to recommend KDs. Methods: This study assessed oncologists' knowledge and perceptions in Saudi Arabia regarding KD use in pediatric brain cancer patients. A cross-sectional survey was conducted with 94 oncologists from five major Riyadh healthcare centers, examining their knowledge, safety concerns, feasibility, and perceived efficacy of KDs. Results: Results showed that 67% correctly identified the basic composition of KDs, though 43% were neutral about its safety. Concerns about malnutrition and side effects were common and 53% found adherence to the diet challenging in pediatric patients. While 48.9% believed KDs could improve outcomes when combined with standard therapies, many stressed the importance of tailoring recommendations to individual medical conditions, including patient age, treatment stage, and overall nutritional status. Participants' responses revealed variability in knowledge and perception levels regarding KDs, with consultants and internationally educated oncologists generally expressing more favorable views compared to fellows, who showed greater hesitancy. Conclusions: This study shows a mixed level of knowledge and perceptions among oncologists, reflecting a lack of consensus about KDs' safety, feasibility, and potential benefits. These findings suggest the need for further education, clearer guidelines, and interdisciplinary collaboration to support informed decision-making, particularly in the local context.
    Keywords:  Saudi Arabia; brain neoplasms; diet therapy; healthcare surveys; ketogenic diet; pediatric oncology
    DOI:  https://doi.org/10.3390/nu17172843
  11. FEBS Lett. 2025 Sep 12.
    ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.
    Mekala Gunasekaran, Gloriana Campos, Natalya M Wells, Khanhlinh Lambuu, Isabelle Draper, Christina A Pacak, Peter B Kang.
      Acyl-coenzyme A synthetase short-chain family member-2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the discovery of a muscular dystrophy associated with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a key enzyme in cholesterol synthesis, we studied Acss2 in mice and the orthologous gene AcCoA in flies. Skeletal muscle from Acss2-/- mice showed atrophic fibers, lipid accumulation, and depleted NADH levels, while myoblasts from these mice displayed precocious differentiation. Exercise induced fatigue in the Acss2-/- mice, which was accentuated by inhibition of ATP-citrate lyase (ACLY) activity. AcCoA knockdown yielded reduced body sizes and locomotor defects in Drosophila. ACSS2 is vital for skeletal muscle function and merits study as a potential factor in muscle diseases related to cholesterol metabolism. Impact statement ACSS2 catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the increasingly apparent links between cholesterol metabolism and skeletal muscle function, we investigated ACSS2 deficiency in mouse and fly models. We identified defects in muscle morphology, muscle metabolism, and motor function. ACSS2 is vital for skeletal muscle.
    Keywords:  ACSS2; cholesterol metabolism; muscle development
    DOI:  https://doi.org/10.1002/1873-3468.70152
  12. Neuron. 2025 Sep 11. pii: S0896-6273(25)00598-7. [Epub ahead of print]
    Absolute measurement of fast and slow neuronal signals with fluorescence lifetime photometry at high temporal resolution.
    Bart Lodder, Tarun Kamath, Ecaterina Savenco, Berend Röring, Michelle Siegel, Julie A Chouinard, Suk Joon Lee, Caroline Zagoren, Paul Rosen, Isa Hartman, Joshua Timmins, Roger Adan, Lin Tian, Bernardo L Sabatini.
      Dynamic signaling by extracellular and intracellular molecules impacts downstream pathways in a cell-type-specific manner. Fluorescent reporters of such signals are typically optimized to detect fast, relative changes in concentration of target molecules. They are less well suited to detect slowly changing signals and rarely provide absolute measurements. Here, we developed fluorescence lifetime photometry at high temporal resolution (FLIPR), which utilizes frequency-domain analog processing to measure the absolute fluorescence lifetime of genetically encoded sensors at high speed but with long-term stability and picosecond precision. We applied FLIPR to investigate dopamine signaling in functionally distinct striatal subregions. We observed higher tonic dopamine levels in the tail of the striatum compared with the nucleus accumbens core and differential and dynamic responses in phasic and tonic dopamine to appetitive and aversive stimuli. Thus, FLIPR reports fast and slow timescale neuronal signaling in absolute units, revealing previously unappreciated spatial and temporal variation even in well-studied signaling systems.
    Keywords:  absolute measurement; behaving mice; fiber photometry; fluorescence lifetime photometry; freely moving mice; neurotransmitter; nucleus accumbens; phasic dopamine; tail of striatum; tonic dopamine
    DOI:  https://doi.org/10.1016/j.neuron.2025.08.013
  13. JCI Insight. 2025 Sep 09. pii: e187758. [Epub ahead of print]10(17):
    Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.
    Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig.
      Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic disorders. Metabolic flux analyses confirmed robust BCAT inhibition, with reduction of labeling of proximal and distal BCAA-derived metabolites in MMA hepatocytes. In vivo experiments verified the BCAT inhibition, but total levels of distal BCAA catabolite disease markers and clinical symptoms were not normalized, indicating contributions of substrates other than BCAA to these distal metabolite pools. Our study demonstrates the importance of understanding the underlying pathology of metabolic disorders for identification of therapeutic targets and the use of multiple, complementary models to evaluate them.
    Keywords:  Amino acid metabolism; Genetics; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.187758
  14. Sci Adv. 2025 Sep 12. 11(37): eadt3873
    Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
    Kelly McCastlain, Catherine Welsh, Yonghui Ni, Liang Ding, Ti-Cheng Chang, Robert J Autry, Besian I Sejdiu, Qingfei Pan, Melissa Franco, Wenan Chen, Huiyun Wu, Veronica Gonzalez-Pena, Patrick Schreiner, Sasi Arunachalam, Joung Hyuck Joo, Samuel Brady, Jinghui Zhang, Charles Gawad, William E Evans, M Madan Babu, Konstantin Khrapko, Jiyang Yu, Gang Wu, Stanley Pounds, Mondira Kundu.
      Somatic mitochondrial DNA (mtDNA) mutations are frequently observed in tumors, yet their role in pediatric cancers remains poorly understood. The heteroplasmic nature of mtDNA-where mutant and wild-type mtDNA coexist-complicates efforts to define its contribution to disease progression. In this study, bulk whole-genome sequencing of 637 matched tumor-normal samples from the Pediatric Cancer Genome Project revealed an enrichment of functionally impactful mtDNA variants in specific pediatric leukemia subtypes. Collectively, the results from single-cell sequencing of five diagnostic leukemia samples demonstrated that somatic mtDNA mutations can arise early in leukemogenesis and undergo positive selection during disease progression, achieving intermediate heteroplasmy-a "sweet spot" that balances mitochondrial dysfunction with cellular fitness. Network-based systems biology analyses link specific heteroplasmic mtDNA mutations to metabolic reprogramming and therapy resistance. We reveal somatic mtDNA mutations as a potential source of functional heterogeneity and cellular diversity among leukemic cells, influencing their fitness and shaping disease progression.
    DOI:  https://doi.org/10.1126/sciadv.adt3873
  15. Mediterr J Hematol Infect Dis. 2025 ;17(1): e2025058
    Efficacy of Venetoclax Combined with Azacitidine in Elderly Patients with Relapsed Acute Myeloid Leukemia.
    Mengni Yan, Gang Wang, Jiaheng Wang, Linjuan Xu.
       Background: Elderly patients with relapsed acute myeloid leukemia (AML) have limited treatment options and a poor prognosis. Venetoclax combined with azacitidine has shown promising activity in newly diagnosed or relapsed/refractory AML, but real-world data on older populations remain scarce. This study aimed to evaluate the efficacy, safety, and prognostic factors - including select blood biomarkers - of venetoclax plus azacitidine in elderly patients with relapsed AML.
    Methods: We conducted a single-center retrospective review of patients aged ≥65 years diagnosed with relapsed AML who received venetoclax plus azacitidine between January 2018 and December 2022. Patient demographics, baseline disease characteristics, and treatment details were collected. Blood biomarkers, such as lactate dehydrogenase (LDH), C-reactive protein (CRP), and selected molecular markers (including FLT3-ITD and NPM1 mutations), were also assessed at baseline to evaluate their prognostic value. The primary endpoint was the overall response rate (ORR), defined as the sum of complete Remission (CR) and CR with incomplete hematologic recovery (CRi). Secondary endpoints included overall survival (OS), event-free survival (EFS), and safety. Prognostic factors were identified through univariate and multivariate analyses using Cox proportional hazards models. Survival curves were constructed via the Kaplan-Meier method.
    Results: A total of 50 patients (median age, 72 years; range, 65-82) met the inclusion criteria. The ORR was 60% (40% CR and 20% CRi). The median OS was 9.2 months (95% CI: 6.8-11.5), and the median EFS was 6.0 months (95% CI: 4.2-8.3). Common Grade 3-4 adverse events included neutropenia (46%) and thrombocytopenia (32%). The 30-day treatment-related mortality rate was 4%. Elevated baseline LDH (≥ the upper limit of normal) was associated with reduced OS (p=0.03). Patients with high CRP levels and/or adverse molecular markers, such as FLT3-ITD positivity, also showed a trend toward poorer survival, which, however, did not reach statistical significance in the multivariate model. Multivariate analysis confirmed poor Eastern Cooperative Oncology Group (ECOG) performance status, baseline LDH level, and adverse cytogenetics as independent predictors of reduced OS.
    Conclusion: Venetoclax combined with azacitidine demonstrated encouraging efficacy and manageable toxicity in this retrospective analysis of elderly patients with relapsed AML. Elevated LDH and adverse molecular/cytogenetic profiles were associated with worse outcomes. These findings highlight the importance of integrating blood biomarker assessment into routine evaluation and suggest venetoclax-based regimens may be a viable therapeutic option in older, relapsed AML populations. Prospective multicenter studies are warranted to confirm these results and refine patient selection.
    Keywords:  Azacitidine; Elderly patients; Prognostic biomarkers; Relapsed acute myeloid leukemia; Venetoclax
    DOI:  https://doi.org/10.4084/MJHID.2025.058
  16. Cancers (Basel). 2025 Aug 23. pii: 2739. [Epub ahead of print]17(17):
    CF10 Displayed Improved Activity Relative to 5-FU in a Mouse CRLM Model Under Conditions of Physiological Folate.
    Charles Chidi Okechukwu, Xue Ma, Wencheng Li, Ralph D'Agostino, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, William H Gmeiner.
       BACKGROUND/OBJECTIVE: At least 25% of colorectal cancer (CRC) patients develop liver metastases (CRLM), and chemotherapeutic regimens based on the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) provide a survival advantage, but long-term survival is uncommon. The primary molecular target of FP drugs is thymidylate synthase (TS).
    METHODS: A TS/Top1 dual-targeting cytotoxic mechanism for CF10/LV was confirmed by TS ternary complex detection by Western blot and by immunofluorescence detection of Top1 cleavage complexes. CF10/LV activated the ATR/Chk1 pathway consistent with enhanced replication stress and induced apoptosis. In vivo studies showed CF10 and CF10/LV eradicated liver metastasis in a CRLM model without scarring or weight loss, displaying therapeutic advantages relative to legacy FPs.
    RESULTS: We demonstrated that a nanoscale FP polymer, CF10, displayed greater potency than expected based on FP content in part through more direct conversion to the TS-inhibitory metabolite, FdUMP. In this study, we tested CF10 for potency advantages relative to 5-FU and trifluorothymidine (TFT, the FP component of TAS-102) and confirmed a general potency advantage for CF10 in CRC cell lines in the Broad Institute PRISM screen. We demonstrated that this potency advantage is retained in CRC cells cultured with human-like folate levels and is enhanced by LV co-treatment to a similar extent as that by 5-FU. Our results confirm CF10 development proceeding as a CF10/LV combination. Mechanistically, CF10 cytotoxicity closely correlates with poisons of DNA topoisomerase 1 (Top1) in the PRISM screen relative to 5-FU and TFT.
    CONCLUSIONS: Our pre-clinical data support an early-phase clinical trial for CF10 for treating liver-metastatic CRC.
    Keywords:  colorectal cancer; fluoropyrimidine; leucovorin; replication stress; thymidylate synthase; topoisomerase 1
    DOI:  https://doi.org/10.3390/cancers17172739
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