bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–04–23
eleven papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
  2. Learning the metabolic language of cancer.
  3. Targeting autophagy and lipid metabolism in cancer stem cells.
  4. STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2.
  5. Editorial: Cancer stem cell differentiation: A realistic potential therapeutic option?
  6. The metabolic cross-talk between cancer and T cells.
  7. Patients with secondary acute myeloid leukemia undergoing allogeneic stem-cell transplant have inferior outcomes than de novo acute myeloid leukemia regardless minimal residual disease level by flow cytometry.
  8. Warburg Effect Revisited: Embodiment of Classical Biochemistry and Organic Chemistry. Current State and Prospects.
  9. Clinical Analysis of Pediatric T-Cell Acute Lymphoblastic Leukemia Using the MRD-Oriented Strategy System.
  10. Editorial: The immune escape mechanism and novel immunotherapeutic strategies of leukemia.
  11. Immune-checkpoint inhibitor resistance in cancer treatment: Current progress and future directions.
  1. Cancer Drug Resist. 2023 ;6(1): 138-150
    Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
    Yoko Tabe, Marina Konopleva.
      In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
    Keywords:  Bone marrow microenvironment; acute myeloid leukemia; energy metabolism; fatty acid oxidation; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.20517/cdr.2022.133
  2. Nature. 2023 Apr;616(7958): 670-671
    Learning the metabolic language of cancer.
    Minervo Perez, Jordan L Meier.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-01024-x
  3. Biochem Pharmacol. 2023 Apr 13. pii: S0006-2952(23)00141-7. [Epub ahead of print]212 115550
    Targeting autophagy and lipid metabolism in cancer stem cells.
    Bandana Chakravarti, Jawed Akhtar Siddiqui, Rohit Anthony Sinha, Sana Raza.
      Cancer stem cells (CSCs) are a subset of cancer cells with self-renewal ability and tumor initiating properties. Unlike the other non-stem cancer cells, CSCs resist traditional therapy and remain a major cause of disease relapse. With the recent advances in metabolomics, various studies have demonstrated that CSCs have distinct metabolic properties. Metabolic reprogramming in CSCs contributes to self-renewal and maintenance of stemness. Accumulating evidence suggests that rewiring of energy metabolism is a key player that enables to meet energy demands, maintains stemness, and sustains cancer growth and invasion. CSCs use various mechanisms such as increased glycolysis, redox signaling, and autophagy modulation to overcome nutritional deficiency and sustain cell survival. The alterations in lipid metabolism acquired by the CSCs support biomass production through increased dependence on fatty acid synthesis and β-oxidation, and contribute to oncogenic signaling pathways. This review summarizes our current understanding of lipid metabolism in CSCs and how pharmacological regulation of autophagy and lipid metabolism influences CSC phenotype. Increased dependence on lipid metabolism appears as an attractive strategy to eliminate CSCs using therapeutic agents that specifically target CSCs based on their modulation of lipid metabolism.
    Keywords:  Autophagy; Cancer stem cells (CSCs); Heterogeneity; Lipid metabolism; Therapy
    DOI:  https://doi.org/10.1016/j.bcp.2023.115550
  4. Future Oncol. 2023 Apr 21.
    STIMULUS-MDS2 design and rationale: a phase III trial with the anti-TIM-3 sabatolimab (MBG453) + azacitidine in higher risk MDS and CMML-2.
    Amer M Zeidan, Aristoteles Giagounidis, Mikkael A Sekeres, Zhijian Xiao, Guillermo F Sanz, Marlies Van Hoef, Fei Ma, Sabine Hertle, Valeria Santini.
      Patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) unfit for hematopoietic stem cell transplantation have poor outcomes. Novel therapies that provide durable benefit with favorable tolerability and clinically meaningful improvement in survival are needed. T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is an immuno-myeloid regulator expressed on immune and leukemic stem cells in myeloid malignancies. Sabatolimab is a novel immunotherapy targeting TIM-3 with a potential dual mechanism of reactivating the immune system and directly targeting TIM-3+ leukemic blasts suppressing the growth of cancer cells. Here, we describe the aims and design of the phase III STIMULUS-MDS2 trial, which aims to demonstrate the potential for sabatolimab plus azacitidine to improve survival for patients with higher-risk MDS and CMML-2 (NCT04266301). Clinical Trial Registration: NCT04266301 (ClinicalTrials.gov).
    Keywords:  clinical trials; hematologic/leukemia; immunotherapy; novel therapy
    DOI:  https://doi.org/10.2217/fon-2022-1237
  5. Front Oncol. 2023 ;13 1188765
    Editorial: Cancer stem cell differentiation: A realistic potential therapeutic option?
    Mariachiara Buccarelli, Simone Beninati, Claudio Tabolacci.
      
    Keywords:  cancer stem cells; cell plasticity; differentiation markers; therapy resistance; trans-differentiation
    DOI:  https://doi.org/10.3389/fonc.2023.1188765
  6. Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]
    The metabolic cross-talk between cancer and T cells.
    Silvia Cadenas-De Miguel, Giulia Lucianer, Ilaria Elia.
      The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.
    Keywords:  antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tibs.2023.03.004
  7. Hematol Oncol. 2023 Apr 20.
    Patients with secondary acute myeloid leukemia undergoing allogeneic stem-cell transplant have inferior outcomes than de novo acute myeloid leukemia regardless minimal residual disease level by flow cytometry.
    Claudia Núñez-Torrón Stock, Carlos Jiménez Chillón, Fernando Martín Moro, Juan Marquet Palomanes, Kyra Velázquez Kennedy, Miguel Piris Villaespesa, Ernesto Roldán Santiago, Eulalia Rodríguez Martín, Anabelle Chinea Rodríguez, Valentín García Gutiérrez, Gemma Moreno Jiménez, Javier López Jiménez, Pilar Herrera Puente.
      Secondary acute myeloid leukemia (s-AML) patients have a poor prognosis and currently the only curative therapy is allogeneic stem-cell transplant (HSCT). However, we do not yet know whether transplantation is sufficient to reverse the poor prognosis compared to de novo AML patients. We analyzed survival after HSCT comparing a cohort of 58 patients with s-AML versus 52 de novo patients who were transplanted between 2012 and 2020. Patients with s-AML had worse event-free survival (EFS) (p = 0.001) and overall survival (OS) (p < 0.001) compared to de novo AML due to an increased risk of relapse (p = 0.06) and non-relapse mortality (p = 0.03). The main difference in survival was observed in patients who achieved complete remission (CR) before HSCT (EFS p = 0.002 OS and <0.001), regardless minimal residual disease (MRD) by |multiparametric flow cytometry cohorts. In patients transplanted with active disease (AD), the prognosis was adverse in both s-AML and de novo AML groups (EFS p = 0.869 and OS p = 0.930). After excluding patients with AD, we stratified the cohort according to conditioning intensity, noticing that s-AML who received MAC had comparable outcomes to de novo AML, but the survival differences remained among reduce intensity conditioning group. In conclusion, transplanted s-AML patients have worse survival among patients in CR before HSCT, regardless of MRD level by flow cytometry compared to de novo AML. MAC patients had similar outcomes irrespective of leukemia ontogeny.
    Keywords:  acute myeloid leukemia; allogeneic bone marrow transplantation; flow cytometry; minimal residual disease; secondary leukemia
    DOI:  https://doi.org/10.1002/hon.3160
  8. Biochemistry (Mosc). 2023 Jan;88(Suppl 1): S1-S20
    Warburg Effect Revisited: Embodiment of Classical Biochemistry and Organic Chemistry. Current State and Prospects.
    Leonid G Menchikov, Alexander A Shestov, Anatoliy V Popov.
      The Nobel Prize Winner (1931) Dr. Otto H. Warburg had established that the primary energy source of the cancer cell is aerobic glycolysis (the Warburg effect). He also postulated the hypothesis about "the prime cause of cancer", which is a matter of debate nowadays. Contrary to the hypothesis, his discovery was recognized entirely. However, the discovery had almost vanished in the heat of battle about the hypothesis. The prime cause of cancer is essential for the prevention and diagnosis, yet the effects that influence tumor growth are more important for cancer treatment. Due to the Warburg effect, a large amount of data has been accumulated on biochemical changes in the cell and the organism as a whole. Due to the Warburg effect, the recovery of normal biochemistry and oxygen respiration and the restoration of the work of mitochondria of cancer cells can inhibit tumor growth and lead to remission. Here, we review the current knowledge on the inhibition of abnormal glycolysis, neutralization of its consequences, and normalization of biochemical parameters, as well as recovery of oxygen respiration of a cancer cell and mitochondrial function from the point of view of classical biochemistry and organic chemistry.
    Keywords:  biochemistry; glycolysis; mitochondria; oncology; oxygen respiration; the Warburg effect
    DOI:  https://doi.org/10.1134/S0006297923140018
  9. Clin Lymphoma Myeloma Leuk. 2023 Mar 29. pii: S2152-2650(23)00110-6. [Epub ahead of print]
    Clinical Analysis of Pediatric T-Cell Acute Lymphoblastic Leukemia Using the MRD-Oriented Strategy System.
    Yu-Juan Xue, Yu Wang, Ai-Dong Lu, Yue-Ping Jia, Ying-Xi Zuo, Ming-Ming Ding, Hui-Min Zeng, Le-Ping Zhang.
      Pediatric T-cell acute lymphoblastic leukemia (T-ALL) has historically been associated with a poor prognosis. However, prognostic indicators and methods of treatment used for T-ALL remain controversial. A total of 136 children newly diagnosed with T-ALL between 2005 and 2018 were consecutively enrolled in this study. We assessed the effect of different prognostic factors, such as clinical characteristics, minimal residual disease (MRD), and the role of transplantation in postremission treatment, as the outcomes. Compared with B-ALL patients, patients with T-ALL are generally older, more likely to be male and have a higher white blood cell count. The complete remission (CR) rate was 95.6%, while the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.3 ± 3.7%, 71.3 ± 3.9%, and 24.4 ± 3.8%, respectively. In the multivariate analysis, day 33 MRD ≥0.1% and hyperleukocytosis were associated with a significantly worse prognosis in the whole group. Transplantation resulted in a significant survival advantage, compared with chemotherapy, for high-risk (HR) patients (5-year CIR: 15.6 ± 10.2% vs. 55.6 ± 11.7%, P = .029). The prognosis of children with T-ALL was poor, and the MRD on day 33 was found to be an important predictive factor of clinical outcome at our center.
    Keywords:  Children; Minimal residual disease; Prognosis; Survival; T-cell acute lymphoblastic leukemia
    DOI:  https://doi.org/10.1016/j.clml.2023.03.013
  10. Front Immunol. 2023 ;14 1188582
    Editorial: The immune escape mechanism and novel immunotherapeutic strategies of leukemia.
    Kang Yu, Jialing Zhang, Qianping Li, Shenghui Zhang.
      
    Keywords:  chimeric antigen receptor T-cell therapy; immune escape; immunotherapeutic strategies; leukemia; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1188582
  11. Cancer Lett. 2023 Apr 17. pii: S0304-3835(23)00133-7. [Epub ahead of print] 216182
    Immune-checkpoint inhibitor resistance in cancer treatment: Current progress and future directions.
    Chenyue Zhang, Chenxing Zhang, Haiyong Wang.
      Cancer treatment has been advanced with the advent of immune checkpoint inhibitors (ICIs) exemplified by anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) drugs. Patients have reaped substantial benefit from ICIs in many cancer types. However, few patients benefit from ICIs whereas the vast majority undergoing these treatments do not obtain survival benefit. Even for patients with initial responses, they may encounter drug resistance in their subsequent treatments, which limits the efficacy of ICIs. Therefore, a deepening understanding of drug resistance is critically important for the explorations of approaches to reverse drug resistance and to boost ICI efficacy. In the present review, different mechanisms of ICI resistance have been summarized according to the tumor intrinsic, tumor microenvironment (TME) and host classifications. We further elaborated corresponding strategies to battle against such resistance accordingly, which include targeting defects in antigen presentation, dysregulated interferon-γ (IFN-γ) signaling, neoantigen depletion, upregulation of other T cell checkpoints as well as immunosuppression and exclusion mediated by TME. Moreover, regarding the host, several additional approaches that interfere with diet and gut microbiome have also been described in reversing ICI resistance. Additionally, we provide an overall glimpse into the ongoing clinical trials that utilize these mechanisms to overcome ICI resistance. Finally, we summarize the challenges and opportunities that needs to be addressed in the investigation of ICI resistance mechanisms, with the aim to benefit more patients with cancer.
    Keywords:  Clinical trials; Combination therapy; Host; Immune checkpoint inhibitor resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216182
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