bims-medica 2026-03-15 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–03–15
ten papers selected by
Brett Chrest, Wake Forest University

Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
Effect of Oral Ketone Body Intake on Human CD8+ T-Cell Immunometabolism.
β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
Venetoclax in Pediatric and Young Adult Patients With Relapsed/Refractory Solid Tumors: Results of a Phase 1 Study.
Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.
Demand-only energetics at 120 ATP per glucose: A reply to Lynch.
Pharmacological inhibition of glycolysis at the pyruvate-to-lactate conversion stage mitigates reperfusion injury without aggravating ischemic injury in mouse hearts.
Improved overall survival in acute myeloid leukemia over the last 15 years.
Addition of Venetoclax to Azacitidine Did Not Improve Survival in Acute Myeloid Leukemia and Was Not Well Tolerated: Real World Experience.
Revisiting the promise and pitfalls of mitochondrial replacement therapies.

Cancer Lett. 2026 Mar 11. pii: S0304-3835(26)00189-8. [Epub ahead of print] 218426

Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.

Emma Martell, Helgi Kuzmychova, Akaljot Grewal, Ujala Chawla, Charul Jain, Christopher M Anderson, Tanveer Sharif.

  Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a unique microenvironment that profoundly shapes tumor metabolism. Many brain tumors exhibit enhanced glucose uptake and fermentative glycolysis, a phenomenon classically described as the Warburg effect. However, accumulating evidence over the past two decades reveals that brain tumors rely on a far broader and more dynamic metabolic repertoire. Beyond glycolysis, metabolic processes such as the pentose phosphate pathway, serine biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, lipid metabolism, and purine and pyrimidine biosynthesis, all contribute to sustaining tumor growth, stemness, epigenetic identity, and therapeutic resistance. These metabolic adaptations differ markedly across tumor types and developmental contexts, from glioblastoma and diffuse astrocytoma to oligodendroglioma, ependymoma, pediatric high-grade glioma, medulloblastoma, and other embryonal tumors. In this review, we provide an overview of the current understanding of the major metabolic hallmarks of brain cancer, emphasizing mechanisms that support tumor identity, proliferation, and survival. We further highlight emerging metabolic vulnerabilities and discuss progress in developing therapies that target these pathways. Together, these insights illuminate how metabolism underpins the remarkable adaptability of brain tumors and suggest new avenues for precision treatment.

Keywords:  Cancer metabolism; brain tumors; epigenetics; metabolic therapy; tumor signaling

DOI:  https://doi.org/10.1016/j.canlet.2026.218426
Nutrients. 2026 Feb 27. pii: 778. [Epub ahead of print]18(5):

Effect of Oral Ketone Body Intake on Human CD8+ T-Cell Immunometabolism.

David Effinger, Simon Hirschberger, Thore Arntjen, Michaela Zell, Lesca Miriam Holdt, Simone Kreth.

  Background/Objectives: The ketogenic diet (KD) has been shown to exert beneficial effects on human immunity by enhancing cytotoxic T lymphocyte function through metabolic reprogramming. However, strict dietary restrictions limit adherence and complicate its use in clinical practice. Exogenous ketone supplements have therefore been promoted as a more feasible alternative to elevate ketone body levels without the need for dietary changes. The objective of this study was to assess whether ketone salt or ketone ester supplementation can reproduce KD-mediated immunometabolic effects on CD8+ T cells in healthy individuals. Methods: In a prospective interventional study, healthy volunteers received either ketone salts (KS) or ketone esters (KE) for three weeks. Plasma β-hydroxybutyrate (BHB) concentrations were determined, and CD8+ T-cell cytokine secretion, functional responses, and mitochondrial energy metabolism were analyzed. In a subgroup, KS supplementation was combined with a carbohydrate-restricted, non-ketogenic diet. Results: While KS supplementation resulted in a short-lived increase in plasma BHB concentrations followed by increased BHB uptake in immune cells, KE supplementation led to more sustained plasma BHB levels, however, without detectable intracellular BHB accumulation. Neither intervention affected CD8+ T-cell cytokine production, functional capacity, or mitochondrial energy metabolism, and KS intake combined with a carbohydrate-restricted, non-ketogenic diet likewise did not alter CD8+ T-cell immunometabolic parameters. Conclusions: Transient elevation of circulating ketone body levels through supplementation seems insufficient to reproduce the immunometabolic effects of a KD, which likely require broader metabolic adaptations. Thus, the impact of exogenous ketones on adaptive immunity in healthy individuals appears limited.

Keywords:  T-cell function; cytotoxic T cells; exogenous ketones; immunometabolism; ketogenic diet; ketone esters; ketone salts

DOI:  https://doi.org/10.3390/nu18050778
Cell. 2026 Mar 06. pii: S0092-8674(26)00169-8. [Epub ahead of print]

β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.

Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N Xu, Alberto Carturan, Chaoting Zhou, Kevin R Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Federico Stella, Andrew Lee, Siena Nason, Xianxin Hua, Michael Schneider, Madeleine Sleeman, Yunlin Zhang, Giulia Gabrielli, Ziqi Yang, Raymone Pajarillo, Ruchi Patel, Guido Ghilardi, Vrutti Patel, Akshita Joshi, Shunzhou Jiang, Yanqing Jiang, Patrizia Porazzi, Julia C Tchou, Brian Keith, Mingyao Li, Elise Chong, Stephen J Schuster, Michael Milone, Joshua Rabinowitz, Roddy S O'Connor, Christoph A Thaiss, Maayan Levy, Marco Ruella.

  The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.

Keywords:  CAR T cell; cancer therapy; ketogenic diet; metabolism; oxidative phosphorylation; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.cell.2026.02.004
Pediatr Blood Cancer. 2026 Mar 13. e70178

Venetoclax in Pediatric and Young Adult Patients With Relapsed/Refractory Solid Tumors: Results of a Phase 1 Study.

Daniel A Morgenstern, Giuseppe Barone, Nadege Corradini, Sara M Federico, Christian Flotho, Nicolas U Gerber, Seong Lin Khaw, Margaret E Macy, Andrew E Place, Kieuhoa T Vo, Mohamed Badawi, Xin Chen, Adam Luo, Mark A Rocco, Jeremy A Ross, Frank Scherer, Gauri Sunkersett, Maika Onishi, Kelly C Goldsmith.

   BACKGROUND: B-cell lymphoma 2 (BCL-2) is overexpressed in certain solid tumors (including neuroblastoma), representing a promising target. Venetoclax is a first-in-class, oral, highly selective BCL-2 inhibitor. We report safety, pharmacokinetics, and efficacy of venetoclax in children and young adults with relapsed/refractory solid tumors.
PROCEDURE: M13-833 (NCT03236857) was a Phase 1, open-label, global, two-part study. Patients received age-/weight-adjusted venetoclax (400 or 800 mg/day adult equivalent dose [AED]) continuously or intermittently (Days 1-10 of 21-day cycles) as monotherapy or with cyclophosphamide and topotecan (Cy-Topo; Cy 250 mg/m2/day + Topo 0.75 mg/m2/day; intravenously Days 1-5) and myeloid growth factor support. Primary objectives included safety and pharmacokinetic assessments of venetoclax; secondary objectives included efficacy.
RESULTS: Fifty-nine patients in the neuroblastoma (n = 36; median age: 8 years [range: 1-17]) and solid tumor cohorts (n = 23; median age: 16 years [range: 3-24]) were assessed. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 35/36 (97%) and 21/23 (91%) neuroblastoma and solid tumor patients, respectively; febrile neutropenia was the most common serious TEAE (neuroblastoma 69%; solid tumors 57%). TEAEs leading to discontinuation of venetoclax occurred in 17% (neuroblastoma) and 9% (solid tumors) of patients. No events of tumor lysis syndrome were observed. Peak venetoclax concentrations (Tmax) occurred 4-6 h post-dose; exposure was comparable across age/weight subgroups. Objective response rates were 31% (neuroblastoma) and 22% (solid tumors).
CONCLUSIONS: Recommended Phase 2 dose of venetoclax was 800 mg/day AED (Days 1-10 of 21-day cycles). Venetoclax combined with Cy-Topo chemotherapy had a predictable safety profile and showed modest clinical activity in these cohorts.

Keywords:  BCL‐2; Phase 1; neuroblastoma; pediatric; solid tumors; venetoclax

DOI:  https://doi.org/10.1002/1545-5017.70178
Blood Neoplasia. 2026 May;3(2): 100202

Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.

Yoke Seng Lee, Jonathan D Good, Noha Awais, Benjamin K Eschle, Maia S Lineberry, Jingting Lin, Mark Wunderlich, Jenna Thibodeau, Holly Edwards, Jessica L Teo, Sarah Bibeau, Morgan Wollman, George Karadimov, Nurefsan Sariipek, Basit Salik, Jean Acosta, Jenny Noel, David G J Cucchi, Erica A K DePasquale, Prafulla C Gokhale, Jerome Ritz, Yubin Ge, Peter G Miller, Fadi J Najm, Richard M Stone, Jacqueline S Garcia, Andrew A Lane, Courtney L Jones, Peter van Galen.

Targeted therapies, such as the BCL-2 inhibitor venetoclax, have expanded the treatment options for patients with acute myeloid leukemia (AML), but survival remains poor because of drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex messenger RNA structures in the 5' untranslated region (UTR) of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells relative to healthy hematopoietic stem and progenitor cells. Inhibition of eukaryotic initiation factor 4A (eIF4A) with the first-in-class small molecule zotatifin reduces the translation efficiency of transcripts related to the cell cycle and oncogenic signaling via the PI3K/AKT/mTOR pathway, as shown by ribosome profiling and gene set enrichment analysis. Western blot analysis corroborated these findings and demonstrated the downregulation of AKT, STAT-5, and MCL-1, factors implicated in resistance to venetoclax-based regimens. The combination of zotatifin and venetoclax synergistically kills AML cells in vitro and induces apoptosis across AML genotypes with selectivity toward progenitor-like cells in primary AML bone marrow (BM); however, its effect in primary healthy BM is limited. Using 3 in vivo xenograft models derived from patients with relapsed/refractory AML, the combination significantly suppressed the tumor burden and prolonged survival. These results support eIF4A-mediated protein translation as a therapeutic target in AML and highlight the potential of zotatifin and venetoclax in relapsed/refractory disease.

DOI: https://doi.org/10.1016/j.bneo.2026.100202
Biochim Biophys Acta Bioenerg. 2026 Mar 06. pii: S0005-2728(26)00007-1. [Epub ahead of print]1867(2): 149587

Demand-only energetics at 120 ATP per glucose: A reply to Lynch.

William F Martin.

  Recently in these pages, a paper by Lynch appeared in response to a report showing that his numbers for biosynthetic costs (ATP demand) in cells are inflated, so much so that they would require E. coli to obtain >100 ATP per glucose and mitochondria to obtain >240 ATP per glucose. The inflated estimates trace to one factor: Lynch exclusively considers ATP demand and systematically neglects ATP supply-the essence of bioenergetics. Thermodynamics stipulate that a cell cannot grow if its ATP demands exceed its ATP supply. Here I compare Lynch's calculated ATP demands to laboratory measurements of the ATP supply that E. coli synthesizes during cell division. The results bear out my case, and leave no doubt: Lynch's calculations require E. coli to synthesize ∼120 ATP per glucose, which is thermodynamically impossible. As a consequence, his demand-only 'energetic' attacks on mitochondria and endosymbiosis in evolution are baseless.

Keywords:  Bioenergetics; Biosynthetic costs; Costs of a gene; Energy in evolution; Eukaryogenesis; Mitochondria

DOI:  https://doi.org/10.1016/j.bbabio.2026.149587
Eur J Pharmacol. 2026 Mar 06. pii: S0014-2999(26)00222-0. [Epub ahead of print]1019 178740

Pharmacological inhibition of glycolysis at the pyruvate-to-lactate conversion stage mitigates reperfusion injury without aggravating ischemic injury in mouse hearts.

Bi-Feng Yao, Jun-Ming Tan, Hao-Nan Xing, Xiu-Ju Luo, Jun Peng.

  While timely reperfusion is essential to rescue ischemic myocardium, it paradoxically induces additional reperfusion injury. Energy metabolic reprogramming is implicated in this process, yet its precise mechanisms remain poorly understood. This study aims to compare the energy metabolic profiles during myocardial ischemia versus reperfusion phases, and to evaluate whether stage-specific inhibition of glycolysis could differentially mitigate injury. In a mouse model, glycolysis was enhanced during myocardial ischemia, accompanied by suppressed glucose and fatty acid oxidation. In contrast, both glycolysis and fatty acid oxidation were upregulated while glucose oxidation remained suppressed in mice hearts subjected to myocardial ischemia/reperfusion. Inhibiting glycolysis at its initial step (glucose phosphorylation) using a hexokinase inhibitor alleviated reperfusion injury but exacerbated ischemic injury. However, inhibition at the pyruvate-to-lactate conversion stage via a lactate dehydrogenase inhibitor alleviated reperfusion injury without aggravating ischemic injury. Similar results were observed in cultured cardiomyocytes exposed to either hypoxia alone or hypoxia/reoxygenation. Based on these observations, we conclude that adaptive glycolysis upregulation during ischemia contributes to energy metabolic reprogramming in reperfusion. Precise intervention at the pyruvate-to-lactate conversion stage restores glycolytic-glucose oxidation coupling in the heart, thereby mitigating reperfusion injury without aggravating ischemic damage.

Keywords:  Energy metabolic reprogramming; Fatty acid oxidation; Glucose oxidation; Glycolysis; Ischemia/reperfusion injury; Metabolic uncoupling; Myocardial ischemia

DOI:  https://doi.org/10.1016/j.ejphar.2026.178740
Leuk Lymphoma. 2026 Mar 07. 1-9

Improved overall survival in acute myeloid leukemia over the last 15 years.

Shailesh Simkhada, Luna Acharya, Bradley Loeffler, Aditya Ravindra, Abhishree Pyakuryal, Spriha Parajuli, Vijaya Raj Bhatt, Prajwal Dhakal.

  This study evaluated changes in overall survival (OS) among patients diagnosed with AML from 2004 to 2019 using the National Cancer Database. The analysis included 67,895 patients aged ≥ 18 years, divided into three diagnosis eras: 2004-2010, 2011-2016, and 2017-2019. Median OS steadily improved over time: 7.6 months in 2004-2010, 8.6 months in 2011-2016, and 10.4 months in 2017-2019. The impact of age, AML subtype, chemotherapy, and HCT on OS changed over time, especially showing a stronger positive association with chemotherapy and HCT after 2017. OS remained lower in males, non-Hispanics, racial groups other than Black or White, individuals with a CCI> 0, those with public or no insurance, and those with an annual income <$35000. Our findings demonstrate that survival has improved significantly, coinciding with the introduction of venetoclax-based regimens and targeted therapies for FLT3 and IDH1/2 mutations, although disparities by socioeconomic factors persist.

Keywords:  Acute myeloid leukemia; chemotherapy; hematopoeitic cell transplantation; overall survival; survival disparities

DOI:  https://doi.org/10.1080/10428194.2026.2635662
Cancers (Basel). 2026 Mar 05. pii: 841. [Epub ahead of print]18(5):

Addition of Venetoclax to Azacitidine Did Not Improve Survival in Acute Myeloid Leukemia and Was Not Well Tolerated: Real World Experience.

David Yanni, Nupur Krishnan, Rouslan Kotchetkov.

  Introduction: Front-line therapy with Azacitidine (AZA) + Venetoclax (Ven) improved overall survival (OS) and remissions in acute myeloid leukemia (AML) patients ineligible for standard induction. Less is known about the outcome of AML treated with AZA + Ven in the "real world". Methods: We assessed the comparative pattern of administration, tolerability, efficacy and safety of AZA vs. AZA + Ven administered at our cancer centre. We retrospectively reviewed all patients treated with AZA alone or AZA + Ven. Patients who received less than one cycle or proceeded with consolidative stem cell transplant were excluded. Results: A total of 53 patients, median age 77 years, received AZA, and 23 patients, median age 73 years, received AZA + Ven. Among those, 69% and 47.8% were ≥75 years old, respectively. Only 52% received Ven doses above 200 mg. Mean time on therapy was 13.1 months in AZA vs. 5.9 months in AZA + Ven. Treatment delays occurred in 22.6% of AZA and 34.8% of AZA + Ven patients, primarily due to infections and cytopenias. Neutropenia grade 3/4 occurred in 28.3% of AZA vs. 56.5% of AZA + Ven patients. Thrombocytopenia grade 3/4 occurred in 15.1% of AZA and 51.2% of AZA + Ven patients. Anemia grade 3/4 occurred in 5.7% of AZA vs. 30.4% of AZA + Ven patients. Moreover, 69.8% of AZA and 69.5% AZA + Ven patients reached stable disease/partial and complete remission. Median overall survival (OS) was similar: 18 months in AZA vs. 14 months in the AZA + Ven group, p = 0.905. Conclusions: In a community setting, the addition of Venetoclax to AZA did not improve overall survival or disease control, mainly due to low tolerability and higher toxicity. However, these results should be interpreted cautiously due to a significant imbalance in the cytogenetic risk profiles and lower tolerability in the combined group. This suggests the need for a larger study with adjusted analyses.

Keywords:  acute myeloid leukemia; azacitidine; efficacy; real world; safety; venetoclax

DOI:  https://doi.org/10.3390/cancers18050841
Hum Reprod. 2026 Mar 08. pii: deag020. [Epub ahead of print]

Revisiting the promise and pitfalls of mitochondrial replacement therapies.

Nuno Costa-Borges, Dagan Wells.

  Mitochondrial replacement therapies (MRTs) have been proposed as a means of avoiding the transmission of pathogenic mitochondrial DNA (mtDNA) mutations from mother to child. While clinical cases using this groundbreaking strategy have now been reported for the two principal MRT methods-pronuclear transfer and maternal spindle transfer-recent data continues to raise questions about the reliability of these approaches for disease prevention.

Keywords:  female infertility; maternal spindle transfer; mitochondrial diseases; mitochondrial replacement therapies; mitochondrial reversal; oocyte quality; pronuclear transfer

DOI:  https://doi.org/10.1093/humrep/deag020